WO2014052792A1 - Halogenated or parylene polymer coating - Google Patents
Halogenated or parylene polymer coating Download PDFInfo
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- WO2014052792A1 WO2014052792A1 PCT/US2013/062247 US2013062247W WO2014052792A1 WO 2014052792 A1 WO2014052792 A1 WO 2014052792A1 US 2013062247 W US2013062247 W US 2013062247W WO 2014052792 A1 WO2014052792 A1 WO 2014052792A1
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- 229920000052 poly(p-xylylene) Polymers 0.000 title claims abstract 75
- 229920000642 polymer Polymers 0.000 title claims abstract 49
- 239000011248 coating agent Substances 0.000 title claims abstract 46
- 238000000576 coating method Methods 0.000 title claims abstract 46
- 239000000758 substrate Substances 0.000 claims abstract 40
- 238000000034 method Methods 0.000 claims abstract 29
- 238000005229 chemical vapour deposition Methods 0.000 claims abstract 19
- 238000000151 deposition Methods 0.000 claims abstract 6
- 238000002347 injection Methods 0.000 claims 561
- 239000007924 injection Substances 0.000 claims 560
- 229940090044 injection Drugs 0.000 claims 557
- 229940079593 drug Drugs 0.000 claims 508
- 239000003814 drug Substances 0.000 claims 508
- 239000011253 protective coating Substances 0.000 claims 86
- 239000011241 protective layer Substances 0.000 claims 86
- 239000000203 mixture Substances 0.000 claims 59
- 239000012530 fluid Substances 0.000 claims 57
- 230000003068 static effect Effects 0.000 claims 50
- 239000010410 layer Substances 0.000 claims 47
- -1 polytetrafluoroethylene Polymers 0.000 claims 46
- 239000003795 chemical substances by application Substances 0.000 claims 39
- 239000000243 solution Substances 0.000 claims 33
- 102000002265 Human Growth Hormone Human genes 0.000 claims 32
- 108010000521 Human Growth Hormone Proteins 0.000 claims 32
- 239000000854 Human Growth Hormone Substances 0.000 claims 31
- 238000000623 plasma-assisted chemical vapour deposition Methods 0.000 claims 30
- 229940102213 injectable suspension Drugs 0.000 claims 25
- 229940054534 ophthalmic solution Drugs 0.000 claims 24
- 239000002997 ophthalmic solution Substances 0.000 claims 24
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims 20
- 230000004888 barrier function Effects 0.000 claims 20
- 239000007789 gas Substances 0.000 claims 20
- 239000002243 precursor Substances 0.000 claims 20
- 230000003628 erosive effect Effects 0.000 claims 18
- 238000004090 dissolution Methods 0.000 claims 17
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims 17
- 238000006116 polymerization reaction Methods 0.000 claims 16
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 15
- 238000005336 cracking Methods 0.000 claims 15
- 239000003792 electrolyte Substances 0.000 claims 15
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims 15
- 239000004810 polytetrafluoroethylene Substances 0.000 claims 15
- 229910052710 silicon Inorganic materials 0.000 claims 15
- 239000010703 silicon Substances 0.000 claims 15
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 14
- 239000003999 initiator Substances 0.000 claims 14
- 238000001990 intravenous administration Methods 0.000 claims 14
- 229910052757 nitrogen Inorganic materials 0.000 claims 14
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- 229940125681 anticonvulsant agent Drugs 0.000 claims 13
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- 238000006243 chemical reaction Methods 0.000 claims 13
- ZDRRIRUAESZNIH-BZGUUIOASA-N (2s)-1-[(4r,7s,10s,13s,16s,19r)-19-amino-7-(2-amino-2-oxoethyl)-13-[(2s)-butan-2-yl]-10-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-n-[(2s)-1-[(2-amino-2-oxoethyl)amino]- Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)[C@@H](C)O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZDRRIRUAESZNIH-BZGUUIOASA-N 0.000 claims 12
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims 12
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- 125000000217 alkyl group Chemical group 0.000 claims 12
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- PIZALBORPSCYJU-QSQMUHTISA-H gadofosveset Chemical compound O.[Na+].[Na+].[Na+].[Gd+3].C1CC(OP([O-])(=O)OC[C@@H](CN(CCN(CC([O-])=O)CC([O-])=O)CC(=O)[O-])N(CC([O-])=O)CC([O-])=O)CCC1(C=1C=CC=CC=1)C1=CC=CC=C1 PIZALBORPSCYJU-QSQMUHTISA-H 0.000 claims 12
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims 12
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 claims 12
- 229940097496 nasal spray Drugs 0.000 claims 12
- 239000007922 nasal spray Substances 0.000 claims 12
- 239000000047 product Substances 0.000 claims 12
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 claims 12
- 229960004532 somatropin Drugs 0.000 claims 12
- 230000002924 anti-infective effect Effects 0.000 claims 11
- 229960005475 antiinfective agent Drugs 0.000 claims 11
- 239000000725 suspension Substances 0.000 claims 11
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 claims 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 10
- RCHHVVGSTHAVPF-ZPHPLDECSA-N apidra Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CNC=N1 RCHHVVGSTHAVPF-ZPHPLDECSA-N 0.000 claims 10
- 239000003054 catalyst Substances 0.000 claims 10
- 125000001153 fluoro group Chemical group F* 0.000 claims 10
- DPNNNPAKRZOSMO-UHFFFAOYSA-K gadoteridol Chemical compound [Gd+3].CC(O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 DPNNNPAKRZOSMO-UHFFFAOYSA-K 0.000 claims 10
- 229920000669 heparin Polymers 0.000 claims 10
- 229940041682 inhalant solution Drugs 0.000 claims 10
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims 10
- 108700039926 insulin glulisine Proteins 0.000 claims 10
- PLBHSZGDDKCEHR-LFYFAGGJSA-N methylprednisolone acetate Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(C)=O)CC[C@H]21 PLBHSZGDDKCEHR-LFYFAGGJSA-N 0.000 claims 10
- 230000000379 polymerizing effect Effects 0.000 claims 10
- OGSBUKJUDHAQEA-WMCAAGNKSA-N pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 claims 10
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims 10
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 claims 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 9
- 238000013265 extended release Methods 0.000 claims 9
- 229910052731 fluorine Inorganic materials 0.000 claims 9
- 238000010253 intravenous injection Methods 0.000 claims 9
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims 9
- RGLRXNKKBLIBQS-XNHQSDQCSA-N leuprolide acetate Chemical compound CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 RGLRXNKKBLIBQS-XNHQSDQCSA-N 0.000 claims 9
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 claims 8
- ZBVJFYPGLGEMIN-OYLNGHKZSA-N (2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-1-[(2s)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-( Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1.C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 ZBVJFYPGLGEMIN-OYLNGHKZSA-N 0.000 claims 8
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 claims 8
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims 8
- WUIABRMSWOKTOF-OYALTWQYSA-O 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS(O)(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-O 0.000 claims 8
- VOMKSBFLAZZBOW-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-9-yl hexadecanoate Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC3=C(C)N=C4N(C3=O)CCCC4OC(=O)CCCCCCCCCCCCCCC)=NOC2=C1 VOMKSBFLAZZBOW-UHFFFAOYSA-N 0.000 claims 8
- ZHSKUOZOLHMKEA-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid;hydron;chloride Chemical compound Cl.ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 ZHSKUOZOLHMKEA-UHFFFAOYSA-N 0.000 claims 8
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- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims 1
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- 229920005989 resin Polymers 0.000 claims 1
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical class OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 claims 1
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- 229940095745 sex hormone and modulator of the genital system progesterone receptor modulator Drugs 0.000 claims 1
- 239000002911 sialidase inhibitor Substances 0.000 claims 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims 1
- 210000002027 skeletal muscle Anatomy 0.000 claims 1
- 229940125706 skeletal muscle relaxant agent Drugs 0.000 claims 1
- 230000005586 smoking cessation Effects 0.000 claims 1
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 claims 1
- 229940088542 solu-cortef Drugs 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 229960000553 somatostatin Drugs 0.000 claims 1
- 229940046810 spiriva Drugs 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 claims 1
- 238000010186 staining Methods 0.000 claims 1
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- 229940110862 starlix Drugs 0.000 claims 1
- 229940034337 stimate Drugs 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- 238000003860 storage Methods 0.000 claims 1
- 229960002317 succinimide Drugs 0.000 claims 1
- 229940035681 sucraid Drugs 0.000 claims 1
- 229960004291 sucralfate Drugs 0.000 claims 1
- 229940124530 sulfonamide Drugs 0.000 claims 1
- 150000003456 sulfonamides Chemical class 0.000 claims 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- 229940107091 suprane Drugs 0.000 claims 1
- 239000004094 surface-active agent Substances 0.000 claims 1
- 229940086546 synarel Drugs 0.000 claims 1
- 229940094890 synthetic ovulation stimulants Drugs 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 claims 1
- 229940037128 systemic glucocorticoids Drugs 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 229940061367 tamiflu Drugs 0.000 claims 1
- 229940120982 tarceva Drugs 0.000 claims 1
- RZXZIZDRFQFCTA-UHFFFAOYSA-N teflurane Chemical compound FC(Br)C(F)(F)F RZXZIZDRFQFCTA-UHFFFAOYSA-N 0.000 claims 1
- 229950010846 teflurane Drugs 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 235000019364 tetracycline Nutrition 0.000 claims 1
- 150000003522 tetracyclines Chemical class 0.000 claims 1
- 229940040944 tetracyclines Drugs 0.000 claims 1
- KTAVBOYXMBQFGR-MAODNAKNSA-J tetrasodium;(6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyimino-1-oxidoethylidene]amino]-3-[(2-methyl-5,6-dioxo-1h-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C KTAVBOYXMBQFGR-MAODNAKNSA-J 0.000 claims 1
- 229940127044 therapeutic radiopharmaceutical Drugs 0.000 claims 1
- 229920001169 thermoplastic Polymers 0.000 claims 1
- 239000004416 thermosoftening plastic Substances 0.000 claims 1
- 239000003451 thiazide diuretic agent Substances 0.000 claims 1
- 150000001467 thiazolidinediones Chemical class 0.000 claims 1
- 150000005075 thioxanthenes Chemical class 0.000 claims 1
- 229940041007 third-generation cephalosporins Drugs 0.000 claims 1
- 229960004072 thrombin Drugs 0.000 claims 1
- 239000003868 thrombin inhibitor Substances 0.000 claims 1
- 229960000103 thrombolytic agent Drugs 0.000 claims 1
- 230000002537 thrombolytic effect Effects 0.000 claims 1
- 229940107955 thymoglobulin Drugs 0.000 claims 1
- 210000001685 thyroid gland Anatomy 0.000 claims 1
- 229940034208 thyroxine Drugs 0.000 claims 1
- 229960004089 tigecycline Drugs 0.000 claims 1
- FPZLLRFZJZRHSY-HJYUBDRYSA-N tigecycline Chemical class C([C@H]1C2)C3=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O FPZLLRFZJZRHSY-HJYUBDRYSA-N 0.000 claims 1
- 229960004605 timolol Drugs 0.000 claims 1
- 229960005221 timolol maleate Drugs 0.000 claims 1
- 229940034744 timoptic Drugs 0.000 claims 1
- 239000004408 titanium dioxide Substances 0.000 claims 1
- 229940113038 tnkase Drugs 0.000 claims 1
- 229940035289 tobi Drugs 0.000 claims 1
- 229940035274 tobradex Drugs 0.000 claims 1
- 229940125712 tocolytic agent Drugs 0.000 claims 1
- 239000003675 tocolytic agent Substances 0.000 claims 1
- 239000003860 topical agent Substances 0.000 claims 1
- 229940061102 topical suspension Drugs 0.000 claims 1
- 229960001612 trastuzumab emtansine Drugs 0.000 claims 1
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 claims 1
- 108010075758 trebananib Proteins 0.000 claims 1
- 229960005294 triamcinolone Drugs 0.000 claims 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 claims 1
- 229960004320 triamcinolone diacetate Drugs 0.000 claims 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 claims 1
- 150000004684 trihydrates Chemical class 0.000 claims 1
- 108010013283 trolamine polypeptide oleate-condensate Proteins 0.000 claims 1
- 239000002753 trypsin inhibitor Substances 0.000 claims 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims 1
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- 229940056521 ultane Drugs 0.000 claims 1
- 229960003853 ultrasound contrast media Drugs 0.000 claims 1
- 229940116269 uric acid Drugs 0.000 claims 1
- 239000002432 uterotonic agent Substances 0.000 claims 1
- 229940072690 valium Drugs 0.000 claims 1
- 229940124549 vasodilator Drugs 0.000 claims 1
- 239000003071 vasodilator agent Substances 0.000 claims 1
- 229960003726 vasopressin Drugs 0.000 claims 1
- 239000003038 vasopressin antagonist Substances 0.000 claims 1
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- 235000019163 vitamin B12 Nutrition 0.000 claims 1
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- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims 1
- 239000008215 water for injection Substances 0.000 claims 1
- 239000010456 wollastonite Substances 0.000 claims 1
- 229910052882 wollastonite Inorganic materials 0.000 claims 1
- 239000002023 wood Substances 0.000 claims 1
- 229940053867 xeloda Drugs 0.000 claims 1
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- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 claims 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
- A61M5/31511—Piston or piston-rod constructions, e.g. connection of piston with piston-rod
- A61M5/31513—Piston constructions to improve sealing or sliding
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
- A61J1/06—Ampoules or carpules
-
- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
- C23C16/04—Coating on selected surface areas, e.g. using masks
- C23C16/045—Coating cavities or hollow spaces, e.g. interior of tubes; Infiltration of porous substrates
-
- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
- C23C16/22—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the deposition of inorganic material, other than metallic material
- C23C16/30—Deposition of compounds, mixtures or solid solutions, e.g. borides, carbides, nitrides
- C23C16/40—Oxides
- C23C16/401—Oxides containing silicon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/178—Syringes
- A61M5/31—Details
- A61M5/3129—Syringe barrels
- A61M2005/3131—Syringe barrels specially adapted for improving sealing or sliding
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2207/00—Methods of manufacture, assembly or production
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2207/00—Methods of manufacture, assembly or production
- A61M2207/10—Device therefor
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Metallurgy (AREA)
- Mechanical Engineering (AREA)
- Materials Engineering (AREA)
- General Chemical & Material Sciences (AREA)
- Vascular Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Anesthesiology (AREA)
- Inorganic Chemistry (AREA)
- Physical Vapour Deposition (AREA)
Abstract
A container, for example a syringe, cartridge, vial or similar article including a barrel or other vessel and a stopper, O-ring, plunger tip or piston. The vessel substrate defines a lumen and an internal sliding surface on the vessel substrate adjacent to the lumen. The stopper, O-ring, plunger tip or piston has an external sliding surface slidable in the lumen at least substantially in contact with the internal sliding surface. The internal sliding surface, the external sliding surface, or both are made at least in part of a parylene or halogenated polymer, which can be in the form of a coating or a bulk material. Methods of making the syringe, cartridge, or similar article using chemical vapor deposition, as by depositing the parylene or halogenated polymer directly or with intervening layers to define the external sliding surface, the internal internal sliding surface, or both are disclosed.
Description
HALOGENATED OR PARYLENE POLYMER COATING
[01 ] The priority of U.S. Provisional Serial Nos. 61 /707,810, filed September 28, 2012; 61 /716,381 , filed October 19, 2012; 61 /753,348, filed January 16, 2013; and 61 /768,334, filed February 22, 2013; is claimed. The preceding applications, as well as U.S. Provisional Serial Nos. 61 /636,377, filed April 20, 2012; 61 /713,435, filed October 12, 2012; and U.S. Pat. No. 7,985,188 are all incorporated here by reference in their entirety.
FIELD OF THE INVENTION
[02] The present invention relates to the technical field of syringes, cartridges, vials, or similar containers and other pharmaceutical packages for storing, dispensing, or other contact with fluids. Examples of suitable fluids include foods or biologically active compounds or body fluids, for example injectable pharmaceuticals or blood. The present invention also relates to a pharmaceutical package or other vessel and to a method for coating an inner or interior surface of a pharmaceutical package or other vessel. The present invention also relates more generally to medical devices, including devices other than packages or vessels, for example catheters.
[03] The present disclosure also relates to improved methods for processing pharmaceutical packages or other vessels, for example multiple identical pharmaceutical packages or other vessels used for pharmaceutical preparation storage and delivery, venipuncture and other medical sample collection, and other purposes. Such pharmaceutical packages or other vessels are used in large numbers for these purposes, and must be relatively economical to manufacture and yet highly reliable in storage and use.
BACKGROUND OF THE INVENTION
[04] Commonly, a prefilled syringe is capped at the distal end, as with a cap, and is closed at the proximal end by its drawn stopper, O-ring, plunger tip or piston. The prefilled syringe can be wrapped in a sterile package before use. To use the prefilled syringe, the packaging and shield are removed, optionally a hypodermic needle or another delivery conduit is attached to the distal end of the barrel, the delivery conduit or syringe is moved to a use position (such as by inserting the hypodermic needle into a patient's blood vessel or into apparatus to be rinsed with the contents of the syringe), and the stopper, O-ring, plunger tip or piston is advanced in the barrel to inject the contents of the barrel.
[05] One important consideration in manufacturing and using pharmaceutical packages or other vessels having a barrel for storing or other contact with fluids, for example syringes, cartridges, or similar articles, is to provide that the contents of the pharmaceutical package or other vessel desirably will have a substantial shelf life. A desirable shelf life is at least one year, preferably at least two years. Prefilled syringes, cartridges, or similar articles are commonly prepared and sold so the syringe does not need to be filled before use, and can be disposed of after use. The syringe can be prefilled with saline solution, a dye for injection, or a pharmaceutically active preparation, for some examples.
[06] During this shelf life and before use, the stopper, O-ring, plunger tip or piston, or other interior structure which slides down the barrel to dispense fluid will be resting or parked in a fixed position in the barrel. It is well known that a parked stopper, O-ring, plunger tip or piston, or other interior structure will tend to adhere to the barrel over time. Typically the syringe, cartridge, or other article is lubricated, commonly with silicone oil, to reduce the friction encountered when advancing the stopper, O-ring, plunger tip or piston, or other interior structure down the barrel. A parked stopper, O-ring, plunger tip or piston, or other interior structure of such an article often will push the lubricant aside and provide a thinner lubricant layer, possibly substantially eliminating the lubricant layer, where the stopper, O-ring, plunger tip or piston, or other interior structure is parked. As a result, the lubrication may be inadequate and the breakout force, the same concept sometimes referred to as the break loose force (the force required to start
the parked stopper, O-ring, plunger tip or piston, or other interior structure moving) may be very high. The break loose force of a syringe also commonly continues to increase over time, and if it increases too much it can limit the shelf life of the syringe, cartridge, or similar article.
[07] High break loose forces are problematic because an important consideration regarding medical syringes, cartridges, or similar articles is to ensure that the stopper, O-ring, plunger tip or piston can move at a constant speed and with a constant force when it is pressed into the barrel
Since many of these pharmaceutical packages or other vessels are inexpensive and used in large quantities, for certain applications it will be useful to reliably obtain the necessary shelf life without increasing the manufacturing cost to a prohibitive level.
[08] Polymeric materials as lubricants in medical devices, such as syringe plunger-barrel assemblies, include low molecular weight silicones (e.g. polydimethylsiloxanes (PDMS)) and polyperfluorocarbons (e.g. polytetrafluoroethylene (PTFE)).
[09] In syringe plunger-barrel assemblies, the elastomeric rubber plunger tip is an area of concern for extractable solutes, potentially interfering with the therapeutic function of the drug. Thick (greater than 50 microns) PTFE molded laminates (rubber elastomer overmolded from PTFE resin preforms) are known to act as a barrier to migration of solutes from elastomeric rubber plunger tips; much thinner linear PTFE coatings (either molded from preformed linear PTFE over molding, or from linear PTFE CVD coatings) tend to be less effective as barriers to solute extraction from the plunger tip.
Through a combination of the over molded PTFE layer thickness and greater stiffness properties of PTFE relative to the underlying elastomer, the PTFE/rubber elastomer laminate can realize an overall increase in stiffness behavior, resulting in poorer container closure integrity (CCI) of the syringe system. CCI integrity is a critical function in syringe systems.
[10] A non-exhaustive list of documents of possible relevance includes CN102581274A; US Pat. Nos. 6,797,343; 6,825,303; 6,881 , 447; 6,962,871 ; 7,009,016; 7,062,052; 7,094,661 ; 7,192,645; 7,238,626; 7,309,395; 7,425,346; 7,901 ,783;
6,068,884; 4,844,986; 8,067,070; and 5,268,202; U.S. Publ. Appl. Nos. 2008/0090039, 2010/0186740, 2012/0003497, 201 1 /0152820, 2006/0046006, 2004/0267194, 201 1 /0212491 , 2010/0232167; WO201 1080543A1 ; G. Hilton, L. Pryce, L. Weibel, K. Ober, K.K. Gleason, E-Beam Patterning Of Hot-Filament CVD Fluoro-Carbon Films Using Supercritical C02 As A Developer, CHEMICAL VAPOR DEPOSITION 7 (2001 ) 195— 197; S.J. Limb, K.K.S.Lau, D.J.Edell, E.F.GIeason, K.K.GIeason, Molecular Design Of Fluorocarbon Film Architecture By Pulsed Plasma Enhanced And Pyrolytic Chemical Vapor Deposition, PLASMA POLYMERIZATION 4 (1999) 21 -32; K.K.S. Lau, K.K. Gleason, Thermal Annealing Of Fluorocarbon Films Grown By Hot Filament Chemical Vapor Deposition, JOURNAL OF PHYSICAL CHEMISTRY B 105 (2001 ) 2303-2307; K.K.S. Lau, S.K. Murthy, H.G. Lewis, J. A. Caulfield, K.K. Gleason, Fluorocarbon Dielectrics Via Hot Filament Chemical Vapor Deposition, JOURNAL OF FLUORINE CHEMISTRY 122 (2003) 93- 96; J. Wang, X. Song, R. lia, J. Shen, G. Yang, H. Huang, Fluorocarbon Thin Film With Superhydrophobic Property Prepared By Pyrolysis Of Hexafluoropropylene Oxide, APPLIED SURFACE SCIENCE 258 (2012) 9782-9785; THIN SOLID FILMS 517 2009) 3551 - 3554; THIN SOLID FILMS 517 2009) 3612-3614; Parylene 101, Diamond-MT, Inc., Johnstown, Pa 15906, http://blog.Paryleneconformalcoating.com/download-Parylene- 101 -coating-facts-sheet/ ; H. Yasuda, B. H. Chun, D. L. Cho, T. J. Lin, D. J. Yang, and J. A. Antonelli (1996) Interface-Engineered Parylene C Coating for Corrosion Protection of Cold-Rolled Steel, CORROSION: March 1996, Vol. 52, No. 3, pp. 169-176 (doi: http://dx.doi.org/ 10.5006/1 .32921 10 ); Chang Hyun Jeong, June Hee Lee, Jong Tae Lim, Nam Gil Cho, Cheol Hee Moon, and Geun Young Yeom, JAPANESE JOURNAL OF APPLIED PHYSICS Vol. 44, No. 2, 2005, pp. 1022-1026; MA Spivack, G Ferrante, Determination of the Water Vapor Permeability and Continuity of Ultrathin Parylene Membranes, JOURNAL OF THE ELECTROCHEMICAL SOCIETY, 1969 - jes.ecsdl.org; HC Han, YR Chang, WL Hsu, CY Chen - Biosensors and Bioelectronics, 2009 - Elsevier. These documents are all incorporated by reference.
SUMMARY OF THE INVENTION
[1 1 ] An aspect of the invention is a container, for example a syringe, cartridge, vial or similar article. The container includes a barrel or other vessel and a stopper, O-ring,
plunger tip or piston. The barrel or other vessel includes a lumen defined at least in part by a internal wall of the barrel or other vessel. The barrel includes a substrate defining at least a portion of the lumen and an internal sliding surface on the vessel substrate adjacent to the lumen. The stopper, O-ring, plunger tip or piston is located within the lumen and has an external sliding surface slidable in the lumen at least substantially in contact with the internal sliding surface.
[12] The internal wall, the internal sliding surface, the external sliding surface, or both are made at least in part of a parylene or halogenated polymer, for example a fluorinated polymer in any embodiment, which can be in the form of a coating or a bulk material. For purposes of the present invention, a fluorinated polymer, fluoropolymer, and fluorocarbon polymer are different terms for the same type of material. One non- limiting example of such a fluorinated polymer, fluoropolymer, or fluorocarbon polymer is polytetrafluoroparaxylylene. Another non-limiting example of such a fluorinated polymer, fluoropolymer, or fluorocarbon polymer is polytetrafluoroethylene.
[13] Another aspect of the invention is a method of making the syringe, cartridge, or similar article. This can be done by depositing the parylene or halogenated polymer directly or with intervening layers to define the external sliding surface, the internal internal sliding surface, or both. Two non-limiting examples of suitable equipment for deposition of the parylene or halogenated polymer are hot filamenthot filament chemical vapor deposition and pyrolysis chemical vapor deposition.
[14] Other aspects of the invention will become apparent to a person of ordinary skill in the art after reviewing the present disclosure and claims.
[15] For example, without limiting the above broad description of the invention, thin (less than 10 microns) parylene polymer coatings can function both as effective lubricants and barriers to solute extraction from the elastomeric plunger tips with minimal changes in CCI.
[16] The Invention optionally can provide in a single coating, both good lubricity and low extractables, defined as
- initiation plunger force, Fi; after plunger insertion into a syringe barrel, Fj(0), and after time t of plunger insertion into a syringe barrel F,(t), and
- maintenance plunger force, Fm, after plunger insertion into a syringe barrel, Fm(0), and after time t of plunger insertion into a syringe barrel Fm(t), and
- extractables barrier, defined as the level of extractable materials from an Inventive Coated Plunger, with comparable CCI,
relative either to a comparative uncoated plunger or to a polydimethylsiloxane (PDMS) coated syringe.
BRIEF DESCRIPTION OF THE DRAWINGS
[17] FIG. 1 shows a side elevation view of a prefilled syringe made according to one embodiment of the invention.
[18] FIG. 2 is a longitudinal section of the prefilled syringe of FIG. 1 .
[19] FIG. 3 is a schematic longitudinal section of a plasma enhanced chemical vapor deposition coating station for coating the interior of a syringe barrel, showing a syringe barrel positioned to be coated.
[20] FIG. 4 is a schematic view of the coating station of FIG. 3, showing more details of the precursor supply apparatus.
[21 ] Fig. 5, which is modified from a Figure in US Publ. Appl. 2012/0003497, is a schematic view of a hot filament chemical vapor deposition machine.
[22] Fig. 6 shows three log-log plots of plunger breakloose force versus parking time, showing short-term test results of HWCVD working examples and extrapolated two-year results.
[23] Fig. 7 shows three log-log plots of plunger breakloose force versus parking time, showing short-term test results of the Parylene working examples, extrapolated to provide two-year results.
[24] Fig. 8 shows a diagrammatic cross-section of a vial 170 which is an embodiment of the preassembly 12.
[25] Fig. 9 is a diagrammatic wall cross section of a barrel 14, which alternatively can be a vial wall or other substrate in any embodiment, in which the fluorinated polymer optionally can comprise a composite of polytetrafluoroethylene 34 and a fluorine substituted derivative of poly(paraxylylene) 31 .
[26] Fig. 10 is a view similar to Fig. 9 in which the fluorinated polymer optionally can comprise a composite of a first layer 31 of one fluorinated polymer, for example a fluorine substituted derivative of poly(paraxylylene), and a second layer of another fluorinated polymer, for example polytetrafluoroethylene, optionally comprising linear polytetrafluoroethylene.
[27] Fig. 1 1 is a view similar to Fig. 9 providing three coating layers: a barrier coating or layer 30, a protective coating or layer 31 , and a separate lubricity coating or layer.
[28] Fig. 12 is a schematic view of a chemical vapor deposition apparatus useful, for example, for depositing a coating of a fluorinated polymer, for example polytetrafluoroethylene.
[29] Fig. 13 is a bar plot showing vacuum decay test results according to the work in Example 20.
[30] Fig. 14 is a log-log plot of Fm results versus park time for Example P19.
[31 ] Fig. 15 is a log-log plot of F, results versus park time for Working Example A.
[32] The following reference characters are used in the drawing figures:
12 Capped container (if a syringe, 42 Rib
just container if not) 44 Cylindrical surface
14 Barrel
46 Barb
16 Internal sliding surface
48 Catch
18 Barrel lumen
50 Vessel holder
20 Dispensing portion
52 Plot
22 Proximal opening
54 Plot
24 Distal opening
56 Line segment (Fig. 9)
26 Dispensing portion lumen
58 Line segment (Fig. 9)
27 Shield
60 coating station
30 (first) Vapor-deposited coating or
82 Opening
layer
32 Opening 84 Closed end
34 (second) vapor-deposited coating 92 Vessel port
or layer 94 Vacuum duct
36 Plunger tip or piston 96 Vacuum port
38 Plunger rod 98 Vacuum source
40 Fluid material 100 O-ring (of 92)
O-ring (of 96) 264 Inner or interior surface (of 28)
Gas inlet port 268 External sliding surface (of 36
O-ring (of 100) 273 Hot filamentfilament chemical
Probe (counter electrode) vapor deposition apparatus
274 Vacuum chamber
Gas delivery port (of 108)
276 Evacuated space
Housing (of 50 or 1 12)
278 Temperature-controlled plate
Collar
280 Support
Exterior surface (of 80)
282 Heated filament array
PECVD gas source
284 Gas inlet
Pressure gauge
286 Gas outlet
Electrode
404 Exhaust
Power supply
574 Main vacuum valve
Sidewall (of 160)
576 Vacuum line
Sidewall (of 160)
578 Manual bypass valve
Closed end (of 160)
580 Bypass line
Vial
582 Vent valve
Pyrolysis chemical vapor
deposition apparatus 584 Main reactant gas valve
Inlet (of 190) 586 Main reactant feed line
Precursor vaporvapor source 588 Organosilicon liquid reservoir
Outlet (of 190) 590 Organosilicon feed line (capillary)
Precursor vaporvapor 592 Organosilicon shut-off valve
Drain 594 Oxygen tank
Pressure releasing valuve 596 Oxygen feed line
Flow meter 598 Mass flow controller
Cracking pipe 600 Oxygen shut-off valve
Thermocouple wrap 602 Additional reservoir
Heating tape 604 Feed line
Temperature controller 606 Shut-off valve
Conduit 614 Headspace
CVD reactor/treated substrate 616 Pressure source
Cooling jacket 618 Pressure line
Electrode 620 Capillary connection
Cold trap
Pharmaceutical package
Barrel
Back end (of 14)
Front end (of 14)
[33] The present invention will now be described more fully, with reference to the accompanying drawings, in which several embodiments are shown. This invention can, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth here. Rather, these embodiments are examples of the invention, which has the full scope indicated by the language of the claims. Like numbers refer to like or corresponding elements throughout. The following disclosure relates to all embodiments unless specifically limited to a certain embodiment.
DEFINITION SECTION
[34] In the context of the present invention, the following definitions and abbreviations are used:
[35] RF is radio frequency.
[36] The term "at least" in the context of the present invention means "equal or more" than the integer following the term. The word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality unless indicated otherwise. Whenever a parameter range is indicated, it is intended to disclose the parameter values given as limits of the range and all values of the parameter falling within said range.
[37] "First" and "second" or similar references to, for example, processing stations or processing devices refer to the minimum number of processing stations or devices that are present, but do not necessarily represent the order or total number of processing stations and devices. These terms do not limit the number of processing stations or the particular processing carried out at the respective stations.
[38] For purposes of the present invention, an "organosilicon precursor" is a compound having at least one of the linkages:
or
— NH— Si— C— H
which is a tetravalent silicon atom connected to an oxygen or nitrogen atom and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom). A volatile organosilicon precursor, defined as such a precursor that can be supplied as a vapor in a PECVD apparatus, is an optional organosilicon precursor. Optionally, the organosilicon precursor is selected from the group consisting of a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, an alkyl trimethoxysilane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, and a combination of any two or more of these precursors.
[39] The feed amounts of PECVD precursors, gaseous reactant or process gases, and carrier or diluent gas are sometimes expressed in "standard volumes" in the specification and claims. The standard volume of a charge or other fixed amount of gas is the volume the fixed amount of the gas would occupy at a standard temperature and pressure (without regard to the actual temperature and pressure of delivery). Standard volumes can be measured using different units of volume, and still be within the scope of the present disclosure and claims. For example, the same fixed amount of gas could be expressed as the number of standard cubic centimeters, the number of standard cubic meters, or the number of standard cubic feet. Standard volumes can also be defined using different standard temperatures and pressures, and still be within the scope of the present disclosure and claims. For example, the standard temperature might be 0°C and the standard pressure might be 760 Torr (as is conventional), or the standard temperature might be 20 °C and the standard pressure might be 1 Torr. But
whatever standard is used in a given case, when comparing relative amounts of two or more different gases without specifying particular parameters, the same units of volume, standard temperature, and standard pressure are to be used relative to each gas, unless otherwise indicated.
[40] The corresponding feed rates of PECVD precursors, gaseous reactant or process gases, and carrier or diluent gas are expressed in standard volumes per unit of time in the specification. For example, in the working examples the flow rates are expressed as standard cubic centimeters per minute, abbreviated as seem. As with the other parameters, other units of time can be used, such as seconds or hours, but consistent parameters are to be used when comparing the flow rates of two or more gases, unless otherwise indicated.
[41 ] A "vessel" in the context of the present invention can be any type of vessel with at least one opening and a wall defining an inner or interior surface. The substrate can be the inside wall of a vessel having a lumen. Though the invention is not necessarily limited to pharmaceutical packages or other vessels of a particular volume, pharmaceutical packages or other vessels are contemplated in which the lumen has a void volume of from 0.5 to 50 ml_, optionally from 1 to 10 ml_, optionally from 0.5 to 5 ml_, optionally from 1 to 3 ml_. The substrate surface can be part or all of the inner or interior surfaceinner or interior surface of a vessel having at least one opening and an inner or interior surfaceinner or interior surface.
[42] The term "at least" in the context of the present invention means "equal or more" than the integer following the term. Thus, a vessel in the context of the present invention has one or more openings. One or two openings, like the openings of a sample tube (one opening) or a syringe barrel (two openings) are preferred. If the vessel has two openings, they can be of same or different size. If there is more than one opening, one opening can be used for the gas inlet for a PECVD coating method according to the present invention, while the other openings are either capped or open. A vessel according to the present invention can be a sample tube, for example for collecting or storing biological fluids like blood or urine, a syringe (or a part thereof, for example a syringe barrel) for storing or delivering a biologically active compound or
composition, for example a medicament or pharmaceutical composition, a vial for storing biological materials or biologically active compounds or compositions, a pipe, for example a catheter for transporting biological materials or biologically active compounds or compositions, or a cuvette for holding fluids, for example for holding biological materials or biologically active compounds or compositions.
[43] A vessel can be of any shape, a vessel having a substantially cylindrical wall adjacent to at least one of its open ends being preferred. Generally, the interior wall of the vessel is cylindrically shaped, like, for example in a sample tube or a syringe barrel. Sample tubes and syringes, cartridges, or similar articles or their parts (for example syringe barrels) are contemplated.
[44] A "hydrophobic layer" in the context of the present invention means that the coating or layer lowers the wetting tension of a surface coated with the coating or layer, compared to the corresponding uncoated surface. Hydrophobicity is thus a function of both the uncoated substrate and the coating or layer. The same applies with appropriate alterations for other contexts wherein the term "hydrophobic" is used. The term "hydrophilic" means the opposite, i.e. that the wetting tension is increased compared to reference sample. The present hydrophobic layers are primarily defined by their hydrophobicity and the process conditions providing hydrophobicity
[45] The values of w, x, y, and z used throughout this specification should be understood as ratios or an empirical formula (for example for a coating or layer), rather than as a limit on the number or type of atoms in a molecule. For example, octamethylcyclotetrasiloxane, which has the molecular composition Si404C8H24, can be described by the following empirical formula, arrived at by dividing each of w, x, y, and z in the molecular formula by 4, the largest common factor: Si-|0-|C2H6. The values of w, x, y, and z are also not limited to integers. For example, (acyclic) octamethyltrisiloxane, molecular composition Si302C8H24, is reducible to Si1O0.67C2.67Hs. Also, although SiOxCyHz is described as equivalent to SiOxCy, it is not necessary to show the presence of hydrogen in any proportion to show the presence of SiOxCy.
[46] "Wetting tension" is a specific measure for the hydrophobicity or hydrophilicity of a surface. An optional wetting tension measurement method in the context of the
present invention is ASTM D 2578 or a modification of the method described in ASTM D 2578. This method uses standard wetting tension solutions (called dyne solutions) to determine the solution that comes nearest to wetting a plastic film surface for exactly two seconds. This is the film's wetting tension. The procedure utilized is varied herein from ASTM D 2578 in that the substrates are not flat plastic films, but are tubes made according to the Protocol for Forming PET Tube and (except for controls) coated according to the Protocol for coating Tube Interior with Hydrophobic Coating or Layer (see Example 9 of EP2251671 A2).
[47] A "lubricity and/or protective coating or layer" according to the present invention is a coating or layer which has a lower frictional resistance than the uncoated surface, which is a lubricity layer, and/or protects an underlying surface or layer from a fluid composition contacting the layer, which is a protective coating or layer (as more extensively defined elsewhere in this specification). In other words, respecting a lubricity layer, it reduces the frictional resistance of the coated surface in comparison to a reference surface that is uncoated. The present lubricity and/or protective coating or layers are primarily defined as lubricity layers by their lower frictional resistance than the uncoated surface and the process conditions providing lower frictional resistance than the uncoated surface, and optionally can have a composition according to the empirical composition SiwOxCyHz, (or its equivalent SiOxCy) as defined herein. It generally has an atomic ratio SiwOxCy (or its equivalent SiOxCy) wherein w is 1 , x is from about 0.5 to about 2.4, y is from about 0.6 to about 3.
[48] Typically, expressed as the formula SiwOxCy, the atomic ratios of Si, O, and C in the "lubricity and/or protective coating or layer" are, as several options:
Si 100 : O 50-150 : C 90-200 (i.e. w = 1 , x = 0.5 to 1 .5, y = 0.9 to 2);
Si 100 : O 70-130 : C 90-200 (i.e. w = 1 , x = 0.7 to 1 .3, y = 0.9 to 2)
Si 100 : O 80-120 : C 90-150 (i.e. w = 1 , x = 0.8 to 1 .2, y = 0.9 to 1 .5)
Si 100 : 0 90-120 : C 90-140 (i.e. w = 1 , x = 0.9 to 1 .2, y = 0.9 to 1 .4), or
Si 100 : O 92-107 : C 1 16-133 (i.e. w = 1 , x = 0.92 to 1 .07, y = 1 .16 to 1 .33)
[49] The atomic ratio can be determined by XPS (X-ray photoelectron spectroscopy). Taking into account the H atoms, which are not measured by XPS, the coating or layer may thus in one aspect have the formula SiwOxCyHz (or its equivalent SiOxCy), for example where w is 1 , x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is from about 2 to about 9. Typically, such coating or layer would hence contain 36% to 41 % carbon normalized to 100% carbon plus oxygen plus silicon.
[50] "Frictional resistance" can be static frictional resistance and/or kinetic frictional resistance.
[51 ] One of the optional embodiments of the present invention is a low friction syringe part, for example a syringe barrel having an internal wall made in least in part of a parylene or halogenated polymer, a stopper, O-ring, plunger tip or piston comprising a sliding surface made at least in part of a parylene or halogenated polymer, or both. In this contemplated embodiment, the relevant static frictional resistance in the context of the present invention is the breakout force as defined herein, and the relevant kinetic frictional resistance in the context of the present invention is the stopper, O-ring, plunger tip or piston sliding force as defined herein. For example, the stopper, O-ring, plunger tip or piston sliding force as defined and determined herein is suitable to determine the presence or absence and the lubricity and/or protective characteristics of a lubricity and/or protective coating or layer in the context of the present invention whenever the coating or layer is applied to any syringe or syringe part, for example to the inner wall of a syringe barrel. The breakout force is of particular relevance for evaluation of the coating or layer effect on a prefilled syringe, i.e. a syringe which is filled after coating and can be stored for some time, for example several months or even years, with the stopper, O-ring, plunger tip or piston "parked," before the stopper, O-ring, plunger tip or piston is moved again (has to be "broken out").
[52] The "stopper, O-ring, plunger tip or piston sliding force" (synonym to "glide force," "maintenance force", or Fm, also used in this description) in the context of the present invention is the force required to maintain movement of a stopper, O-ring, plunger tip or piston in a syringe barrel, for example during aspiration or dispensing. It can advantageously be determined using the ISO 7886-1 :1993 test described herein
and known in the art. A synonym for "stopper, O-ring, plunger tip or piston sliding force" often used in the art is "stopper, O-ring, plunger tip or piston force" or "pushing force".
[53] The "stopper, O-ring, plunger tip or piston breakout force" (synonym to "breakout force", "break loose force", "initation force", Fi, also used in this description) in the context of the present invention is the initial force required to move the stopper, O- ring, plunger tip or piston in a syringe, for example in a prefilled syringe.
[54] Both "stopper, O-ring, plunger tip or piston sliding force" and "stopper, O-ring, plunger tip or piston breakout force" and methods for their measurement are described in more detail in subsequent parts of this description. These two forces can be expressed in N, lbs or kg and all three units are used herein. These units correlate as follows: 1 N = 0.102 kg = 0.2248 lbs (pounds).
[55] Sliding force and breakout force are sometimes used herein to describe the forces required to advance a stopper or other closure into a pharmaceutical package or other vessel, such as a medical sample tube or a vial, to seat the stopper in a vessel to close the vessel. Its use is analogous to use in the context of a syringe and its stopper, O-ring, plunger tip or piston, and the measurement of these forces for a vessel and its closure are contemplated to be analogous to the measurement of these forces for a syringe, except that at least in most cases no liquid is ejected from a vessel when advancing the closure to a seated position.
[56] "Slidably" means that the stopper, O-ring, plunger tip or piston, closure, or other removable part is permitted to slide in a syringe barrel or other vessel.
DETAILED DESCRIPTION
[57] Details and parameters disclosed only in the claims are expressly contemplated as part of this description.
[58] Referring to the Figures, an aspect of the invention in any embodiment is a pharmaceutical package illustrated in any of the Figures having:
• a substrate 14, which can be a syringe barrel or other vessel 12 or a stopper,
O-ring, plunger tip or piston, and is either made of thermoplastic material or glass;
• optionally, an oxygen barrier coating or layer, which can be made of SiOx as defined in this specification or of other materials known to form a barrier coating or layer, typically provided adjacent to the substrate 14;
• optionally, a protective coating or layer, which can either be a fluorinated Parylene polymer or can be made of SiOxCy as defined in this specification and can function as a pH protective coating or layer, a solute barrier, or both; and
• optionally a lubricity coating or layer, which can either be a fluorinated Parylene polymer or can be made of SiOxCy as defined in this specification and can function to improve lubricity,
in which the substrate and at least one of the parylene or halogenated polymer layers must be present.
[59] Another aspect of the invention is a method in which a vapor-deposited coating or layer 30 is directly or indirectly applied to at least a portion of the internal sliding surface of the barrel or wall 14 of a container 12, alternatively referred to as a pre-assembly or capped container in the case of a syringe.
[60] A capped container 12 can be a portion of a complete article adapted to dispense fluid, such as a syringe, a cartridge, a catheter, or other article. Optionally in any embodiment, the capped container 12 optionally can comprise a barrel or wall 14, a dispensing portion 20, and a shield 28. The container 12 alternatively can be a complete article such as a vial having a wall 14. In either case, the container or capped container 12 to be processed optionally has a single opening in any embodiment at the time of chemical vapor deposition or similar treatment, so it can be treated through one opening at a pressure different from ambient, without the need for a separate vacuum chamber.
[61 ] The barrel or wall 14 has an internal sliding surface defining a barrel lumen 18. Optionally in any embodiment, the barrel or wall 14 can further include an opening 32 spaced from the dispensing portion 20 and communicating through the internal sliding surface. Such an opening is conventional, for example, in a syringe or cartridge,
where a typical example is the back opening 32 of a prefilled syringe barrel, through which the stopper, O-ring, plunger tip or piston 36 is inserted after the barrel lumen 18 is filled with a suitable pharmaceutical preparation or other fluid material 40 to be dispensed.
[62] The barrel or wall 14 can be formed, for example, by molding, although the manner of its formation is not critical and it can also be formed, for example, by machining a solid preform. Preferably, the barrel is molded by injection molding thermoplastic material, although it can also be formed by blow molding or a combined method.
[63] As one preferred example, the barrel or wall 14 can be formed by placing a dispensing portion 20 as described below in an injection mold and injection molding thermoplastic material about the dispensing portion, thus forming the barrel and securing the dispensing portion to the barrel. Alternatively, the dispensing portion and the barrel can be molded or otherwise formed as a single piece, or can be formed separately and joined in other ways. The barrel of any embodiment can be made of any suitable material. Several barrel materials particularly contemplated are COC (cyclic olefin copolymer), COP (cyclic olefin polymer), PET (polyethylene terephthalate), and polypropylene. Alternatively, the barrel or wall 14 can be made of any suitable glass, for example borosilicate glass.
[64] The dispensing portion 20 of the container 12 is provided to serve as an outlet for fluid dispensed from the barrel lumen 18 of a completed article made from the container 12. One example of a suitable dispensing portion illustrated in the Figures is a hypodermic needle 20.
[65] Alternatively, in any embodiment the dispensing portion 20 can instead be a needle-free dispenser. One example of a suitable needle-free dispenser is a blunt or flexible dispensing portion intended to be received in a complementary coupling to transfer fluid material 40. Such blunt or flexible dispensing portions are well known for use in syringes, intravenous infusion systems, and other systems and equipment to dispense material while avoiding the hazard of working with a sharp needle that may accidentally stick a health professional or other person. Another example of a needle-
free dispenser is a fluid jet or spray injection system that injects a free jet or spray of fluid directly through a patient's skin, without the need for an intermediate needle. Any type of dispensing portion 20, whether a hypodermic needle or any form of needle-free dispenser, is contemplated for use according to any embodiment of the present invention.
[66] The dispensing portion 20 is secured to the barrel or wall 14 and includes a proximal opening 22, a distal opening 24, and a dispensing portion lumen 26. The proximal opening 22 communicates with the barrel lumen 18. The distal opening 24 is located outside the barrel or wall 14. The dispensing portion lumen 26 communicates between the proximal and distal openings 22, 24 of the dispensing portion 20. In the illustrated embodiment, the distal opening 24 is at the sharpened tip of a hypodermic needle 20.
[67] The shield 28 is secured to the barrel or wall 14 and at least substantially isolates the distal opening 24 of the dispensing portion 20 from pressure conditions outside the shield 28. Optionally in any embodiment, the shield 28 sufficiently isolates portions of the container 12 to provide a sufficient bio-barrier to facilitate safe use of the capped container 12 for transdermal injections.
[68] The shield 28 can isolate the distal opening 24 in various ways. Effective isolation can be provided at least partially due to contact between the shield 28 and the distal opening 24, as shown in present FIGS. 2, 3, 4, and 7. In the illustrated embodiment, the tip of the dispensing portion 20 is buried in the material of the shield 28. Alternatively in any embodiment, effective isolation can be provided at least partially due to contact between the shield 28 and the barrel or wall 14, as also shown in present FIGS. 2, 3, 4, and 7. In the illustrated embodiment, the primary line of contact between the shield 28 and the barrel or wall 14 is at a rib 42 (best seen in FIG. 3) encircling and seated against a generally cylindrical surface 44 at the nose of the barrel or wall 14. Alternatively in any embodiment, effective isolation can be provided due to both of these types of contact as illustrated in FIGS. 2-3, or in other ways, without limitation.
[69] The shield 28 of any embodiment optionally has a latching mechanism, best shown in FIG. 3, including a barb 46 and a catch 48 which engage to hold the shield 28 in place. The catch 48 is made of sufficiently resilient material to allow the shield 28 to be removed and replaced easily.
[70] If the dispensing portion 20 is a hypodermic needle, the shield 28 can be a specially formed needle shield. The original use of a needle shield is to cover the hypodermic needle before use, preventing accidental needle sticks and preventing contamination of the needle before it is injected in a patient or an injection port. A comparable shield preferably is used, even if the dispensing portion 20 is a needle-free dispenser, to prevent contamination of the dispenser during handling.
[71 ] The shield 28 can be formed in any suitable way. For example, the shield 28 can be formed by molding thermoplastic material. Optionally in any embodiment, the thermoplastic material is elastomeric material or other material that is suitable for forming a seal. One suitable category of elastomeric materials is known generically as thermoplastic elastomer (TPE). An example of a suitable thermoplastic elastomer for making a shield 28 is Stelmi® Formulation 4800 (flexible shield formulation). Any other material having suitable characteristics can instead be used in any embodiment.
[72] As another optional feature in any embodiment the shield 28 can be sufficiently permeable to a sterilizing gas to sterilize the portions of the container 12 isolated by the shield. One example of a suitable sterilizing gas is ethylene oxide. Shields 28 are available that are sufficiently permeable to the sterilizing gas that parts isolated by the shield can nonetheless be sterilized. An example of a shield formulation sufficiently permeable to accommodate ethylene oxide gas sterilization is Stelmi® Formulation 4800.
[73] Thus, an optional step in the present methods is sterilizing the container 12 using a sterilizing gas. Sterilization can be performed at any suitable step, such as sterilizing the container 12 alone or sterilizing a complete pre-filled syringe after it is filled with a suitable pharmaceutical preparation or other material.
[74] When carrying out the present method, a vapor-deposited coating or layer 30 is applied directly or indirectly to at least a portion of the internal sliding surface of the
barrel or wall 14. The coating or layer 30 is applied while the container 12 is capped. The coating or layer 30 is applied under conditions effective to maintain communication between the barrel lumen 18 and the dispensing portion lumen 26 via the proximal opening 22 at the end of the applying step.
[75] In any embodiment the vapor-deposited coating or layer 30 optionally can be applied through the opening 32.
[76] In any embodiment the vapor-deposited coating or layer 30 optionally can be applied by introducing a vapor-phase precursor material through the opening and employing chemical vapor deposition to deposit a reaction product of the precursor material on the internal wall of the barrel.
[77] In any embodiment the vapor-deposited coating or layer (30) optionally can be applied by flowing a precursor reactant vapor material through the opening and employing chemical vapor deposition to deposit a reaction product of the precursor reactant vapor material on the internal wall of the barrel.
[78] In any embodiment the reactant vapor material optionally can be a precursor.
[79] In any embodiment the reactant vapor material for an oxygen barrier, pH protective, or lubricity coating or layer optionally can be an organosilicon precursor.
[80] In any embodiment the reactant vapor material optionally can be an oxidant gas.
[81 ] In any embodiment the reactant vapor material optionally can be oxygen.
[82] In any embodiment the reactant vapor material optionally can include a carrier gas or diluent.
[83] In any embodiment the reactant vapor material optionally can include helium, argon, krypton, xenon, neon, or a combination of two or more of these as a diluent or carrier gas.
[84] In any embodiment the reactant vapor material optionally can include argon.
[85] In any embodiment the reactant vapor material optionally can be a precursor material mixture with one or more oxidant gases in a partial vacuum through the opening and employing chemical vapor deposition to deposit a reaction product of the precursor material mixture on the internal wall of the barrel.
[86] In any embodiment the reactant vapor material optionally can be passed through the opening at sub-atmospheric pressure.
[87] In any embodiment the chemical vapor deposition optionally can be plasma- enhanced chemical vapor deposition.
[88] In any embodiment the vapor-deposited coating or layer optionally can be a gas barrier coating or layer.
[89] In any embodiment the vapor-deposited coating or layer optionally can be an oxygen barrier coating or layer.
[90] In any embodiment the vapor-deposited coating or layer is a water vapor barrier coating or layer.
[91 ] In any embodiment the vapor-deposited coating or layer optionally can be a solvent barrier coating or layer.
[92] In any embodiment the vapor-deposited coating or layer optionally can be a water barrier coating or layer.
[93] In any embodiment the vapor-deposited coating or layer optionally can be a solvent barrier coating or layer for a solvent comprising a co-solvent used to increase drug solubilization.
[94] In any embodiment the vapor-deposited coating or layer optionally can be a barrier coating or layer for water, glycerin, propylene glycol, methanol, ethanol, n- propanol, isopropanol, acetone, benzyl alcohol, polyethylene glycol, cotton seed oil, benzene, dioxane, or combinations of any two or more of these.
[95] In any embodiment the vapor-deposited coating or layer optionally can be a solute barrier coating or layer. Examples of solutes in drugs usefully excluded by a barrier layer in any embodiment include antibacterial preservatives, antioxidants, chelating agents, pH buffers, and combinations of any of these.
[96] In any embodiment the vapor-deposited coating or layer optionally can be a metal ion barrier coating or layer.
[97] In any embodiment the vapor-deposited coating or layer optionally can be a barrel wall material barrier coating or layer, to prevent or reduce the leaching of barrel
material such as any of the base barrel resins mentioned previously and any other ingredients in their respective compositions.
[98] The vapor deposited coating or layer for any embodiment defined in this specification (unless otherwise specified in a particular instance) optionally can be a coating or layer, optionally applied by PECVD as indicated in U.S. Pat. No. 7,985,188. The vapor deposited coating or layer can be a barrier coating or layer, optionally a barrier coating or layer characterized as an "SiOx" coating or layer containing silicon, oxygen, and optionally other elements, in which x, the ratio of oxygen to silicon atoms, optionally can be from about 1 .5 to about 2.9, or 1 .5 to about 2.6, or about 2. These alternative definitions of x apply to any use of the term SiOx in this specification. The barrier coating or layer optionally can be applied, for example to the interior of a pharmaceutical package or other vessel, for example a sample collection tube, a syringe barrel, a vial, or another type of vessel. The SiOx coating or layer is particularly contemplated as a barrier to oxygen ingress or egress and a solute barrier to prevent migration of drug constituents (as in the barrel lumen 18 of a prefilled syringe or cartridge) into the barrel wall or the migration of barrel wall constituents into the drug or other contents of the barrel lumen.
[99] In any embodiment plasma optionally can be generated in the barrel lumen 18 by placing an inner electrode into the barrel lumen 18 through the opening 32, placing an outer electrode outside the barrel or wall 14 and using the electrodes to apply plasma-inducing electromagnetic energy which optionally can be microwave energy, radio frequency energy, or both in the barrel lumen 18.
[100] In any embodiment the electromagnetic energy optionally can be direct current.
[101 ] In any embodiment the electromagnetic energy optionally can be alternating current. The alternating current optionally can be modulated at frequencies including audio, or microwave, or radio, or a combination of two or more of audio, microwave, or radio.
[102] In any embodiment the electromagnetic energy optionally can be applied across the barrel lumen (18).
[103] In any embodiment, in addition to or instead of applying a first coating or layer as described above, the method optionally can include applying another, either sole or second or further coating or layer of the same material or a different material. As one example useful in any embodiment, particularly contemplated if the first coating or layer is an SiOx barrier coating or layer or the substrate is made of glass, a further coating or layer can be placed directly or indirectly over the glass or barrier coating or layer. One example of such a further coating or layer useful in any embodiment is a pH protective coating or layer. A pH protective coating or layer can be used in any embodiment, and is particularly useful if the internal sliding surface yields measurable dissolved silicon when contacted with 0.1 N aqueous potassium hydroxide at 40 °C. and the fluoropolymer layer functions as a pH protective coating or layer having an interior surface facing the lumen, the protective coating or layer being effective to increase the calculated shelf life of the article (total Si / Si dissolution rate). Additionally or instead in any embodiment, the rate of erosion of the protective coating or layer on the internal sliding surface 16, if directly contacted by a fluid composition having a pH at some point between 5 and 9, can be less than the rate of erosion of the internal sliding surface 16 without the protective coating or layerbarrier coating or layer, if directly contacted by the fluid composition.
[104] The pH protective coating or layer optionally can be applied over at least a portion of the SiOx coating or layer to protect the SiOx coating or layer from contents stored in a vessel, where the contents otherwise would be in contact with the SiOx coating or layer. The pH protective coating or layers or layers are particularly contemplated to protect an SiOx barrier layer of a prefilled syringe or cartridge that is exposed to contents, such as a pharmaceutical preparation, having a pH between 4 and 9, alternatively between 4 and 8, alternatively between 5 and 9. Such pharmaceutical preparations have been found to attack and remove the SiOx coating or layer if unprotected by a protective coating or layer.
[105] Thus, in any embodiment, after the applying step, another vapor-deposited coating 34 optionally can be applied directly or indirectly over the coating 30, while the container 12 is capped, under conditions effective to maintain communication between
the barrel lumen 18 and the dispensing portion lumen 26 via the proximal opening 22 at the end of applying the second vapor-deposited coating 34.
[106] In any embodiment, the other vapor-deposited coating 34 can be a pH protective coating or layer.
[107] In any embodiment, the pH protective coating or layer can include or consist essentially of a parylene or halogenated polymer, for example a fluorinated polymer of a polyxylylene, for example a Parylene coating.
[108] Alternatively in any embodiment, the pH protective coating or layer can include or consist essentially of SiOxCy or SiNxCy wherein x is from about 0.5 to about 2.4, optionally about 1 .1 , and y is from about 0.6 to about 3, optionally about 1 .1 .
[109] In any embodiment, the pH protective coating or layer can include or consist essentially of SiOxCyHz, in which x is from about 0.5 to about 2.4, optionally from about 0.5 to 1 , y is from about 0.6 to about 3, optionally from about 2 to about 3, and z is from about 2 to about 9, optionally from 6 to about 9.
[1 10] Optionally in any embodiment, the pH protective coating or layer can be applied as the first or sole vapor-deposited coating or layer (30), instead of or in addition to its application as a further layer. This expedient may be useful, for example, where the barrel is made of glass, which is optional in any embodiment. An example of suitable glass is borosilicate glass of a type commonly used to fabricate syringe parts, vials, and other implements. The presently disclosed pH protective coating or layer also reduces the dissolution of glass, for example borosilicate glass, by contents having the pH values indicated as attacking SiOx coatings or layers.
[1 1 1 ] Surprisingly, it has been found that the above stated coatings or layers can be applied to the container 12 with substantially no deposition of the vapor-deposited coating 30 in the dispensing portion lumen 26. This is shown by a working example below.
PRECURSORS
[1 12] The precursor for the SiOx barrier coating or layer or for the alternative (non- parylene or halogenated polymer) pH protective coating or layer can include any of the
following precursors useful for PECVD. The precursor for the PECVD pH protective coating or layer of the present invention optionally can be broadly defined as an organometallic precursor. An organometallic precursor is defined in this specification as comprehending compounds of metal elements from Group III and/or Group IV of the Periodic Table having organic residues, for example hydrocarbon, aminocarbon or oxycarbon residues. Organometallic compounds as presently defined include any precursor having organic moieties bonded to silicon or other Group III/ IV metal atoms directly, or optionally bonded through oxygen or nitrogen atoms. The relevant elements of Group III of the Periodic Table are Boron, Aluminum, Gallium, Indium, Thallium, Scandium, Yttrium, and Lanthanum, Aluminum and Boron being preferred. The relevant elements of Group IV of the Periodic Table are Silicon, Germanium, Tin, Lead, Titanium, Zirconium, Hafnium, and Thorium, with Silicon and Tin being preferred. Other volatile organic compounds can also be contemplated. However, organosilicon compounds are preferred for performing present invention.
[1 13] An organosilicon precursor is contemplated, where an "organosilicon precursor" is defined throughout this specification most broadly as a compound having at least one of the linkages:
— O— Si— C— H or
— NH— Si— C— H
[1 14] The first structure immediately above is a tetravalent silicon atom connected to an oxygen atom and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom). The second structure immediately above is a tetravalent silicon atom connected to an -NH- linkage and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom).
Optionally, the organosilicon precursor is selected from the group consisting of a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, and a combination of any two or more of these precursors. Also contemplated as a precursor, though not within the two formulas immediately above, is an alkyl trimethoxysilane.
[1 15] If an oxygen-containing precursor (for example a Siloxane) is used, a representative predicted empirical composition resulting from PECVD under conditions forming a hydrophobic or lubricating pH protective coating or layer would be SiwOxCyHz or its equivalent SiOxCy as defined in the Definition Section, while a representative predicted empirical composition resulting from PECVD under conditions forming a barrier coating or layer would be SiOx, where x in this formula is from about 1 .5 to about 2.9. If a nitrogen-containing precursor (for example a silazane) is used, the predicted composition would be Siw*Nx*Cy*Hz*, i.e. in SiwOxCyHz or its equivalent SiOxCy as specified in the Definition Section, O is replaced by N and the indices for H are adapted to the higher valency of N as compared to O (3 instead of 2. The latter adaptation will generally follow the ratio of w, x, y and z in a Siloxane to the corresponding indices in its aza counterpart. In a particular aspect of the invention, Siw*Nx*Cy*Hz* (or its equivalent SiNx*Cy*) in which w*, x*, y*, and z* are defined the same as w, x, y, and z for the siloxane counterparts, but for an optional deviation in the number of hydrogen atoms.
[1 16] One type of precursor starting material having the above empirical formula is a linear siloxane, for example a material having the following formula:
in which each R is independently selected from alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others, and n is 1 , 2, 3, 4, or greater, optionally two or greater. Several examples of contemplated linear siloxanes are
hexamethyldisiloxane (HMDSO),
octamethyltrisiloxane,
decamethyltetrasiloxane,
dodecamethylpentasiloxane,
or combinations of two or more of these. The analogous silazanes in which -NH- is substituted for the oxygen atom in the above structure are also useful for making analogous pH protective coating or layers or coating or layers. Several examples of contemplated linear silazanes are octamethyltrisilazane, decamethyltetrasilazane, or combinations of two or more of these.
[1 17] Another type of precursor starting material, among the preferred starting materials in the present context, is a monocyclic siloxane, for example a material having the following structural formula:
in which R is defined as for the linear structure and "a" is from 3 to about 10, or the analogous monocyclic silazanes. Several examples of contemplated hetero-substituted and unsubstituted monocyclic siloxanes and silazanes include
1 ,3,5-trimethyl-1 ,3,5-tris(3,3,3-trifluoropropyl)methyl]cyclotrisiloxane
2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane,
pentamethylcyclopentasiloxane,
pentavinylpentamethylcyclopentasiloxane,
hexamethylcyclotrisiloxane,
hexaphenylcyclotrisiloxane,
octamethylcyclotetrasiloxane (OMCTS),
octaphenylcyclotetrasiloxane,
decamethylcyclopentasiloxane
dodecamethylcyclohexasiloxane,
methyl(3,3,3-trifluoropropl)cyclosiloxane,
Cyclic organosilazanes are also contemplated, such as
Octamethylcyclotetrasilazane,
1 ,3,5,7-tetravinyl-1 ,3,5,7-tetramethylcyclotetrasilazane hexamethylcyclotrisilazane, octamethylcyclotetrasilazane,
decamethylcyclopentasilazane,
dodecamethylcyclohexasilazane, or
combinations of any two or more of these.
[1 18] Another type of precursor starting material, among the preferred starting materials in the present context, is a polycyclic siloxane, for example a material having one of the followin structural formulas:
in which Y can be oxygen or nitrogen, E is silicon, and Z is a hydrogen atom or an organic substituent, for example alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others. When each Y is oxygen, the respective structures, from left to right, are a Silatrane, a Silquasilatrane, and a Silproatrane. When Y is nitrogen, the respective structures are an azasilatrane, an azasilquasiatrane, and an azasilproatrane.
[1 19] Another type of polycyclic siloxane precursor starting material, among the preferred starting materials in the present context, is a polysilsesquioxane, with the empirical formula RSiOi.5 and the structural formula:
Tg cub in which each R is a hydrogen atom or an organic substituent, for example alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others. Two commercial materials of this sort are SST-eM01 poly(methylsilsesquioxane), in which each R is methyl, and SST-3MH1 .1 poly(Methyl-Hydridosilsesquioxane), in which 90% of the R groups are methyl, 10% are hydrogen atoms. This material is available in a 10% solution in tetrahydrofuran, for example. Combinations of two or more of these are also contemplated. Other examples of a contemplated precursor are methylsilatrane, CAS No. 2288-13-3, in which each Y is oxygen and Z is methyl, methylazasilatrane, poly(methylsilsesquioxane) (for example SST-eM01 poly(methylsilsesquioxane)), in which each R optionally can be methyl, SST-3MH1 .1 poly(Methyl- Hydridosilsesquioxane) (for example SST-3MH1 .1 poly(Methyl-Hydridosilsesquioxane)), in which 90% of the R groups are methyl and 10% are hydrogen atoms, or a combination of any two or more of these.
[120] The analogous polysilsesquiazanes in which -NH- is substituted for the oxygen atom in the above structure are also useful for making analogous pH protective coating or layer. Examples of contemplated polysilsesquiazanes are a poly(methylsilsesquiazane), in which each R is methyl, and a poly(Methyl- Hydridosilsesquiazane, in which 90% of the R groups are methyl, 10% are hydrogen atoms. Combinations of two or more of these are also contemplated.
[121 ] One particularly contemplated precursor for the barrier coating or layer according to the present invention is a linear siloxane, for example is HMDSO. One particularly contemplated precursor for the pH protective coating or layer and the pH protective coating or layer according to the present invention is a cyclic siloxane, for example octamethylcyclotetrasiloxane (OMCTS).
[122] It is believed that the OMCTS or other cyclic siloxane molecule provides several advantages over other siloxane materials. First, its ring structure results in a less dense pH protective coating or layer (as compared to pH protective coating or layer prepared from HMDSO). The molecule also allows selective ionization so that the final structure and chemical composition of the pH protective coating or layer can be directly controlled through the application of the plasma power. Other organosilicon molecules are readily ionized (fractured) so that it is more difficult to retain the original structure of the molecule.
[123] In any of the PECVD methods according to the present invention, the applying step optionally can be carried out by vaporizing the precursor and providing it in the vicinity of the substrate. For example, OMCTS is usually vaporized by heating it to about 50 °C before applying it to the PECVD apparatus.
[124] Cyclic organosilicon precursors, in particular monocyclic organosilicon precursors (like the monocyclic precursors listed elsewhere in present description), and specifically OMCTS, are particularly suitable to achieve a pH protective coating or layer.
Other Components of PECVD Reaction Mixture and Ratios of Components For pH protective coating or layer
[125] Generally, for a pH protective coating or layer formed from an organosilicon precursor, O2 can be present as a coreactant in an amount (which can, for example be expressed by the flow rate in seem) which is less than one order of magnitude greater than the organosilicon amount. In contrast, in order to achieve a barrier coating or layer, the amount of O2 typically is at least one order of magnitude higher than the amount of organosilicon precursor. In particular, the volume ratio (in seem) of organosilicon precursor to O2 for a pH protective coating or layer can be in the range from 0.1 : 1 to
10 : 1 , optionally in the range from 0.3 : 1 to 8 : 1 , optionally in the range from 0.5 : 1 to 5 : 1 , optionally from 1 : 1 to 3 : 1 . The presence of the precursor and 02 in the volume ratios as given in Tables 9-1 1 is specifically suitable to achieve a pH protective coating or layer.
[126] In one aspect of the invention, a carrier or diluent gas is absent in the reaction mixture, in another aspect of the invention, it is present. Suitable carrier or diluent or diluent gases include Argon, Helium and other noble gases such as Neon and Xenon. When the carrier or diluent gas is present in the reaction mixture, it is typically present in a volume (in seem) exceeding the volume of the organosilicon precursor. For example, the ratio of the organosilicon precursor to carrier or diluent gas can be from 1 : 1 to 1 : 50, optionally from 1 : 5 to 1 : 40, optionally from 1 : 10 to 1 : 30. One function of the carrier or diluent gas is to dilute the reactants in the plasma, encouraging the formation of a coating or layer on the substrate instead of powdered reaction products that do not adhere to the substrate and are largely removed with the exhaust gases.
[127] Since the addition of Argon gas improves the pH protective performance (see the working examples below), it is believed that additional ionization of the molecule in the presence of Argon contributes to providing lubricity. The Si-O-Si bonds of the molecule have a high bond energy followed by the Si-C, with the C-H bonds being the weakest. pH protective appears to be achieved when a portion of the C-H bonds are broken. This allows the connecting (cross-linking) of the structure as it grows. Addition of oxygen (with the Argon) is understood to enhance this process. A small amount of oxygen can also provide C-O bonding to which other molecules can bond. The combination of breaking C-H bonds and adding oxygen all at low pressure and power leads to a chemical structure that is solid while providing lubricity.
[128] In any of embodiments, one preferred combination of process gases includes octamethylcyclotetrasiloxane (OMCTS) or another cyclic siloxane as the precursor, in the presence of oxygen as an oxidizing gas and argon as a carrier or diluent gas. Without being bound to the accuracy of this theory, the inventors believe this particular combination is effective for the following reasons. The presence of O2, N2O, or another oxidizing gas and/or of a carrier or diluent gas, in particular of a carrier or
diluent gas, for example a noble gas, for example Argon (Ar), is contemplated to improve the resulting pH protective coating or layer.
[129] Some non-exhaustive alternative selections and suitable proportions of the precursor vapor, oxygen, and a carrier or diluent gas are provided below.
OMCTS: 0.5 - 5.0 seem
Oxygen: 0.1 - 5.0 seem
Argon: 1 .0 - 20 seem
PECVD Apparatus for Forming Organosilicon pH Protective coating or layer
[130] The low-pressure PECVD process described in U.S. Patent No. 7,985,188 can be used to provide the organosilicon barrier, lubricity, and pH protective coatings or layers described in this specification. A brief synopsis of that process follows, with reference to present FIGS 3-4.
[131 ] A PECVD apparatus suitable for performing the present invention includes a vessel holder 50, an inner electrode defined by the probe108, an outer electrode 160, and a power supply 162. The container 12 seated on the vessel holder 50 defines a plasma reaction chamber, which optionally can be a vacuum chamber. Optionally, a source of vacuum 98, a reactant gas source 144, a gas feed (probe 108) or a combination of two or more of these can be supplied.
[132] The PECVD apparatus can be used for atmospheric-pressure PECVD, in which case the plasma reaction chamber defined by the container 12 does not need to function as a vacuum chamber.
[133] Referring to FIGS. 3-4, the vessel holder 50 optionally can comprise a gas inlet port 104 for conveying a gas into the container 12 seated on the opening 82. The gas inlet port 104 has a sliding seal provided for example by at least one O-ring 106, or two O-rings in series, or three O-rings in series, which can seat against a cylindrical probe 108 when the probe 108 is inserted through the gas inlet port 104. The probe 108 can be a gas inlet conduit that extends to a gas delivery port at its distal end 1 10. The distal end 1 10 of the illustrated embodiment can be inserted deep into the container
12 for providing one or more PECVD reactants and other precursor feed or process gases.
[134] FIG. 4 shows additional optional details of the coating station 60 that are usable, for example, with all the illustrated embodiments. The coating station 60 can also have a main vacuum valve 574 in its vacuum line 576 leading to the pressure sensor 152. A manual bypass valve 578 is provided in the bypass line 580. A vent valve 582 controls flow at the vent 404.
[135] Flow out of the PECVD gas or precursor source 144 is controlled by a main reactant gas valve 584 regulating flow through the main reactant feed line 586. One component of the gas source 144 is the organosilicon liquid reservoir 588. The contents of the reservoir 588 are drawn through the organosilicon capillary line 590, which is provided at a suitable length to provide the desired flow rate. Flow of organosilicon vapor is controlled by the organosilicon shut-off valve 592. Pressure is applied to the headspace 614 of the liquid reservoir 588, for example a pressure in the range of 0-15 psi (0 to 78 cm. Hg), from a pressure source 616 such as pressurized air connected to the headspace 614 by a pressure line 618 to establish repeatable organosilicon liquid delivery that is not dependent on atmospheric pressure (and the fluctuations therein). The reservoir 588 is sealed and the capillary connection 620 is at the bottom of the reservoir 588 to ensure that only neat organosilicon liquid (not the pressurized gas from the headspace 614 flows through the capillary tube 590. The organosilicon liquid optionally can be heated above ambient temperature, if necessary or desirable to cause the organosilicon liquid to evaporate, forming an organosilicon vapor. To accomplish this heating, the pH protective coating or layer apparatus can advantageously include heated delivery lines from the exit of the precursor reservoir to as close as possible to the gas inlet into the syringe. Preheating is useful, for example, when feeding OMCTS.
[136] Oxygen is provided from the oxygen tank 594 via an oxygen feed line 596 controlled by a mass flow controller 598 and provided with an oxygen shut-off valve 600.
[137] Optionally in any embodiment, other precursor, reactant, and/or carrier or diluent gas reservoirs such as 602 can be provided to supply additional materials if needed for a particular deposition process. Each such reservoir such as 602 has the appropriate feed line 604 and shut-off valve 606.
[138] Referring especially to FIG. 4, the processing station 28 can include an electrode 160 fed by a radio frequency power supply 162 for providing an electric field for generating plasma within the container 12 during processing. In this embodiment, the probe 108 is also electrically conductive and is grounded, thus providing a counter- electrode within the container 12. Alternatively, in any embodiment the outer electrode 160 can be grounded and the probe 108 directly connected to the power supply 162.
[139] In the embodiment of FIGS. 4-6, the outer electrode 160 can either be generally cylindrical as illustrated in FIGS. 4 and 5 or a generally U-shaped elongated channel as illustrated in FIG. 6 (FIG. 5 being an embodiment of the section taken along section line A— A of FIG. 4). Each illustrated embodiment has one or more sidewalls, such as 164 and 166, and optionally a top end 168, disposed about the container 12 in close proximity.
[140] Specific PECVD conditions for application of a pH protective coating or layer are provided below.
Plasma Conditions for Organosilicon pH Protective coating or layer
[141 ] Typically, the plasma in the PECVD process is generated at RF frequency. For providing a pH protective coating or layer on the interior of a vessel by a plasma reaction carried out within the vessel, the plasma of any embodiment can be generated with an electric power of from 0.1 to 500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300 W, optionally from 1 to 250 W, optionally from 1 to 200 W, even optionally from 10 to 150 W, optionally from 20 to 150 W, for example of 40 W, optionally from 40 to 150 W, even optionally from 60 to 150 W. The ratio of the electrode power to the plasma volume can be less than 100 W/ml, optionally is from 5 W/ml to 75 W/ml, optionally is from 6 W/ml to 60 W/ml, optionally is from 10 W/ml to 50
W/ml, optionally from 20 W/ml to 40 W/ml. These power levels are suitable for applying pH protective coating or layers or coating or layers to syringes and cartridges and sample tubes and pharmaceutical packages or other vessels of similar geometry having a void volume of 5 ml_ in which PECVD plasma is generated. It is contemplated that for larger or smaller objects the power applied, in Watts, should be increased or reduced accordingly to scale the process to the size of the substrate.
[142] Exemplary reaction conditions for preparing a pH protective coating or layer according to the present invention in a 3 ml sample size syringe with a 1 /8" diameter tube (open at the end) are as follows:
Flow rate ranges:
OMCTS: 0.5 - 10 seem
Oxygen: 0.1 - 10 seem
Argon: 1 .0 - 200 seem
Power: 0.1 - 500 watts
Specific Flow rates:
OMCTS: 2.0 seem
Oxygen: 0.7 seem
Argon: 7.0 seem
Power: 3.5 watts
[143] The pH protective coating or layer and its application are described in more detail below. A method for applying the coating or layer includes several steps. A vessel wall is provided, as is a reaction mixture comprising plasma forming gas, i.e. an organosilicon compound gas, optionally an oxidizing gas, and optionally a hydrocarbon gas.
[144] Plasma can be formed in the reaction mixture that is substantially free of hollow cathode plasma. The vessel wall is contacted with the reaction mixture, and the
pH protective coating or layer of SiOx is deposited on at least a portion of the vessel wall.
[145] In certain embodiments, the generation of a uniform plasma throughout the portion of the vessel to be coated is contemplated, as it has been found in certain instances to generate a better pH protective coating or layer. Uniform plasma means regular plasma that does not include a substantial amount of hollow cathode plasma (which has a higher emission intensity than regular plasma and is manifested as a localized area of higher intensity interrupting the more uniform intensity of the regular plasma).
Tie coating or layer
[146] Another useful coating or layer in any embodiment is a tie coating or layer between the injection molded barrel substrate and the barrier layer as described in this specification. The tie coating or layer can be formed under similar conditions, using similar equipment and material feeds, to those used to deposit the pH protective coating or layer, although normally the tie coating or layer can be relatively thin compared to the pH protective coating or layer. The tie coating or layer promotes adhesion of the barrier layer to the substrate, and also has been found to reduce the rate at which the SiOx barrier coating or layer is attacked, in an embodiment in which the coatings on the barrel substrate include a tie coating or layer, an SiOx barrier coating or layer, and a pH protective coating or layer.
[147] In the absence of the tie coating or layer, such an attack can be accelerated if a pinhole or other defect is present in the pH protective coating or layer overlying the barrier coating or layer. The inventors theorize, although the scope or validity of the claims does not depend on the accuracy or applicability of this theory, that this attack is accelerated by a pinhole or other defect in the pH protective layer because the defect allows access by a fluid material directly to the barrier coating or layer. As a result, the fluid material can undercut the pH protective coating or layer from the side and separate flakes or other particles of the pH protective coating or layer. This opens up the pinhole, allowing the rate of attack to accelerate as the undercut area increases.
[148] The inventors further theorize that if a tie coating or layer similar in composition to the pH protective layer underlies the barrier layer, the barrier layer is sandwiched between a tightly adherent, pH resistant layer on both sides. In the event of a pinhole in the pH protective coating or layer, the immediately underlying portion of the barrier layer can be attacked, but the superior adhesion of the tie layer to both the barrier layer and the substrate, plus the resistance to erosion of the pH protective composition of the tie coating or layer, prevents such flakes or particles from separating and prevents acceleration of the attack.
Parylene Or Halogenated Polymer
[149] The internal sliding surface 16, the external sliding surface 268, or both of any embodiment can be made at least in part of a parylene or halogenated polymer. In the illustrated embodiment, a parylene or halogenated polymer can be used as a coating or layer, which includes a situation in which the entire part is made of the parylene or halogenated polymer.
[150] The parylene or halogenated polymer sliding surface 268 of a stopper, O-ring, plunger tip or piston 36 can be provided in various ways in any embodiment.
[151 ] As one alternative, an entire stopper, O-ring, plunger tip or piston 36 can be injection molded of a parylene or halogenated polymer.
[152] As another alternative, a parylene or halogenated polymer film can be inserted into an injection mold for the stopper, O-ring, plunger tip or piston 36, adjacent to a wall of the mold, prior to molding another material in the mold. The other material can be a resilient polymer, for example a natural or (preferably) synthetic rubber composition such as filled rubber or filled thermoplastic elastomer (TPE). This method is commonly referred to as insert molding or in mold labelling.
[153] As another alternative, a parylene or halogenated polymer, provided for example as a film or sheet, can be laminated or wrapped about an already-molded stopper, O-ring, plunger tip or piston 36 made of another material such as filled rubber or filled TPE. The parylene or halogenated polymer can be applied either locally as just the external sliding surface 268 or more generally, for example defining the external
sliding surface 268 and also the leading or lumen-facing surface of the stopper, O-ring, plunger tip or piston, alternatively as all surfaces of the stopper, O-ring, plunger tip or piston. This technique is described, for example, in the following U.S. patents and published U.S. patent applications:
20120109076
20100305513
20100264139
20100185157
20100145284
20100106086
20100042055
20080195059
20070107204
20070060896
20060178643
20040099994
20030094429
8,105,294
8,101 ,674
8,002,754
7,927,315
7,766,882
7,749,202
7,691 ,308
7,547,297
7,214,214
6,822,015
6,645,635
6,524,282
6,344,034
6,129,712
6,090,081
5,951 ,527
5,288,560
5,009,646
4,978,714
[154] As yet another alternative, a coating of a parylene or halogenated polymer can be applied to a stopper, O-ring, plunger tip or piston. The coating can be applied either locally as just the external sliding surface 268 or more generally, for example defining the external sliding surface 268 and also the leading or lumen-facing surface, alternatively every surface, of the stopper, O-ring, plunger tip or piston.
[155] The coating can be applied by dip coating or spray coating of a coating material, which in some cases can be heated or dissolved or dispersed in a solvent or diluent for ease of application. The coated material can be appropriately dried, crosslinked, or otherwise cured or fixed to form a coating.
[156] The coating can be applied by vapor deposition, as by evaporation of a coating material and deposition of the material on the stopper, O-ring, plunger tip or piston.
[157] The coating can be applied by any variant of chemical vapor deposition (CVD), which is broadly defined as exposing a substrate to a gaseous precursor, optionally with other gaseous reactants present, such that the precursor engages in a chemical reaction, yielding a coating on the substrate of modified material. Several alternative processes that can be used.
[158] One contemplated example of a useful CVD process is plasma enhanced chemical vapor deposition (PECVD), for which the chemical reaction is promoted by exposing the precursor to a plasma, and heat-initiated chemical vapor deposition, for which the chemical reaction is promoted by heating the precursor.
[159] One variant of heat-initiated chemical vapor deposition is hot filament chemical vapor deposition (HWCVD), also known as initiated chemical vapor deposition
or iCVD, practiced for example by GVD Corporation, as described in PCT Pat. Publ. WO 201 1 /090717 A1 .
[160] Another example of heat-initiated chemical vapor deposition is the heat- initiated polymerization of Parylene, sometimes known as the Parylene Process, practiced for example by Specialty Coating Systems, Inc., discussed for example in Lonny Wolgemuth, Challenges With Prefilled Syringes: The Parylene Solution, www.ondrugdelivery.com, pp. 44-45 (Frederick Furness Publishing, 2012). The documents mentioned in this paragraph are incorporated by reference here. The Parylene Process can be carried out using several different species of Parylene, four of which are:
• Parylene N or poly(paraxylylene);
• Parylene C or poly(2-chloroparaxylylene);
• Parylene D or poly(2,5-dichloroparaxylylene); and
• Parylene HT® or the similar compound Parylene HTX poly(tetrafluoroparaxylylene).
The above Parylene species have the following structures:
[161 ] Any parylene or halogenated polymer coating may find use in the present invention, although the parylene or halogenated polymer, Parylene HT® (trademark of Specialty Coating Systems, Inc) or poly(tetrafluoroparaxylylene), is presently preferred.
[162] Because Parylene coatings are optically clear, there is an inherent level of difficulty involved in identifying if a component has been coated with Parylene. In the military and aerospace industries, for example, customers require a method to guarantee that a component is indeed Parylene coated. SCS Parylene C-UVF coatings are available containing a flourescent marker incorporated into the Parylene C deposition process. The result is a coating that fluoresces under a ultraviolet ("black") light, verifying that components are coated and ready for use, while maintaining the same electrical, mechanical and physical properties of Parylene C film. It is contemplated to use the same type of process, except substituting Parylene HT®, when manufacturing a Parylene lubricated syringe to allow verification of Parylene coating of an an internal sliding surface 16, a stopper, O-ring, plunger tip or piston 36, or other portions of a syringe or other medical device. This allows downstream purchasers and users as well to easily verify that the syringe is Parylene treated.
[163] The present inventors further contemplate the use of a Parylene coating or layer to provide pH protective properties comparable to those of the organosilicon pH protective coatings or layers defined in this specification
[164] Other examples of chemical vapor deposition contemplated for use herein include the following.
[165] Via a radical mechanism, it is contemplated that other co-monomers (perfluoropropene, etc.) can be reacted with a fluorinated co-monomer that can be any of the primary parylene or halogenated polymer precursors identified in this disclosure, such as hexafluoropropylene oxide (HFPO) or the dimer used to make Parylene HT®, to make fluorinated co-polymers. For example, perfluoropropene epoxide and a fluorinated co-monomer can be reacted to produce perfluorinated copolymers via thermal CVD.
[166] It is contemplated that free radical polymerization initiators such as t-butyl peroxide can be reacted with a fluorinated co-monomer e.g. perfluoropropene to produce perfluroropolymers.
[167] It is contemplated that with appropriate co-monomers (divinyl benzene, DVB), branching of the (co)polymers could be accomplished. For example, perfluoropropene epoxide, a fluorinated co-monomer, and DVB can be reacted to provide branched fluorinated (co)polymers via thermal CVD. For another example, t-butyl peroxide can be reacted with a fluorinated co-monomer e.g. perfluoropropene and DVB to produce branched perfluororopolymers.
[168] These reactions are not limited to perfluorinated monomer species: partially or unfluorinated (co)reactants may also be effective. Nor is iCVD or hot filament CVD required, as defined here or in the literature. Any method which can generate sufficient localized heat (hot tube, laser, platinum wire, induction, microwave) for a CVD process is contemplated to enable the practice of this chemistry on plastic substrates.
[169] T-butylperoxide (TBPO) has also been proposed as an initiator to polymerize fluorinated alkyl(methy)acrylates using iCVD as a thermal cracking source for TBPO radical formation. Using a relatively cool wire temperature in HWCVD (270 °C) the TBPO reaction with a fluorinated alkyl(methy)acrylate forms a radical and generates a
fluoropolymer chain with its orientation parallel with the surface. If the wire temperature is raised to 300 °C, the TBPO is cracked to form methyl radicals (*CH3), resulting in a reaction with a fluorinated alkyl(methy)acrylate to generate a parylene or halogenated polymer chain alignment perpendicular to the surface.
[170] Coating the selected substrate with a parylene or halogenated polymer by this chemistry is contemplated to cause the formation of PTFE oriented in either a parallel or perpendicular orientation.
[171 ] The presence of an oriented surface which PTFE forms onto is contemplated to provide both modification and orientation of PTFE crystal growth as well as amorphous segment orientation, affecting lubricity and barrier performance.
Long Chain Fluorocarbon lubricants are also contemplated utilizing polyhedral oligomeric silsesquioxane (POSS) lubricants. One source {POSS Molecules, http://www.reade.com/Products/Polymeric/poss.html, 1997 Reade Advanced Materials) indicates that POSS is a "Cage-like hybrid molecule [ ] of silicon and oxygen with similarities to both silica and silicone. When mixed with virtually any ordinary polymer, POSS bonds to the organic molecules and to itself, forming large chains that weave through the polymer. The result is a nanostructured organic- inorganic hybrid polymer. The POSS chains act like nanoscale reinforcing fibers."
[172] While short chain systems have been ineffective as syringe lubricants in certain testing, these long chain systems have potential to be effective syringe barrel molecular "rolling ball" lubricants with their longer Rf chains. Further, the "diol" modified systems could be grafted directly onto a silica or silicone surface (either PECVD SiOx or OMCTS based pH protective coatings, both as described here) to bind the molecular lubricant to the surface.
[173] As another alternative in any embodiment, a parylene or halogenated polymer can be used as a coating or layer defining the internal sliding surface 16. The parylene or halogenated polymer can be applied to the internal sliding surface 16 in any of the same ways as described above for making the external sliding surface 268 at least in part of a parylene or halogenated polymer.
[174] As still another alternative in any embodiment, a parylene or halogenated polymer can be used as a coating or layer defining both the internal sliding surface 16 and the external sliding surface 268.
[175] Other details of construction of the syringe shown in FIGS. 1 and 2, for example the provision or details of a Luer tip or staked hypodermic needle on the front end 260, a shield 28, a plunger rod, ears or finger grips, or a thumb pad are not part of the invention and are not required in any embodiment. Additionally, the lumen 18 can be prefilled with a fluid, for example a parenteral drug. Further, the syringe of FIG. 1 optionally can have a fixed injection needle permanently installed. Still further, any embodiment of the syringe shown in FIG. 1 optionally can have a barrier coating or layer 30 and/or a protective coating or layer, or both, as further described below.
[176] In any embodiment described in this specification, the parylene or halogenated polymer optionally can be a parylene polymer including a halogen element bonded to a carbon atom, either in the aromatic ring or ethylene chain.
[177] Parylene C and HT processes have been found in some testing to provide a low precision in reproducible coating thicknesses (+/- 20%). The Parylene HTX process has been found in some testing to provide higher precision in reproducible coating thicknesses. Thus, the parylene or halogenated polymer coating, applied for example by the Parylene HTX process, can be applied with a precision in reproducible coating thicknesses of +/- 1 -15%, optionally +/- 1 -10%, optionally +/- 1 to 5%, optionally +/- 2% or less.
[178] In any embodiment described in this specification, the parylene or halogenated polymer optionally can comprise a polymer having the structure:
T-[CXmHn-C6XoUp-CXqHr]s-V
in which:
• each X is a halogen atom,
• each T and V is a terminal group,
• each CXmHn and CXqHr moiety is a methylene or substituted methylene moiety,
• each -C6X0UP- moiety is a benzene or substituted benzene nucleus,
• each U is hydrogen or lower alkyl, in which lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, i-butyl, or t-butyl,
• m & q are independently 0-2,
• o is 0-4,
• n & r are independently (2-m) and (2-q),
• p is (4-o), and
• s is from 3 to 100,000, optionally from 10 to 100,000, optionally from 10-10,000.
[179] In any embodiment described in this specification, the parylene or halogenated polymer optionally can be applied by hot filament chemical vapor deposition.
[180] In any embodiment described in this specification, the parylene or halogenated polymer optionally can be applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor (182) in a pyrolysis (high heat) step/region such as a cracking pipe, cracking tube, or cracking capillary (190) and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus (198) to form at least one of the internal and external sliding surfaces.
[181 ] In any embodiment described in this specification, the precursor for the parylene or halogenated polymer optionally can comprise xylene or its ethyl, propyl, or butyl-substituted analog, fully halogenated on each pendant alkyl moiety.
[182] In any embodiment described in this specification, each pendant alkyl moiety optionally can be trihalogenated methyl.
[183] In any embodiment described in this specification, each pendant alkyl moiety optionally can be trifluoromethyl.
[184] In any embodiment described in this specification, the halogen optionally can be one nonfluoro halogen terminal moiety selected from chloro, bromo, or iodo and the balance fluoro.
[185] In any embodiment described in this specification, the alkyl moieties optionally can be bromodifluoromethyl.
[186] In any embodiment described in this specification, the precursor vapor optionally can be decomposed in the presence of a catalyst. "Decomposed" is broadly defined to include activation of a precursor without necessarily removing any atoms.
[187] In any embodiment described in this specification, the catalyst optionally can comprise copper, zinc, magnesium, titanium, cadmium, silver, indium, tin, aluminum, or other solid reducing agent, or a combination of two or more of these.
[188] In any embodiment described in this specification, the catalyst optionally can comprise zinc or a zinc halide, for example zinc bromide.
[189] In any embodiment described in this specification, the catalyst optionally can comprise copper or a copper halide, for example copper bromide.
[190] In any embodiment described in this specification, the precursor vapor optionally can be decomposed in the presence of an initiator different from the precursor.
[191 ] In any embodiment described in this specification, the initiator optionally can comprise xylene (a methyl-substituted compound) or its ethyl, propyl, or butyl- substituted analog, at least partially halogenated on each pendant alkyl moiety.
[192] In any embodiment described in this specification, the methyl pendant groups optionally can be di- or tri-halogen-substituted.
[193] In any embodiment described in this specification, the initiator optionally can comprise m-bis-(dibromomethyl)benzene.
[194] In any embodiment described in this specification, the initiator optionally can comprise p-bis-(dibromomethyl)benzene.
[195] In any embodiment described in this specification, the initiator optionally can comprise m-bis-(difluorobromo)benzene.
[196] In any embodiment described in this specification, the initiator optionally can comprise p-bis-(difluorobromo)benzene.
[197] In any embodiment described in this specification, the parylene or halogenated polymer optionally can be applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor comprising p-bis(trifluoromethyl)benzene in a cracking pipe or other pyrolysis apparatus and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus (198) to form at least the external sliding surface. In the Parylene HTX process, the pyrolysis can be carried out in the presence of an initiator comprising bis(difluorobromomethyl)benzene and a catalyst as previously defined. The deposition equipment optionally can incorporate stacked plunger holder trays in the coating chamber to increase output.
[198] In any embodiment described in this specification, the stopper, O-ring, plunger tip or piston optionally can consist essentially of an elastomeric seal having a molded external sliding surface directly coated by chemical vapor deposition with the parylene or halogenated polymer.
[199] In any embodiment described in this specification, the F, and Fm values for advance of the external sliding surface along the internal sliding surface optionally each can be from 1 to 20 N, alternatively from 3 to 18 N, optionally from 5 to 15 N, respectively after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
[200] In any embodiment described in this specification, the F, and Fm values for advance of the external sliding surface along the internal sliding surface optionally do not increase more than 50 percent, alternatively more than 40 percent, alternatively more than 30 percent, alternatively more than 20 percent, alternatively more than 10 percent, alternatively at all, and optionally decrease up to 10%, optionally up to 20%,
optionally up to 30%, after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
[201 ] In any embodiment described in this specification, a substrate supporting the parylene or halogenated polymer optionally can be molded, the parylene or halogenated polymer optionally can be applied to the supporting substrate by chemical vapor deposition, and the presence of the parylene or halogenated polymer optionally can reduce the extractables obtainable from the injection molded substrate.
[202] In any embodiment described in this specification, the parylene or halogenated polymer optionally can comprise poly(tetrafluoro-p-xylylene), and the extractables obtainable from the injection molded substrate by isopropanol extraction optionally can be reduced by at least 10%, optionally at least 25%, optionally at least 30%, optionally at least 40%, optionally at least 47%, optionally at least 50%, optionally at least 60%, optionally at least 70%, optionally at least 80%, optionally at least 90%, optionally from 10% to 95%, optionally from 10% to 90%, optionally from 10% to 80%, optionally from 10% to 70%, optionally from 10% to 60%, optionally from 10% to 50%, optionally from 25% to 50%, compared to the uncoated substrate.
[203] In any embodiment described in this specification, the parylene or halogenated polymer optionally can be applied as a coating on an elastomeric stopper, O-ring, plunger tip or piston 36 as a substrate and the container closure integrity (CCI) result for the parylene or halogenated polymer coated substrate, measured using the Bonfiglioli or other vacuum decay test, optionally can be a vacuum decay of less than 50 mbar (500 N/cm2), alternatively less than 40 mbar (400 N/ cm2), alternatively less than 30 mbar (300 N/cm2), alternatively less than 20 mbar (200 N/cm2), as an upper limit, and at least 3 mbar (30 N/cm2), alternatively at least 5 mbar (50 N/cm2), alternatively at least 7 mbar (70 N/cm2), alternatively at least 10 mbar (100 N/cm2), alternatively at least 12 mbar (120 N/cm2), as a lower limit. CCI and vacuum decay can alternatively be measured in other ways, as well.
[204] In any embodiment described in this specification, the parylene or halogenated polymer coating optionally can be 0.5-20 microns thick, optionally 0.5-10
microns thick, optionally 0.5-4.5 microns thick, optionally 1 to 5 microns thick, optionally 1 to 4.5 microns thick, optionally 1 -3 microns thick.
[205] In any embodiment described in this specification, the parylene or halogenated polymer coating optionally consists essentially of Poly[1 ,4- phenylene(1 ,1 ,2,2-tetrafluoro-1 ,2-ethanediyl), which can be generated, for example, using the Parylene HT or HTX process conditions.
[206] In any embodiment described in this specification, the parylene or halogenated polymer optionally can be provided in the form of a coating having a crystallinity of greater than 10%, optionally from 15% to 50%, optionally from 20 to 40%, optionally 20 to 30%.
Barrier coating or layer 30
[207] Coatings of SiOx are deposited by plasma enhanced chemical vapor deposition (PECVD) or other chemical vapor deposition processes on the vessel of a pharmaceutical package, in particular a thermoplastic package, to serve as a barrier coating or layer 30) preventing oxygen, carbon dioxide, or other gases from entering the vessel and/or to prevent leaching of the pharmaceutical material into or through the package wall.
[208] The barrier coating 30 optionally can comprise or consist essentially of SiOx, wherein x is from 1 .5 to 2.9, from 2 to 1000 nm thick, the barrier coating 288 of SiOx having an interior surface facing the lumen and an outer surface facing the barrel internal sliding surface 16, the barrier coating being effective to reduce the ingress of atmospheric gas into the lumen compared to an uncoated vessel such as the syringe 250. One suitable barrier composition is one where x is 2.3, for example.
[209] The details of such SiOx coatings and the manner of applying them are described, for example, in the various embodiments U.S. Patent No. 7,985,188 incorporated by reference herein.
pH Protective coating or layer
[210] The inventors have found, however, that such barrier layers or coatings of SiOx as well as borosilicate and other glass substrates are eroded or dissolved at some rate by some fluid compositions, for example aqueous compositions having a pH above about 5. Since coatings applied by chemical vapor deposition can be very thin - tens to hundreds of nanometers thick - even a relatively slow rate of erosion can remove or reduce the effectiveness of the barrier layer in less time than the desired shelf life of a product package. Additionally, while a glass substrate normally will not be compromised as quickly as a barrier layer, the erosion of glass can cause flaking during the shelf life of a vial. These are particularly problems for fluid pharmaceutical compositions, since many of them have a pH of roughly 7, or more broadly in the range of 5 to 9, similar to the pH of blood and other human or animal fluids. The higher the pH of the pharmaceutical preparation, the more quickly it erodes or dissolves the SiOx coating.
[21 1 ] The inventors have further found that certain protective coatings or layers 272 of SiOxCy or SiNxCy formed from cyclic polysiloxane precursors, which protective coating or layers have a substantial organic component, do not erode quickly when exposed to fluid compositions, and in fact erode or dissolve more slowly when the fluid compositions have higher pHs within the range of 5 to 9. For example, at pH 8, the dissolution rate of a protective coating or layer made from the precursor octamethylcyclotetrasiloxane, or OMCTS, is quite slow. These protective coatings or layers of SiOxCy or SiNxCy can therefore be used to cover a barrier layer of SiOx, retaining the benefits of the barrier layer by protecting it from the contents of the vessel 12.
[212] Although the present invention does not depend upon the accuracy of the following theory, it is further believed that the most effective organosilicon pH protective coating or layers 272 are those made from cyclic siloxanes and silazanes as described in this disclosure. SiOxCy or SiNxCy coatings deposited from linear siloxane or linear silazane precursors, for example hexamethyldisiloxane (HMDSO), are believed to contain fragments of the original precursor to a large degree and low organic content.
Such SiOxCy or SiNxCy coatings have a degree of water miscibility or swellability, allowing them to be attacked by aqueous solutions. SiOxCy or SiNxCy coatings deposited from cyclic siloxane or linear silazane precursors, for example octamethylcyclotetrasiloxane (OMCTS), however, are believed to include more intact cyclic siloxane rings and longer series of repeating units of the precursor structure. These coatings are believed to be nanoporous but structured and hydrophobic, and these properties are believed to contribute to their success as protective coating or layers. This is shown, for example, in U.S. Pat. No. 7,901 ,783.
[213] The protective coating or layer is made of SiOxCy or SiNxCy wherein x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3. The protective coating or layer has an interior surface facing the lumen and an outer surface facing the interior surface of the barrier coating. The protective coating or layer can be formed by chemical vapor deposition of a precursor selected from a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a Silatrane, a Silquasilatrane, a Silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors. This process is described in more detail throughout this specification.
[214] The rate of erosion of the protective coating or layer, if directly contacted by the fluid composition, is less than the rate of erosion of the barrier coating, if directly contacted by the fluid composition.
[215] The protective coating or layer is effective to isolate the fluid composition from the barrier coating 30).
Parylene or halogenated polymer Layer
[216] As explained, the syringe, cartridge, or similar article 12 optionally can comprise a barrel 250) including a lumen 18) defined at least in part by a internal sliding surface 16; and a stopper, O-ring, plunger tip or piston 36 within the lumen comprising a sliding surface 268 slidable in the lumen at least substantially in contact with the internal sliding surface 16. The internal sliding surface 16, the external sliding surface 268, or both is made at least in part of a parylene or halogenated polymer.
[217] The parylene or halogenated polymer can be deposited directly or with intervening or subsequent layers on the external sliding surface 268, the internal sliding surface 16, or both. The parylene or halogenated polymer optionally is applied by chemically modifying a precursor, while on or in the vicinity of the fluid receiving interior surface.
[218] Optionally, the precursor optionally can comprise:
• dimeric tetrafluoroparaxylylene,
• difluorocarbene,
• monomeric tetrafluoroethylene,
• oligomeric tetrafluoroethylene having the formula F2C=CF(CF2)xF in which x is from 1 to 100, optionally 2 to 50, optionally 2-20, optionally 2-10,
• sodium chlorodifluoroacetate,
• chlorodifluoromethane,
• bromodifluoromethane,
• hexafluoropropylene oxide,
• 1 H,1 H,2H,2H-perfluorodecyl acrylate (FDA),
• a bromofluoroalkane in which the alkane moiety has from 1 to 6 carbon atoms,
• an iodofluoroalkane in which the alkane moiety has from 1 to 6 carbon atoms, or
• a combination of any two or more of these.
[219] The parylene or halogenated polymer is:
• optionally from at least 0.01 micrometer to at most 100 micrometers thick,
• optionally from at least 0.05 micrometers to at most 90 micrometers thick,
• optionally from at least 0.1 micrometers to at most 80 micrometers thick,
• optionally from at least 0.1 micrometers to at most 70 micrometers thick,
• optionally from at least 0.1 micrometers to at most 60 micrometers thick,
• optionally from at least 0.1 micrometers to at most 50 micrometers thick,
• optionally from at least 0.1 micrometers to at most 40 micrometers thick,
• optionally from at least 0.1 micrometers to at most 30 micrometers thick,
opt onal iy from at least 0.1 micrometers to at most 20 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 15 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 12 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 10 micrometers thick opt onal iy from at least 0.1 micrometers to at most 8 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 6 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 4 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 2 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 1 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 0.9 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 0.8 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 0.7 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 0.6 micrometers thick, opt onal iy from at least 0.1 micrometers to at most 0.5 micrometers thick, opt onal iy from at least 0.5 micrometers to at most 5 micrometers thick, opt onal iy from at least 0.5 micrometers to at most 4 micrometers thick, opt onal iy from at least 0.5 micrometers to at most 3 micrometers thick, opt onal iy from at least 0.5 micrometers to at most 2 micrometers thick, opt onal iy from at least 0.5 micrometers to at most 1 micrometer thick,
opt onal iy about 1 0 micrometers thick,
opt onal iy about 2 micrometers thick.
[220] The parylene or halogenated polymer optionally can be applied by vapor deposition, for example chemical vapor deposition. Optionally, the parylene or halogenated polymer can be applied by chemical vapor deposition of dimeric tetrafluoroparaxylylene. An example of a suitable parylene or halogenated polymer is polytetrafluoroparaxylylene. Optionally, the parylene or halogenated polymer consists essentially of polytetrafluoroparaxylylene.
[221 ] Optionally in any embodiment, the parylene or halogenated polymer coating or layer optionally can comprise polytetrafluoroethylene. Optionally in any embodiment, the parylene or halogenated polymer coating or layer optionally can consist essentially of polytetrafluoroethylene. The polytetrafluoroethylene optionally can comprise or consist essentially of linear polytetrafluoroethylene with little or no branching.
[222] Optionally in any embodiment, illustrated for example in Figs. 9 and 10, the parylene or halogenated polymer can comprise a composite of polytetrafluoroethylene 34 and a fluorine substituted derivative of poly(paraxylylene) 31 .
[223] Optionally in any embodiment, the parylene or halogenated polymer can comprise: polytetrafluoroethylene particles (as in Fig. 9) or a layer (34) (as in Fig. 10) defining at least one of the internal 16 and external (268 sliding surfaces, and a fluorine substituted derivative of poly(paraxylylene) (31 ) between the polytetrafluoroethylene particles or layer and the substrate 14.
[224] Fig. 9 (as well as Fig. 10) is to be understood for present purposes as an instance of a fluorine substituted derivative of poly(paraxylylene) 30 between the polytetrafluoroethylene particles 34 and the substrate 14, even though both the particles 34 and layer 30 of Fig. 9 both are shown in contact with the substrate 14, as line segments like 56 can be drawn in Fig. 9 between the particles 34 and the substrate 14 (diagonally in Fig. 9) with portions of the layer 30 between the particles 34 and the substrate 14.
[225] Fig. 9 (but not Fig. 10) is also to be understood for present purposes as an instance of polytetrafluoroethylene particles 34 between the fluorine substituted derivative of poly(paraxylylene) 30 and the substrate 14, even though both the particles 34 and layer 30 both are shown in contact with the substrate 14, as line segments like 58 can be drawn in Fig. 9 between the layer 30 and the substrate 14 (diagonally in Fig. 9) with portions of the particles 34 between the layer 30 and the substrate 14.
[226] Optionally in any embodiment, the parylene or halogenated polymer can comprise polytetrafluoroethylene particles or a layer (34) effective to improve the lubricity between the internal sliding surface 16 and the external sliding surface.
[227] Optionally in any embodiment, the parylene or halogenated polymer of at least one of the internal and external sliding surfaces (16, 268 can comprise a composite layer (30) of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene) (34), formed by at least partial co-deposition or sequential deposition of the polytetrafluoroethylene and a fluorine substituted poly(paraxylylene).
[228] Optionally in any embodiment, the composite layer (30) can be formed by sequential deposition of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene).
[229] Optionally in any embodiment, the composite layer (30) can be formed at least in part by overlapping deposition of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene). Optionally in any embodiment, during the overlapping deposition a gradient composition can be formed transitioning from predominantly the previously deposited composition, optionally the fluorine substituted derivative of poly(paraxylylene), to predominantly the later deposited composition, optionally polytetrafluoroethylene.
[230] Optionally in any embodiment, the composite layer can be formed by substantially simultanous deposition of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene).
[231 ] For example, in any embodiment, the parylene or halogenated polymer coating or layer can be applied by chemically modifying a precursor, while on or in the vicinity of the fluid receiving interior surface, to produce the parylene or halogenated polymer coating or layer on the fluid receiving interior surface. Optionally in any embodiment, the parylene or halogenated polymer coating or layer can be applied by chemical vapor deposition, for example by chemical vapor deposition of polytetrafluoroethylene, or by chemical vapor deposition of dimeric tetrafluoroparaxylylene, or both.
[232] For one example, in any embodiment, the parylene or halogenated polymer coating or layer can be applied by heated wire chemical vapor deposition (HWCVD), althernatively the same process being known as hot filament chemical vapor deposition. For another example, in any embodiment, the parylene or halogenated polymer coating
or layer can be applied by plasma enhanced chemical vapor deposition (PECVD). Mixed processes or other processes for applying a suitable coating are also contemplated, in any embodiment.
[233] An example of a suitable HWCVD process for applying the parylene or halogenated polymer coating is the process described in Hilton G. Pryce Lewis, Neeta P. Bansal, Aleksandr J. White, Erik S. Handy, HWCVD of Polymers: Commercialization and Scale-up, THIN SOLID FILMS 517 2009) 3551 -3554; and US Publ. Appl. 2012/0003497 A1 , published Jan. 5, 2012, which are incorporated here by reference in their entirety for their description of repellant coatings and their application.
[234] Another useful process for applying the parylene or halogenated polymer coating in any embodiment is pyrolysis chemical vapor deposition, as illustrated in FIG. 12 which is reproduced with annotations from Jun Wang, Xue Song, Rui li, Jinpeng Shen, Guangcheng Yang, Hui Huang, Fluorocarbon Thin Film With Superhydrophobic Property Prepared By Pyrolysis Of Hexafluoropropylene Oxide, APPLIED SURFACE SCIENCE 258 (2012) 9782-9785. The laboratory-built apparatus 180 shown in FIG. 12 broadly includes a precursor vapor source 182 for delivering a precursor vapor 184, a cracking pipe 190 or other suitable pyrolysis reactor, a substrate 198 to be treated, a cold trap 201 (for example a cold trap Dewar bottle or basic quenching solution or both, among other expedients) and a drain 185 for receiving the reaction effluent gases. In any embodiment the substrate 198 can be a surface within the vessel or syringe 12 without a reaction chamber, as illustrated in more detail in FIGS. 3 and 4. Commercial chemical vapor deposition apparatus of this type can also be used, for example an MTI CVD Tube Furnace with Gas Delivery and a Vacuum Pump, disclosed for example at http://mtixtl.com/MiniCVDTubeFurnace2ChannelsGasVacuum-OTF-1200X-S50- 2F.aspx.
[235] Returning to FIG. 12, the illustrated apparatus further can include a pressure releasing valve 186, a flow meter 188, heating tape 194 or other suitable apparatus for heating the cracking pipe 190 or its various parts, and a thermocouple wrap 192 or other apparatus for determining the temperature of the cracking pipe 190 or its various parts. A temperature controller 196 can be provided to control the heating tape 194
according to the data obtained from the thermocouple 192. A vessel or reactor 12 can be provided where chemical vapor deposition will occur. The cracking pipe 190 has an inlet generally indicated as 181 and an outlet generally indicated at 183. The outlet 183 of the cracking pipe and the treated substrate 198 on the reaction vessel 12 or other surface to be treated are connected via a conduit 197.
[236] The substrate 198 can be cooled as necessary or convenient to prevent distortion of the vessel or other workpiece as it is treated with the decomposition products produced in the cracking tube 190, as by a cooling jacket 199. The gases departing from the outlet 183 of the cracking tube 190 also can be allowed to cool to an appropriate degree by selecting an appropriate length, diameter, material, and ambient or applied temperature for the conduit 197 separating the outlet 183 from the treated substrate 198.
[237] The pyrolysis chemical vapor deposition process can be carried out, for example, by decomposing a precursor vapor 184 in the cracking pipe 190 and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus 198 to form at least one of the internal and external sliding surfaces 16, 268. The internal sliding surfaces can be formed in any embodiment by connecting the vessel 12 as the reactor 198 and forming the internal sliding surfaces inside the vessel 12. In this embodiment, during deposition the chemical vapor deposition apparatus 198 optionally can comprise the barrel 14 functioning as its own reaction vessel.
[238] The external sliding surfaces can be formed in any embodiment by placing the stopper, O-ring, plunger tip or piston 36 to be provided with an external sliding surface into a separate reactor 198.
[239] The following reaction conditions can be used, varied as appropriate for a specific process, vessel 12 and materials.
[240] The temperature within the cracking pipe 190 can be maintained, for example, between150°C and 1300°C during decomposition.
[241 ] In any embodiment, during the decomposing step a difluorocarbene precursor vapor 184 can be decomposed in the cracking pipe 190 to generate difluorocarbene
free radicals. In any embodiment, the difluorocarbene precursor vapor can be one or more of hexafluoroepoxypropane, trifluoromethane and difluorochloromethane. In any embodiment, a polytetrafluoroethylene coating film can be formed on the substrate due to polymerization of the difluorocarbene free radicals.
[242] In any embodiment, the difluorocarbene precursor vapor can be fed at the flow rate of 5-600 seem.
[243] In any embodiment, the minimum distance through the conduit 197 between the outlet 183 of the cracking pipe and the treated substrate 198 can be from 1 to 60 cm, alternatively from 1 to 50 cm, alternatively from 1 to 40 cm, alternatively from 1 to 30 cm, alternatively from 1 to 20 cm, alternatively from 10 to 60 cm, alternatively from 10 to 50 cm, alternatively from 10 to 40 cm, alternatively from 10 to 30 cm, alternatively from 10 to 20 cm, alternatively from 20 to 60 cm, alternatively from 20 to 50 cm, alternatively from 20 to 40 cm, alternatively from 20 to 30 cm, alternatively from 30 to 60 cm, alternatively from 30 to 50 cm, alternatively from 30 to 40 cm. Longer distances in this area provide more cooling, and vice versa.
[244] In any embodiment, the polymerization reaction can be performed at a temperature controlled to be below 100°C, alternatively below 90 °C, alternatively below 80° C, alternatively below 70° C, alternatively below 60° C, alternatively below 50 °C at the substrate 198.
[245] In any embodiment, the polymerization reaction can be performed under a reaction environment selected from vacuum environment or an environment filled with a filler gas. In any embodiment, 30 the filler gas can be nitrogen and can have a pressure within 10 standard atmosphere pressures.
[246] In any embodiment, depending on process materials and conditions, acid gases can be generated when the difluorocarbene precursor vapor is decomposed in a cracking pipe to generate difluorocarbene free radicals. Optionally, the other acid gases can be removed from the effluent by freezing them in a cold trap 201 such as a Dewar bottle or by absorbing them with a basic solution.
[247] In any embodiment, during the decomposing step a dimeric tetrafluoroparaxylylene precursor vapor can be decomposed in the cracking pipe to generate tetrafluoroparaxylyl free radicals.
[248] In any embodiment, the polytetrafluoroparaxylylene coating film can be formed on the substrate due to polymerization of tetrafluoroparaxylylene free radicals.
[249] In any embodiment, the dimeric tetrafluoroparaxylylene precursor vapor can be fed at the flow rate of 5-600 seem and the minimum distance through the conduit, between the outlet of the cracking pipe and the treated substrate, can be from 1 to 60 cm, alternatively from 1 to 50 cm, alternatively from 1 to 40 cm, alternatively from 1 to 30 cm, alternatively from 1 to 20 cm, alternatively from 10 to 60 cm, alternatively from 10 to 50 cm, alternatively from 10 to 40 cm, alternatively from 10 to 30 cm, alternatively from 10 to 20 cm, alternatively from 20 to 60 cm, alternatively from 20 to 50 cm, alternatively from 20 to 40 cm, alternatively from 20 to 30 cm, alternatively from 30 to 60 cm, alternatively from 30 to 50 cm, alternatively from 30 to 40 cm.
[250] In any embodiment, the polytetrafluoroparaxylylene polymerization reaction can be performed at a temperature controlled to be below 100° C, alternatively 30 below 90° C, alternatively 30 below 80° C, alternatively 30 below 70° C, alternatively 30 below 60° C, alternatively 30 below 50 °C at the substrate.
[251 ] In any embodiment, 30 the polytetrafluoroparaxylylene polymerization reaction can be performed under a reaction environment selected from vacuum environment or an environment filled with a filler gas. The filler gas can be nitrogen and can have a pressure within 10 standard atmosphere pressures.
[252] 33 In any embodiment, the effluent gases for formation of polytetrafluoroparaxylylene can be frozen by a cold trap Dewar bottle or absorbed with a basic solution, or both.
[253] In the present methods for applying composite coatings, it is contemplated that two different precursors (having different vapor pressures) can be fed to a CVD coating apparatus by utilizing a combination of vaporization boats and mass flow controllers and thermolysis tube configurations.
[254] It is further contemplated that the respective constituents of the composite coating will either form physical mixtures or random, block, or graft copolymers of Parylene and tetrafluoroethylene precursor molecular species.
[255] In the composite coatings, it is contemplated that the polytetrafluoropara- xylylene component will provide a pinhole free composite coating providing an excellent solute barrier, and both the polytetrafluoroethylene component and the polytetrafluoroparaxylylene component will provide a lubricious coating.
[256] It is contemplated that the composite coatings will provide simultaneous (a) solute barrier performance (inhibition of organic and inorganic extractables/leachables) and (b) lubricity performance to parenteral medical devices including syringe assemblies and cartridges, as well as any contained material to be delivered through a mechanical delivery device. Further, the invention can provide a pH protective coating or layer contributing dissolution protection of SiOx gas barrier coatings to alkaline pH media. The non-wetting nature of the coating can provide superior air bubble removal in filling operations and high delivery transfer efficiency for expensive drugs or payloads.
Syringe Barrel or Plunger Materials
[257] Optionally for any of the embodiments of FIG. 1 , at least a portion of the wall of the syringe barrel or plunger or other substrate optionally can comprise or consist essentially of a polymer, for example a polyolefin (for example a cyclic olefin polymer, a cyclic olefin copolymer, or polypropylene), a polyester, for example polyethylene terephthalate, a polycarbonate, or any combination or copolymer of any of these. Optionally at least a portion of the barrel or plunger optionally can comprise or consist essentially of glass, for example borosilicate glass. A combination of any two or more of the materials in this paragraph can also be used.
[258] Optionally for any of the embodiments, the fluid composition has a pH between 5 and 6, optionally between 6 and 7, optionally between 7 and 8, optionally between 8 and 9, optionally between 6.5 and 7.5, optionally between 7.5 and 8.5, optionally between 8.5 and 9.
[259] Optionally for any of the embodiments, the fluid composition is a liquid at 20 °C and ambient pressure at sea level, which is defined as a pressure of 760 mm Hg.
[260] Optionally for any of the embodiments, the fluid composition is an aqueous liquid.
[261 ] Optionally for any of the embodiments, the barrier coating is from 4 nm to 500 nm thick, optionally from 7 nm to 400 nm thick, optionally from 10 nm to 300 nm thick, optionally from 20 nm to 200 nm thick, optionally from 30 nm to 100 nm thick.
[262] Optionally for any of the embodiments, the protective coating or layer 272 optionally can comprise or consist essentially of SiOxCy. Optionally for any of the embodiments, the protective coating or layer optionally can comprise or consist essentially of SiNxCy.
[263] Optionally for any of the organosilicon embodiments, the precursor optionally can comprise a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors.
[264] Optionally for any of the organosilicon embodiments, the precursor optionally can comprise a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a Silatrane, a Silquasilatrane, a Silproatrane, or a combination of any two or more of these precursors. Optionally for any of the embodiments, the precursor optionally can comprise octamethylcyclotetrasiloxane (OMCTS) or consists essentially of OMCTS. Other precursors described elsewhere in this specification or known in the art are also contemplated for use according to the invention.
[265] Optionally for any of the organosilicon embodiments, the precursor optionally can comprise a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors.
[266] Optionally for any of the organosilicon embodiments, the protective coating or layer as applied is between 10 and 1000 nm thick, optionally between 50 and 800 nm thick, optionally between 100 and 700 nm thick, optionally between 300 and 600 nm
thick. The thickness does not need to be uniform throughout the vessel, and will typically vary from the preferred values in portions of a vessel.
[267] Optionally for any of the embodiments, the protective coating or layer contacting the fluid composition is between 10 and 1000 nm thick, optionally between 50 and 500 nm thick, optionally between 100 and 400 nm thick, optionally between 150 and 300 nm thick two years after the pharmaceutical package is assembled.
[268] Optionally for any of the embodiments, the rate of erosion of the protective coating or layer, if directly contacted by a fluid composition having a pH of 8, is less than 20%, optionally less than 15%, optionally less than 10%, optionally less than 7% , optionally from 5% to 20% , optionally 5% to 15% , optionally 5% to 10%, optionally 5% to 7%, of the rate of erosion of the barrier coating 288, if directly contacted by the same fluid composition under the same conditions.
[269] Optionally for any of the embodiments, the protective coating or layer is at least coextensive with the barrier coating. The protective coating or layer alternatively can be less extensive than the barrier coating, as when the fluid composition does not contact or seldom is in contact with certain parts of the barrier coating absent the protective coating or layer. The protective coating or layer alternatively can be more extensive than the barrier coating, as it can cover areas that are not provided with a barrier coating.
[270] Optionally for any of the embodiments, the pharmaceutical package can have a shelf life, after the pharmaceutical package 210 is assembled, of at least one year, alternatively at least two years.
[271 ] Optionally for any of the embodiments, the shelf life is measured at 3°C, alternatively at 4°C or higher, alternatively at 20°C or higher, alternatively at 23°C, alternatively at 40 °C.
[272] Optionally for any of the embodiments, the pH of the fluid composition is between 5 and 6 and the thickness by TEM of the protective coating or layer is at least 80 nm at the end of the shelf life. Alternatively, the pH of the fluid composition is between 6 and 7 and the thickness by TEM of the protective coating or layer is at least 80 nm at the end of the shelf life. Alternatively, the pH of the fluid composition is
between 7 and 8 and the thickness by TEM of the protective coating or layer is at least 80 nm at the end of the shelf life. Alternatively, the pH of the fluid composition is between 8 and 9 and the thickness by TEM of the protective coating or layer is at least 80 nm at the end of the shelf life. Alternatively, the pH of the fluid composition is between 5 and 6 and the thickness by TEM of the protective coating or layer is at least 150 nm at the end of the shelf life. Alternatively, the pH of the fluid composition is between 6 and 7 and the thickness by TEM of the protective coating or layer is at least 150 nm at the end of the shelf life. Alternatively, the pH of the fluid composition is between 7 and 8 and the thickness by TEM of the protective coating or layer is at least 150 nm at the end of the shelf life. Alternatively, the pH of the fluid composition is between 8 and 9 and the thickness by TEM of the protective coating or layer is at least 150 nm at the end of the shelf life.
[273] Optionally for any of the embodiments, the fluid composition removes the protective coating or layer at a rate of 1 nm or less of lubricity and/or protective coating or layer thickness per 44 hours of contact with the fluid composition 200 nm per year), alternatively 1 nm or less of lubricity and/or protective coating or layer thickness per 88 hours of contact with the fluid composition (100 nm per year), alternatively 1 nm or less of lubricity and/or protective coating or layer thickness per 175 hours of contact with the fluid composition (50 nm per year), alternatively 1 nm or less of lubricity and/or protective coating or layer thickness per 250 hours of contact with the fluid composition (35 nm per year), alternatively 1 nm or less of lubricity and/or protective coating or layer thickness per 350 hours of contact with the fluid composition 25 nm per year). The rate of removing the protective coating or layer can be determined by TEM from samples exposed to the fluid composition for known periods.
[274] Optionally for any of the embodiments, the protective coating or layer is effective to provide a lower frictional resistance than the uncoated interior surface 16. Preferably the frictional resistance is reduced by at least 25 %, more preferably by at least 45%, even more preferably by at least 60% in comparison to the uncoated interior surface 16. For example, the protective coating or layer preferably is effective to reduce the frictional resistance between a portion of the wall contacted by the fluid composition
and a relatively sliding part 36 after the pharmaceutical package 210 is assembled. Preferably, the protective coating or layer is effective to reduce the frictional resistance between the wall and a relatively sliding part 36 at least two years after the pharmaceutical package 210 is assembled.
[275] Optionally for any of the embodiments, the fluid composition optionally can comprise a member or a combination of two or more members selected from the group consisting of the compositions described in the claims.
[276] As several examples, the fluid composition can be an inhalation anesthetic, a drug, or a diagnostic test material. Any of these fluid compositions can be an injectable material, a volatile material capable of being inhaled, or otherwise capable of being introduced into a subject.
[277] In the embodiment of FIGS. 1 and 2 in particular, the pharmaceutical package 210 can be a syringe. The syringe can comprise a syringe barrel or wall 14 and a stopper, O-ring, plunger tip or piston 36. The wall can define at least a portion of the syringe barrel or wall 14syringe barrel or wall 14syringe barrel or wall 14. The stopper, O-ring, plunger tip or piston 36 can be a relatively sliding part of the syringe, with respect to the syringe barrel or wall 14. The term "syringe," however, is broadly defined to include cartridges, injection "pens," and other types of barrels or reservoirs adapted to be assembled with one or more other components to provide a functional syringe. "Syringe" is also broadly defined to include related articles such as auto-injectors, which provide a mechanism for dispensing the contents.
[278] Another aspect of the invention is an article such as any pharmaceutical package or other vessel such as the vial 170 as shown in FIG. 8.
[279] The wall has an inner or interior surface 16.
[280] The fluid composition is contained in the lumen and has a pH between 5 and 9.
[281 ] The barrier coating or layer 30 is made at least in part of SiOx, wherein x is from 1 .5 to 2.9, from 2 to 1000 nm thick. The barrier coating or layer 30 of SiOx has an interior surface 220 facing the lumen 212 and an outer surface 222 facing the wall inner or interior surface 16. The barrier coating or layer 30 is effective to reduce the ingress
of atmospheric gas into the lumen 212, compared to an uncoated container otherwise the same as the pharmaceutical package or other vessel 210.
[282] The protective coating or layer can be made of a parylene or halogenated polymer, for example the fluorinated Parylene previously described. Alternatively, the protective coating or layer can be made at least in part of SiOxCy or SiNxCy where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3. The protective coating or layer has an interior surface facing the lumen and an outer surface facing the barrier coating or layer 30. The protective coating or layer can be formed by chemical vapor deposition of a precursor selected from a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors. One specific example of a suitable protective coating or layer precursor of this type is octamethylcyclotetrasiloxane or OMCTS. Other specific examples of precursors within this broad definition are provided elsewhere in this specification.
[283] The rate of erosion, dissolution, or leaching (different names for related concepts) of the protective coating or layer, if directly contacted by the fluid composition, is less than the rate of erosion of the barrier coating or layer 30, if directly contacted by the fluid composition.
[284] The protective coating or layer is effective to isolate the fluid composition from the barrier coating or layer 30, at least for sufficient time to allow the barrier coating to act as a barrier during the shelf life of the pharmaceutical package or other vessel 210.
[285] Still another aspect of the invention, again illustrated by Figs. 24-26, is a pharmaceutical package or other vessel 210 including a thermoplastic wall having an inner or interior surface 220 enclosing a lumen 212. A fluid composition contained in the lumen 212 has a pH greater than 5.
[286] A barrier coating or layer 30 of SiOx, in which x is between 1 .5 and 2.9, is applied by plasma enhanced chemical vapor deposition (PECVD) directly or indirectly to the thermoplastic wall so that in the filled pharmaceutical package or other vessel 210 the barrier coating or layer 30 is located between the inner or interior surface 220 of the
thermoplastic wall and the fluid composition. The barrier coating or layer 30 of SiOx is supported by the thermoplastic wall. The barrier coating or layer 30 has the characteristic of being subject to being measurably diminished in barrier improvement factor in less than six months as a result of attack by the fluid composition. The barrier coating or layer 30 as described elsewhere in this specification, or in U.S. Patent No. 7,985,188, can be used in any embodiment.
[287] The barrier improvement factor (BIF) of the barrier layer can be determined by providing two groups of identical containers, adding a barrier layer to one group of containers, testing a barrier property (such as the rate of outgassing in micrograms per minute or another suitable measure) on containers having a barrier, doing the same test on containers lacking a barrier, and taking a ratio of the properties of the materials with versus without a barrier. For example, if the rate of outgassing through the barrier is one-third the rate of outgassing without a barrier, the barrier has a BIF of 3.
[288] A protective coating or layer of SiOxCy, in which x is between 0.5 and 2.4 and y is between 0.6 and 3, is applied by PECVD directly or indirectly to the barrier coating or layer 30 so it is located between the barrier coating or layer 30 and the fluid composition in the finished article. The protective coating or layer is supported by the thermoplastic wall. The protective coating or layer is effective to keep the barrier coating or layer 30 at least substantially undissolved as a result of attack by the fluid composition for a period of at least six months.
[289] Any embodiment can further optionally include a lubricity layer 287. The lubricity layer 287 can be applied between the protective coating or layer and the lumen. Lubricity layers 287 as described elsewhere in this specification, or in U.S. Patent No. 7,985,188, can be used in any embodiment.
[290] Any embodiment can further optionally include a further coating applied adjacent to the inner surface of the protective coating or layer, the further coating having an outer surface facing the interior surface of the thermoplastic wall and an inner surface facing the lumen.
[291 ] Optionally, any embodiment can further include a fluid composition in contact with the protective coating or layer
[292] The protective and lubricity layers 286 and 287 of any embodiment can be either separate layers with a sharp transition or a single, graduated layer that transitions between the protective coating or layer and the lubricity layer 287, without a sharp interface between them.
[293] Optionally an FTIR absorbance spectrum of the protective coating or layer of any organosilicon embodiment has a ratio greater than 0.75 between the maximum amplitude of the Si-O-Si symmetrical stretch peak normally located between about 1000 and 1040 cm-1 , and the maximum amplitude of the Si-O-Si assymmetric stretch peak normally located between about 1060 and about 1 100 cm-1 . Alternatively in any embodiment, this ratio can be at least 0.8, or at least 0.9, or at least 1 .0, or at least 1 .1 , or at least 1 .2. Alternatively in any embodiment, this ratio can be at most 1 .7, or at most 1 .6, or at most 1 .5, or at most 1 .4, or at most 1 .3. Any minimum ratio stated here can be combined with any maximum ratio stated here, as an alternative embodiment of the invention.
[294] Optionally, in any embodiment the protective coating or layer, in the absence of the medicament, has a non-oily appearance. This appearance has been observed in some instances to distinguish an effective protective coating or layer from a lubricity layer, which in some instances has been observed to have an oily (i.e. shiny) appearance.
[295] Optionally, in any embodiment the silicon dissolution rate by a 50 mM potassium phosphate buffer diluted in water for injection, adjusted to pH 8 with concentrated nitric acid, and containing 0.2 wt. % polysorbate-80 surfactant, (measured in the absence of the medicament, to avoid changing the dissolution reagent), at 40 °C, is less than 170 ppb/day. (Polysorbate-80 is a common ingredient of pharmaceutical preparations, available for example as Tween®-80 from Uniqema Americas LLC, Wilmington Delaware.) As will be seen from the working examples, the silicon dissolution rate is measured by determining the total silicon leached from the vessel into its contents, and does not distinguish between the silicon derived from the protective coating or layer, the lubricity layer 287, the barrier coating or layer 30, or other materials present.
[296] Optionally, in any embodiment the silicon dissolution rate is less than 160 ppb/day, or less than 140 ppb/day, or less than 120 ppb/day, or less than 100 ppb/day, or less than 90 ppb/day, or less than 80 ppb/day. Optionally, in any embodiment the silicon dissolution rate is more than 10 ppb/day, or more than 20 ppb/day, or more than 30 ppb/day, or more than 40 ppb/day, or more than 50 ppb/day, or more than 60 ppb/day. Any minimum rate stated here can be combined with any maximum rate stated here, as an alternative embodiment of the invention.
[297] Optionally, in any embodiment the total silicon content of the protective coating or layer and barrier coating, upon dissolution into a test composition with a pH of 8 from the vessel, is less than 66 ppm, or less than 60 ppm, or less than 50 ppm, or less than 40 ppm, or less than 30 ppm, or less than 20 ppm.
[298] Optionally, in any embodiment the calculated shelf life of the package (total Si / Si dissolution rate) is more than six months, or more than 1 year, or more than 18 months, or more than 2 years, or more than 2½ years, or more than 3 years, or more than 4 years, or more than 5 years, or more than 10 years, or more than 20 years. Optionally, in any embodiment the calculated shelf life of the package (total Si / Si dissolution rate) is less than 60 years.
[299] Any minimum time stated here can be combined with any maximum time stated here, as an alternative embodiment of the invention.
[300] Optionally, in any embodiment the protective coating or layer is applied by PECVD at a power level per of more than 22,000 kJ/kg of mass of precursor, or more than 30,000 kJ/kg of mass of precursor, or more than 40,000 kJ/kg of mass of precursor, or more than 50,000 kJ/kg of mass of precursor, or more than 60,000 kJ/kg of mass of precursor, or more than 62,000 kJ/kg of mass of precursor, or more than 70,000 kJ/kg of mass of precursor, or more than 80,000 kJ/kg of mass of precursor, or more than 100,000 kJ/kg of mass of precursor, or more than 200,000 kJ/kg of mass of precursor, or more than 300,000 kJ/kg of mass of precursor, or more than 400,000 kJ/kg of mass of precursor, or more than 500,000 kJ/kg of mass of precursor.
[301 ] Optionally, in any embodiment the protective coating or layer is applied by PECVD at a power level per of less than 2,000,000 kJ/kg of mass of precursor, or less
thanl ,000,000 kJ/kg of mass of precursor, or less than 700,000 kJ/kg of mass of precursor, or less than 500,000 kJ/kg of mass of precursor, or less than 100,000 kJ/kg of mass of precursor, or less than 90,000 kJ/kg of mass of precursor, or less than 81 ,000 kJ/kg of mass of precursor.
[302] Optionally, in any embodiment, the thermoplastic wall is a syringe barrel. A stopper, O-ring, plunger tip or piston is positioned for sliding in the barrel and a lubricity coating or layer is present on at least a portion of the stopper, O-ring, plunger tip or piston.
[303] Optionally, in any embodiment, the lubricity coating or layer is configured to provide a lower piston sliding force or breakout force than the uncoated substrate.
[304] Optionally, in any embodiment, the lubricity layer has one of the atomic ratios previously defined for the lubricity and/or protective coating or layer, measured by X-ray photoelectron spectroscopy (XPS). The lubricity layer has a thickness by transmission electron microscopy (TEM) between 10 and 500 nm; the lubricity layer deposited by plasma enhanced chemical vapor deposition (PECVD) under conditions effective to form a coating from a precursor selected from a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors.
[305] Even another aspect of the invention is a composite material including a substrate such as a wall, a barrier coating or layer 30 disposed on the substrate or wall, and a passivation layer or protective coating or layer on the barrier layer or coating 288. Several examples of articles made from such a composite material are a syringe barrel, a vial, and a medical device of any kind. The passivation layer or protective coating or layer is deposited by PECVD using a source material comprising a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, a silatrane, a silquasilatrane, a silproatrane, an azasilatrane, an azasilquasiatrane, an azasilproatrane, or a combination of any two or more of these precursors.
[306] The passivation layer or protective coating or layer, taking into account the H atoms, may thus in one aspect have the formula SiwOxCyHz, for example where w is 1 , x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is from about 2 to about 9. Typically, expressed as the formula SiwOxCy, the atomic ratios of Si, O, and C are, as several options:
Si 100 : 0 80-130 : C 90-150,
Si 100 : O 90-120 : C 90-140, or
Si 100 : O 92-107 : C 1 16-133.
[307] The passivation layer or protective coating or layer shows an O-Parameter measured with attenuated total reflection (ATR) of less than 0.4, measured as:
O-Parameter = Intensity at 1253 cm"1
Maximum intensity in the range 1000 to 1 100 cm"1.
The O-Parameter is defined in U.S. Patent No. 8,067,070, which claims an O-parameter value of most broadly from 0.4 to 0.9. It can be measured from physical analysis of an FTIR amplitude versus wave number plot to find the numerator and denominator of the above expression, as shown in Fig. 27, which is the same as Fig. 5 of U.S. Patent No. 8,067,070, except annotated to show interpolation of the wave number and absorbance scales to arrive at an absorbance at 1253 cm"1 of .0424 and a maximum absorbance at 1000 to 1 100 cm"1 of 0.08, resulting in a calculated O-parameter of 0.53. The O- Parameter can also be measured from digital wave number versus absorbance data.
[308] U.S. Patent No. 8,067,070 asserts that the claimed O-parameter range provides a superior protective coating or layer, relying on experiments only with HMDSO and HMDSN, which are both non-cyclic siloxanes. Surprisingly, it has been found by the present inventors that if the PECVD precursor is a cyclic siloxane, for example OMCTS, O-parameters outside the ranges claimed in U.S. Patent No.
8,067,070, using OMCTS, provide even better results than are obtained in U.S. Patent No. 8,067,070 with HMDSO.
[309] Alternatively in the embodiment, the O-parameter has a value of from 0.1 to 0.39, or from 0.15 to 0.37, or from 0.17 to 0.35.
[310] Even another aspect of the invention is a composite material as just described, exemplified in FIGS. 24-26, wherein the passivation layer shows an N- Parameter measured with attenuated total reflection (ATR) of less than 0.7, measured as:
N-Parameter = Intensity at 840 cm"1
Intensity at 799 cm"1.
The N-Parameter is also described in U.S. Patent No. 8,067,070, and is measured analogously to the O-Parameter except that intensities at two specific wave numbers are used - neither of these wave numbers is a range. U.S. Patent No. 8,067,070 claims a passivation layer with an N-Parameter of 0.7 to 1 .6. Again, the present inventors have made better coatings employing a protective coating or layer having an N- Parameter lower than 0.7, as described above. Alternatively, the N-parameter has a value of at least 0.3, or from 0.4 to 0.6, or at least 0.53.
Theory of Operation
[31 1 ] The inventors offer the following theory of operation of the protective coating or layer described here. The invention is not limited by the accuracy of this theory or to the embodiments predictable by use of this theory.
[312] The dissolution rate of the SiOx barrier layer is believed to be dependent on SiO bonding within the layer. Oxygen bonding sites (silanols) are believed to increase the dissolution rate.
[313] It is believed that the OMCTS-based protective coating or layer bonds with the silanol sites on the SiOx barrier layer to "heal" or passivate the SiOx surface and thus dramatically reduces the dissolution rate. In this hypothesis, the thickness of the
OMCTS layer is not the primary means of protection - the primary means is passivation of the SiOx surface. It is contemplated that a protective coating or layer as described in this specification can be improved by increasing the crosslink density of the protective coating or layer.
Additional Embodiments
[314] The protective coating or layer described in this specification can be applied in many different ways. For one example, the low-pressure PECVD process described in U.S. Patent No. 7,985,188 can be used. For another example, instead of using low- pressure PECVD, atmospheric PECVD can be employed to deposit the protective coating or layer. For another example, the coating can be simply evaporated and allowed to deposit on the SiOx layer to be protected. For another example, the coating can be sputtered on the SiOx layer to be protected. For still another example, the protective coating or layer can be applied from a liquid medium used to rinse or wash the SiOx layer.
[315] Other precursors and methods can be used to apply the protective coating or layer or passivating treatment. For example, hexamethylene disilazane (HMDZ) can be used as the precursor. HMDZ has the advantage of containing no oxygen in its molecular structure. This passivation treatment is contemplated to be a surface treatment of the SiOx barrier layer with HMDZ. To slow down and/or eliminate the decomposition of the silicon dioxide coatings at silanol bonding sites, the coating must be passivated. It is contemplated that passivation of the surface with HMDZ (and optionally application of a few mono layers of the HMDZ-derived coating) will result in a toughening of the surface against dissolution, resulting in reduced decomposition. It is contemplated that HMDZ will react with the -OH sites that are present in the silicon dioxide coating, resulting in the evolution of NH3 and bonding of S-(CH3)3 to the silicon (it is contemplated that hydrogen atoms will be evolved and bond with nitrogen from the HMDZ to produce NH3).
[316] It is contemplated that this HMDZ passivation can be accomplished through several possible paths.
[317] One contemplated path is dehydration/vaporization of the HMDZ at ambient temperature. First, an SiOx surface is deposited, for example using hexamethylene disiloxane (HMDSO). The as-coated silicon dioxide surface is then reacted with HMDZ vapor. In an embodiment, as soon as the SiOx surface is deposited onto the article of interest, the vacuum is maintained. The HMDSO and oxygen are pumped away and a base vacuum is achieved. Once base vacuum is achieved, HMDZ vapor is flowed over the surface of the silicon dioxide (as coated on the part of interest) at pressures from the mTorr range to many Torr. The HMDZ is then pumped away (with the resulting NH3 that is a byproduct of the reaction). The amount of NH3 in the gas stream can be monitored (with a residual gas analyzer - RGA - as an example) and when there is no more NH3 detected, the reaction is complete. The part is then vented to atmosphere (with a clean dry gas or nitrogen). The resulting surface is then found to have been passivated. It is contemplated that this method optionally can be accomplished without forming a plasma.
[318] Alternatively, after formation of the SiOx barrier coating or layer 30), the vacuum can be broken before dehydration/vaporization of the HMDZ. Dehydration/vaporization of the HMDZ can then be carried out in either the same apparatus used for formation of the SiOx barrier coating or layer 30) or different apparatus.
[319] Dehydration/vaporization of HMDZ at an elevated temperature is also contemplated. The above process can alternatively be carried out at an elevated temperature exceeding room temperature up to about 150°C. The maximum temperature is determined by the material from which the coated part is constructed. An upper temperature should be selected that will not distort or otherwise damage the part being coated.
[320] Dehydration/ vaporization of HMDZ with a plasma assist is also contemplated. After carrying out any of the above embodiments of dehydration/vaporization, once the HMDZ vapor is admitted into the part, a plasma is
generated. The plasma power can range from a few watts to 100+ watts (similar powers as used to deposit the SiOx). The above is not limited to HMDZ and could be applicable to any molecule that will react with hydrogen, for example any of the nitrogen-containing precursors described in this specification.
[321 ] Another way of applying the protective coating or layer is to apply as the protective coating or layer an amorphous carbon or parylene or halogenated polymer coating, or a combination of the two.
[322] Amorphous carbon coatings can be formed by PECVD using a saturated hydrocarbon, (e.g. methane or propane) or an unsaturated hydrocarbon (e.g. ethylene, acetylene) as a precursor for plasma polymerization, parylene or halogenated polymer coatings can be derived from parylene or halogenated polymers (for example, hexafluoroethylene or tetrafluoroethylene). Either type of coating, or a combination of both, can be deposited by vacuum PECVD or atmospheric pressure PECVD. It is contemplated that that an amorphous carbon and/or parylene or halogenated polymer coating will provide better passivation of an SiOx barrier layer than a siloxane coating since an amorphous carbon and/or parylene or halogenated polymer coating will not contain silanol bonds.
[323] It is further contemplated that fluorosilicon precursors can be used to provide a protective coating or layer over an SiOx barrier layer. This can be carried out by using as a precursor a fluorinated silane precursor such as hexafluorosilane and a PECVD process. The resulting coating would also be expected to be a non-wetting coating.
[324] It is further contemplated that any embodiment of the protective coating or layer processes described in this specification can also be carried out without using the article to be coated to contain the plasma. For example, external surfaces of medical devices, for example catheters, surgical instruments, closures, and others can be protected or passivated by sputtering the coating, employing a radio frequency target.
[325] Yet another coating modality contemplated for protecting or passivating an SiOx barrier layer is coating the barrier layer using a polyamidoamine epichlorohydrin resin. For example, the barrier coated part can be dip coated in a fluid polyamidoamine epichlorohydrin resin melt, solution or dispersion and cured by autoclaving or other
heating at a temperature between 60 and 100°C. It is contemplated that a coating of polyamidoamine epichlorohydrin resin can be preferentially used in aqueous environments between pH 5-8, as such resins are known to provide high wet strength in paper in that pH range. Wet strength is the ability to maintain mechanical strength of paper subjected to complete water soaking for extended periods of time, so it is contemplated that a coating of polyamidoamine epichlorohydrin resin on an SiOx barrier layer will have similar resistance to dissolution in aqueous media. It is also contemplated that, because polyamidoamine epichlorohydrin resin imparts a lubricity improvement to paper, it will also provide lubricity in the form of a coating on a thermoplastic surface made of, for example, COC or COP.
[326] Even another approach for protecting an SiOx layer is to apply as a protective coating or layer a liquid-applied coating of a polyfluoroalkyl ether, followed by atmospheric plasma curing the protective coating or layer. For example, it is contemplated that the process practiced under the trademark TriboGlide®, described in this specification, can be used to provide a protective coating or layer that is also a lubricity layer, as TriboGlide® is conventionally used to provide lubricity.
PECVD APPARATUS AND METHODS FOR PROTECTIVE COATING OR LAYER
[327] Suitable methods and apparatus for applying a barrier or protective coating or layer such as 90 of SiOx, SiOxCy, or SiNxCy to a substrate such as the vessel 80 (FIG. 1 ) or a vial are described, for example, in U.S. Patent No. 7,985,188 or the EP applications cited in paragraph [002], under conditions effective to form a coating or layer.
[328] For depositing a protective coating or layer, a precursor feed or process gas can be employed having a standard volume ratio of, for example:
• from 0.5 to 10 standard volumes, optionally from 1 to 6 standard volumes, optionally from 2 to 4 standard volumes, optionally equal to or less than 6 standard volumes, optionally equal to or less than 2.5 standard volumes, optionally equal to or less than 1 .5 standard volumes, optionally equal to
or less than 1 .25 standard volumes of the precursor, for example OMCTS or one of the other precursors of any embodiment;
• from 0 to 100 standard volumes, optionally from 1 to 80 standard volumes, optionally from 5 to 100 standard volumes, optionally from 10 to 70 standard volumes, of a carrier or diluent gas of any embodiment;
• from 0.1 to 10 standard volumes, optionally from 0.1 to 2 standard volumes, optionally from 0.2 to 1 .5 standard volumes, optionally from 0.2 to 1 standard volumes, optionally from 0.5 to 1 .5 standard volumes, optionally from 0.8 to 1 .2 standard volumes of an oxidizing agent.
[329] Another embodiment is a protective coating or layer of the type made by the above process.
[330] Another embodiment is a vessel such as the vessel 80 (FIG. 1 ) including a lumen defined by a surface defining a substrate. A protective coating or layer is present on at least a portion of the substrate, typically deposited over an SiOx barrier layer to protect the barrier layer from dissolution. The protective coating or layer is made by the previously defined process.
Precursors for PECVD protective coating or layer
[331 ] The organosilicon precursor for the protective coating or layer can include any of the following precursors useful for PECVD. The precursor for the PECVD protective coating or layer of the present invention is broadly defined as an organometallic precursor. An organometallic precursor is defined in this specification as comprehending compounds of metal elements from Group III and/or Group IV of the Periodic Table having organic residues, for example hydrocarbon, aminocarbon or oxycarbon residues. Organometallic compounds as presently defined include any precursor having organic moieties bonded to silicon or other Group III/ IV metal atoms directly, or optionally bonded through oxygen or nitrogen atoms. The relevant elements of Group III of the Periodic Table are Boron, Aluminum, Gallium, Indium, Thallium, Scandium, Yttrium, and Lanthanum, Aluminum and Boron being preferred. The
relevant elements of Group IV of the Periodic Table are Silicon, Germanium, Tin, Lead, Titanium, Zirconium, Hafnium, and Thorium, with Silicon and Tin being preferred. Other volatile organic compounds can also be contemplated. However, organosilicon compounds are preferred for performing present invention.
[332] An organosilicon precursor is contemplated, where an "organosilicon precursor" is defined throughout this specification most broadly as a compound having at least one of the linkages:
— O— Si— C— H
[333] The first structure immediately above is a tetravalent silicon atom connected to an oxygen atom and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom). The second structure immediately above is a tetravalent silicon atom connected to an -NH- linkage and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom). Optionally, the organosilicon precursor is selected from the group consisting of a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, and a combination of any two or more of these precursors. Also contemplated as a precursor, though not within the two formulas immediately above, is an alkyl trimethoxysilane.
[334] If an oxygen-containing precursor (for example a Siloxane) is used, a representative predicted empirical composition resulting from PECVD under conditions forming a hydrophobic or lubricating protective coating or layer would be SiwOxCyHz or its equivalent SiOxCy as defined in the Definition Section, while a representative predicted empirical composition resulting from PECVD under conditions forming a
barrier coating or layer 30) would be SiOx, where x in this formula is from about 1 .5 to about 2.9. If a nitrogen-containing precursor (for example a silazane) is used, the predicted composition would be Siw*Nx*Cy*Hz*, i.e. in SiwOxCyHz or its equivalent SiOxCy as specified in the Definition Section, O is replaced by N and the indices for H are adapted to the higher valency of N as compared to O (3 instead of 2. The latter adaptation will generally follow the ratio of w, x, y and z in a Siloxane to the corresponding indices in its aza counterpart. In a particular aspect of the invention, Siw*Nx*Cy*Hz* (or its equivalent SiNx*Cy*) in which w*, x*, y*, and z* are defined the same as w, x, y, and z for the siloxane counterparts, but for an optional deviation in the number of hydrogen atoms.
[335] One type of precursor starting material having the above empirical formula is a linear siloxane, for example a material having the following formula:
in which each R is independently selected from alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others, and n is 1 , 2, 3, 4, or greater, optionally two or greater. Several examples of contemplated linear siloxanes are hexamethyldisiloxane (HMDSO),
octamethyltrisiloxane,
decamethyltetrasiloxane,
dodecamethylpentasiloxane,
or combinations of two or more of these. The analogous silazanes in which -NH- is substituted for the oxygen atom in the above structure are also useful for making analogous protective coating or layers or layers. Several examples of contemplated linear silazanes are octamethyltnsilazane, decamethyltetrasilazane, or combinations of two or more of these.
[336] Another type of precursor starting material, among the preferred starting materials in the present context, is a monocyclic siloxane, for example a material having the following structural formula:
in which R is defined as for the linear structure and "a" is from 3 to about 10, or the analogous monocyclic silazanes. Several examples of contemplated hetero-substituted and unsubstituted monocyclic siloxanes and silazanes include
1 ,3,5-trimethyl-1 ,3,5-tris(3,3,3-trifluoropropyl)methyl]cyclotrisiloxane
2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane,
pentamethylcyclopentasiloxane,
pentavinylpentamethylcyclopentasiloxane,
hexamethylcyclotrisiloxane,
hexaphenylcyclotrisiloxane,
octamethylcyclotetrasiloxane (OMCTS),
octaphenylcyclotetrasiloxane,
decamethylcyclopentasiloxane
dodecamethylcyclohexasiloxane,
methyl(3,3,3-trifluoropropl)cyclosiloxane,
Cyclic organosilazanes are also contemplated, such as
Octamethylcyclotetrasilazane,
1 ,3,5,7-tetravinyl-1 ,3,5,7-tetramethylcyclotetrasilazane hexamethylcyclotnsilazane, octamethylcyclotetrasilazane,
decamethylcyclopentasilazane,
dodecamethylcyclohexasilazane, or
combinations of any two or more of these.
[337] Another type of precursor starting material, among the preferred starting materials in the present context, is a polycyclic siloxane, for example a material having one of the followin structural formulas:
in which Y can be oxygen or nitrogen, E is silicon, and Z is a hydrogen atom or an organic substituent, for example alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others. When each Y is oxygen, the respective structures, from left to right, are a Silatrane, a Silquasilatrane, and a Silproatrane. When Y is nitrogen, the respective structures are an azasilatrane, an azasilquasiatrane, and an azasilproatrane.
[338] Another type of polycyclic siloxane precursor starting material, among the preferred starting materials in the present context, is a polysilsesquioxane, with the empirical formula RSiOi.5 and the structural formula:
in which each R is a hydrogen atom or an organic substituent, for example alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others. Two commercial materials of this sort are SST-eM01 poly(methylsilsesquioxane), in which each R is methyl, and SST-3MH1 .1 poly(Methyl-Hydridosilsesquioxane), in which 90% of the R groups are methyl, 10% are hydrogen atoms. This material is available in a 10% solution in tetrahydrofuran, for example. Combinations of two or more of these are also contemplated. Other examples of a contemplated precursor are methylsilatrane, CAS No. 2288-13-3, in which each Y is oxygen and Z is methyl, methylazasilatrane, poly(methylsilsesquioxane) (for example SST-eM01 poly(methylsilsesquioxane)), in which each R optionally can be methyl, SST-3MH1 .1 poly(Methyl- Hydridosilsesquioxane) (for example SST-3MH1 .1 poly(Methyl-Hydridosilsesquioxane)), in which 90% of the R groups are methyl and 10% are hydrogen atoms, or a combination of any two or more of these.
[339] The analogous polysilsesquiazanes in which -NH- is substituted for the oxygen atom in the above structure are also useful for making analogous protective coating or layer. Examples of contemplated polysilsesquiazanes are a poly(methylsilsesquiazane), in which each R is methyl, and a poly(Methyl- Hydridosilsesquiazane, in which 90% of the R groups are methyl, 10% are hydrogen atoms. Combinations of two or more of these are also contemplated.
[340] One particularly contemplated precursor for the barrier coating or layer 30) according to the present invention is a linear siloxane, for example is HMDSO. One particularly contemplated precursor for the lubricity coating or layer and the protective coating or layer according to the present invention is a cyclic siloxane, for example octamethylcyclotetrasiloxane (OMCTS).
[341 ] It is believed that the OMCTS or other cyclic siloxane molecule provides several advantages over other siloxane materials. First, its ring structure results in a less dense protective coating or layer (as compared to protective coating or layer prepared from HMDSO). The molecule also allows selective ionization so that the final structure and chemical composition of the protective coating or layer can be directly controlled through the application of the plasma power. Other organosilicon molecules
are readily ionized (fractured) so that it is more difficult to retain the original structure of the molecule.
[342] In any of the PECVD methods according to the present invention, the applying step optionally can be carried out by vaporizing the precursor and providing it in the vicinity of the substrate. For example, OMCTS is usually vaporized by heating it to about 50 °C before applying it to the PECVD apparatus.
[343] Cyclic organosilicon precursors, in particular monocyclic organosilicon precursors (like the monocyclic precursors listed elsewhere in present description), and specifically OMCTS, are particularly suitable to achieve a protective coating or layer.
Other Components of PECVD Reaction Mixture and Ratios of Components For protective coating or layer
[344] Generally, for a protective coating or layer, O2 can be present in an amount (which can, for example be expressed by the flow rate in seem) which is less than one order of magnitude greater than the organosilicon amount. In contrast, in order to achieve a barrier coating or layer 30), the amount of O2 typically is at least one order of magnitude higher than the amount of organosilicon precursor. In particular, the volume ratio (in seem) of organosilicon precursor to O2 for a protective coating or layer can be in the range from 0.1 : 1 to 10 : 1 , optionally in the range from 0.3 : 1 to 8 : 1 , optionally in the range from 0.5 : 1 to 5 : 1 , optionally from 1 : 1 to 3 : 1 . The presence of the precursor and O2 in the volume ratios as given in Tables 9-1 1 is specifically suitable to achieve a protective coating or layer.
[345] In one aspect of the invention, a carrier or diluent gas is absent in the reaction mixture, in another aspect of the invention, it is present. Suitable carrier or diluent gases include Argon, Helium and other noble gases such as Neon and Xenon. When the carrier or diluent gas is present in the reaction mixture, it is typically present in a volume (in seem) exceeding the volume of the organosilicon precursor. For example, the ratio of the organosilicon precursor to carrier or diluent gas can be from 1 : 1 to 1 : 50, optionally from 1 : 5 to 1 : 40, optionally from 1 : 10 to 1 : 30. One function of the carrier or diluent gas is to dilute the reactants in the plasma, encouraging the formation
of a coating on the substrate instead of powdered reaction products that do not adhere to the substrate and are largely removed with the exhaust gases.
[346] Since the addition of Argon gas improves the lubricity and/or protective performance (see the working examples below), it is believed that additional ionization of the molecule in the presence of Argon contributes to providing lubricity. The Si-O-Si bonds of the molecule have a high bond energy followed by the Si-C, with the C-H bonds being the weakest. Lubricity and/or protective appears to be achieved when a portion of the C-H bonds are broken. This allows the connecting (cross-linking) of the structure as it grows. Addition of oxygen (with the Argon) is understood to enhance this process. A small amount of oxygen can also provide C-0 bonding to which other molecules can bond. The combination of breaking C-H bonds and adding oxygen all at low pressure and power leads to a chemical structure that is solid while providing lubricity.
[347] In any of embodiments, one preferred combination of process gases includes octamethylcyclotetrasiloxane (OMCTS) or another cyclic siloxane as the precursor, in the presence of oxygen as an oxidizing gas and argon as a carrier or diluent gas. Without being bound to the accuracy of this theory, the inventors believe this particular combination is effective for the following reasons. The presence of 02, N20, or another oxidizing gas and/or of a carrier or diluent gas, in particular of a carrier or diluent gas, for example a noble gas, for example Argon (Ar), is contemplated to improve the resulting protective coating or layer.
[348] Some non-exhaustive alternative selections and suitable proportions of the precursor vapor, oxygen, and a carrier or diluent gas are provided below.
OMCTS: 0.5 - 5.0 seem
Oxygen: 0.1 - 5.0 seem
Argon: 1 .0 - 20 seem
PECVD Apparatus for Forming protective coating or layer
[349] The low-pressure PECVD process described in U.S. Patent No. 7,985,188 can be used to provide the barrier, lubricity, and protective coating or layers described in this specification. A brief synopsis of that process follows.
[350] A PECVD apparatus suitable for performing the present invention includes a vessel holder, an inner electrode, an outer electrode, and a power supply. A vessel seated on the vessel holder defines a plasma reaction chamber, which optionally can be a vacuum chamber. Optionally, a source of vacuum, a reactant gas source, a gas feed or a combination of two or more of these can be supplied. Optionally, a gas drain, not necessarily including a source of vacuum, is provided to transfer gas to or from the interior of a vessel seated on the port to define a closed chamber.
[351 ] The PECVD apparatus can be used for atmospheric-pressure PECVD, in which case the plasma reaction chamber does not need to function as a vacuum chamber.
[352] Referring to FIGS. 1 and 2 of U.S. Patent No. 7,985,188, the vessel holder 50 optionally can comprise a gas inlet port 104 for conveying a gas into a vessel seated on the vessel port. The gas inlet port 104 has a sliding seal provided by at least one O-ring 106, or two O-rings in series, or three O-rings in series, which can seat against a cylindrical probe 108 when the probe 108 is inserted through the gas inlet port 104. The probe 108 can be a gas inlet conduit that extends to a gas delivery port at its distal end 1 10. The distal end 1 10 of the illustrated embodiment can be inserted deep into the vessel 80 for providing one or more PECVD reactants and other precursor feed or process gases.
[353] FIG. 1 1 of U.S. Patent No. 7,985,188 shows additional optional details of the coating or layer station 28 that are usable, for example, with all the illustrated embodiments. The coating or layer station 28 can also have a main vacuum valve 574 in its vacuum line 576 leading to the pressure sensor 152. A manual bypass valve 578 is provided in the bypass line 580. A vent valve 582 controls flow at the vent 404.
[354] Flow out of the PECVD gas or precursor source 144 is controlled by a main reactant gas valve 584 regulating flow through the main reactant feed line 586. One component of the gas source 144 is the organosilicon liquid reservoir 588. The contents of the reservoir 588 are drawn through the organosilicon capillary line 590, which is provided at a suitable length to provide the desired flow rate. Flow of organosilicon vapor is controlled by the organosilicon shut-off valve 592. Pressure is applied to the headspace 614 of the liquid reservoir 588, for example a pressure in the range of 0-15 psi (0 to 78 cm. Hg), from a pressure source 616 such as pressurized air connected to the headspace 614 by a pressure line 618 to establish repeatable organosilicon liquid delivery that is not dependent on atmospheric pressure (and the fluctuations therein). The reservoir 588 is sealed and the capillary connection 620 is at the bottom of the reservoir 588 to ensure that only neat organosilicon liquid (not the pressurized gas from the headspace 614 flows through the capillary tube 590. The organosilicon liquid optionally can be heated above ambient temperature, if necessary or desirable to cause the organosilicon liquid to evaporate, forming an organosilicon vapor. To accomplish this heating, the protective coating or layer apparatus can advantageously include heated delivery lines from the exit of the precursor reservoir to as close as possible to the gas inlet into the syringe. Preheating is useful, for example, when feeding OMCTS.
[355] Oxygen is provided from the oxygen tank 594 via an oxygen feed line 596 controlled by a mass flow controller 598 and provided with an oxygen shut-off valve 600.
[356] Referring especially to FIG. 1 of U.S. Patent No. 7,985,188, the processing station 28 can include an electrode 160 fed by a radio frequency power supply 162 for providing an electric field for generating plasma within the vessel 80 during processing. In this embodiment, the probe 108 is also electrically conductive and is grounded, thus providing a counter-electrode within the vessel 80. Alternatively, in any embodiment the outer electrode 160 can be grounded and the probe 108 directly connected to the power supply 162.
[357] In the embodiment of FIG. 1 of U.S. Patent No. 7,985,188, the outer electrode 160 can either be generally cylindrical as illustrated in FIGS. 1 and 2 or a generally U- shaped elongated channel as illustrated in FIG. 1 (FIG. 2 being an embodiment of the section taken along section line A— A of FIG. 1 ). Each illustrated embodiment has one or more sidewalls, such as 164 and 166, and optionally a top end 168, disposed about the vessel 80 in close proximity.
[358] Referring to FIGS. 8 and 9 of U.S. Patent No. 7,985,188, a specific adaptation of the PECVD process is described for applying PECVD coatings to a vessel such as a syringe barrel that is open at both ends.
[359] FIGS. 8 and 9 of U.S. Patent No. 7,985,188 show a method and apparatus generally indicated at 290 for coating or layer an inner or interior surface 292 of a restricted opening 294 of a generally tubular vessel 250 to be processed, for example the restricted front opening 294 of a syringe barrel or wall 14syringe barrel or wall 14syringe barrel or wall 14, by PECVD. The previously described process is modified by connecting the restricted opening 294 to a processing vessel 296 and optionally making certain other modifications.
[360] The generally tubular vessel 250 to be processed includes an outer surface 298, an inner or inner or interior surface 16 defining a lumen 300, a larger opening 302 having an inner diameter, and a restricted opening 294 that is defined by an inner or interior surface 292 and has an inner diameter smaller than the inner diameter of the larger opening 302.
[361 ] The processing vessel 296 has a lumen 304 and a processing vessel opening 306, which optionally is the only opening, although in other embodiments a second opening can be provided that optionally is closed off during processing. The processing vessel opening 306 is connected with the restricted opening 294 of the vessel 250 to be processed to establish communication between the lumen 300 of the vessel 250 to be processed and the processing vessel lumen via the restricted opening 294.
[362] At least a partial vacuum is drawn within the lumen 300 of the vessel 250 to be processed and lumen 304 of the processing vessel 296. A PECVD reactant is flowed from the gas source 144 through the first opening 302, then through the lumen
300 of the vessel 250 to be processed, then through the restricted opening 294, then into the lumen 304 of the processing vessel 296.
[363] The PECVD reactant can be introduced through the larger opening 302 of the vessel 250 by providing a generally tubular inner electrode 308 having an interior passage 310, a proximal end 312, a distal end 314, and a distal opening 316, in an alternative embodiment multiple distal openings can be provided adjacent to the distal end 314 and communicating with the interior passage 310. The distal end of the electrode 308 can be placed adjacent to or into the larger opening 302 of the vessel 250 to be processed. A reactant gas can be fed through the distal opening 316 of the electrode 308 into the lumen 300 of the vessel 250 to be processed. The reactant will flow through the restricted opening 294, then into the lumen 304, to the extent the PECVD reactant is provided at a higher pressure than the vacuum initially drawn before introducing the PECVD reactant.
[364] Plasma 318 is generated adjacent to the restricted opening 294 under conditions effective to deposit a coating or layer of a PECVD reaction product on the inner or interior surface 292 of the restricted opening 294.
[365] More details concerning adapting the PECVD process to syringe processing are provided, for example, in U.S. Patent No. 7,985,188.
[366] Specific PECVD conditions for application of a protective coating or layer are provided below.
Plasma Conditions for protective coating or layer
[367] Typically, the plasma in the PECVD process is generated at RF frequency. For providing a protective coating or layer on the interior of a vessel by a plasma reaction carried out within the vessel, the plasma of any embodiment can be generated with an electric power of from 0.1 to 500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300 W, optionally from 1 to 250 W, optionally from 1 to 200 W, even optionally from 10 to 150 W, optionally from 20 to 150 W, for example of 40 W, optionally from 40 to 150 W, even optionally from 60 to 150 W. The ratio of the
electrode power to the plasma volume can be less than 100 W/ml, optionally is from 5 W/ml to 75 W/ml, optionally is from 6 W/ml to 60 W/ml, optionally is from 10 W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml. These power levels are suitable for applying protective coating or layers or layers to syringes, cartridges, or similar articles and sample tubes and pharmaceutical packages or other vessels of similar geometry having a void volume of 5 ml_ in which PECVD plasma is generated. It is contemplated that for larger or smaller objects the power applied, in Watts, should be increased or reduced accordingly to scale the process to the size of the substrate.
[368] Exemplary reaction conditions for preparing a protective coating or layer according to the present invention in a 3 ml sample size syringe with a 1 /8" diameter tube (open at the end) are as follows:
Flow rate ranges:
OMCTS: 0.5 - 10 seem
Oxygen: 0.1 - 10 seem
Argon: 1 .0 - 200 seem
Power: 0.1 - 500 watts
Specific Flow rates:
OMCTS: 2.0 seem
Oxygen 0.7 seem
Argon: 7.0 seem
Power: 3.5 watts
[369] The protective coating or layer and its application are described in more detail below. A method for applying the coating includes several steps. A vessel wall is provided, as is a reaction mixture comprising plasma forming gas, i.e. an organosilicon compound gas, optionally an oxidizing gas, and optionally a hydrocarbon gas.
[370] Plasma can be formed in the reaction mixture that is substantially free of hollow cathode plasma. The vessel wall is contacted with the reaction mixture, and the protective coating or layer of SiOx is deposited on at least a portion of the vessel wall.
[371 ] In certain embodiments, the generation of a uniform plasma throughout the portion of the vessel to be coated is contemplated, as it has been found in certain instances to generate a better protective coating or layer. Uniform plasma means regular plasma that does not include a substantial amount of hollow cathode plasma (which has a higher emission intensity than regular plasma and is manifested as a localized area of higher intensity interrupting the more uniform intensity of the regular plasma).
Hydrophobic Layer
[372] The protective or lubricity coating or layer of SiwOxCy or its equivalent SiOxCy also can have utility as a hydrophobic layer. A coating or layer of this kind is contemplated to be hydrophobic, independent of whether it also functions as a lubricity and/or protective coating or layer. A coating or layer or treatment is defined as "hydrophobic" if it lowers the wetting tension of a surface, compared to the corresponding uncoated or untreated surface. Hydrophobicity is thus a function of both the untreated substrate and the treatment.
[373] Suitable hydrophobic coatings or layers and their application, properties, and use are described in U.S. Patent No. 7,985,188. Dual functional protective / hydrophobic coatings or layers having the properties of both types of coatings or layers can be provided for any embodiment of the present invention.
Measurement of Coating Thickness
[374] The thickness of a PECVD coating or layer such as the protective coating or layer, the barrier coating or layer 30), the lubricity coating or layer, and/or a composite of any two or more of these layers can be measured, for example, by transmission electron microscopy (TEM). An exemplary TEM image for a lubricity and/or protective
coating or layer is shown in Fig. 21 . An exemplary TEM image for an Si02 barrier coating or layer 30) is shown in Fig. 22.
[375] The TEM can be carried out, for example, as follows. Samples can be prepared for Focused Ion Beam (FIB) cross-sectioning in two ways. Either the samples can be first coated with a thin layer of carbon (50-1 OOnm thick) and then coated with a sputtered coating or layer of platinum (50-1 OOnm thick) using a K575X Emitech protective coating or layer system, or the samples can be coated directly with the protective sputtered Pt layer. The coated samples can be placed in an FEI FIB200 FIB system. An additional coating or layer of platinum can be FIB-deposited by injection of an organometallic gas while rastering the 30kV gallium ion beam over the area of interest. The area of interest for each sample can be chosen to be a location half way down the length of the syringe barrel. Thin cross sections measuring approximately 15 m ("micrometers") long, 2 m wide and 15 m deep can be extracted from the die surface using an in-situ FIB lift-out technique. The cross sections can be attached to a 200 mesh copper TEM grid using FIB-deposited platinum. One or two windows in each section, measuring about 8 m wide, can be thinned to electron transparency using the gallium ion beam of the FEI FIB.
[376] Cross-sectional image analysis of the prepared samples can be performed utilizing either a Transmission Electron Microscope (TEM), or a Scanning Transmission Electron Microscope (STEM), or both. All imaging data can be recorded digitally. For STEM imaging, the grid with the thinned foils can be transferred to a Hitachi HD2300 dedicated STEM. Scanning transmitted electron images can be acquired at appropriate magnifications in atomic number contrast mode (ZC) and transmitted electron mode (TE). The following instrument settings can be used.
Instrument ining Transmission Electron Microscope
Manufacturer/Model Hitachi HD2300
Accelerating Voltage 200kV
Objective Aperture #2
Condenser Lens 1 Setting 1 .672
Condenser Lens 2 Setting 1 .747
Approximate Objective Lens Setting 5.86
ZC Mode Projector Lens 1 .149
TE Mode Projector Lens 0.7
Image Acquisition
Pixel Resolution 1280x960
Acquisition Time 20sec.(x4
[377] For TEM analysis the sample grids can be transferred to a Hitachi HF2000 transmission electron microscope. Transmitted electron images can be acquired at appropriate magnifications. The relevant instrument settings used during image acquisition can be those given below.
Instrument Transmission Electron Microscope
Manufacturer/Model Hitachi HF2000
Accelerating Voltage 200 kV
Condenser Lens 1 0.78
Condenser Lens 2 0
Objective Lens 6.34
Condenser Lens Aperture #1
Instrument Transmission Electron Microscope
Objective Lens Aperture for #3
imaging
Selective Area Aperture for SAD N/A
Liquid-applied protective coating or layer
[378] Another example of a suitable barrier or other type of protective coating or layer, usable in conjunction with the PECVD-applied protective coating or layer or other PECVD treatment as disclosed here, can be a liquid barrier, lubricant, surface energy tailoring, or protective coating or layer 90 applied to the inner or interior surface of a pharmaceutical package or other vessel, either directly or with one or more intervening PECVD-applied coatings or layers described in this specification, for example SiOx, a lubricity coating or layer and/or a protective coating or layer, or both.
[379] A suitable liquid barrier, lubricity, or protective coating or layer 90 also optionally can be applied, for example, by applying a liquid monomer or other polymerizable or curable material to the inner or interior surface of the vessel 80 and curing, polymerizing, or crosslinking the liquid monomer to form a solid polymer, or by applying a solvent-dispersed polymer to the surface 88 and removing the solvent.
[380] Any of the above methods can include as a step forming a protective coating or layer 90 on the interior 88 of a vessel 80 via the vessel port 92 at a processing station or device 28. One example is applying a liquid protective coating or layer, for example of a curable monomer, prepolymer, or polymer dispersion, to the inner or interior surface 88 of a vessel 80 and curing it to form a film that physically isolates the contents of the vessel 80 from its inner or interior surface 88. The prior art describes polymer protective coating or layer technology as suitable for treating plastic blood collection tubes. For example, the acrylic and polyvinylidene chloride (PVdC) protective coating or layer materials and methods described in US Patent 6,165,566, which is hereby incorporated by reference, optionally can be used.
[381 ] Any of the above methods can also include as a step forming a coating or layer on the exterior outer wall of a vessel 80. The exterior coating or layer optionally can be a barrier coating or layer 30), optionally an oxygen barrier coating or layer 30), or optionally a water barrier coating or layer 30). The exterior coating or layer can also be an armor layer that protects the outer wall of a vessel 80. One example of a suitable exterior coating or layer is polyvinylidene chloride, which functions both as a water barrier and an oxygen barrier. Optionally, the exterior coating or layer can be applied as a water-based coating or layer. The exterior coating or layer optionally can be applied by dipping the vessel in it, spraying it on the pharmaceutical package or other vessel, or other expedients.
PECVD TREATED PHARMACEUTICAL PACKAGES OR OTHER VESSELS Coated Pharmaceutical Packages or Other Vessels
[382] Pharmaceutical packages or other vessels, such as a prefilled syringe are contemplated having a barrier coating or layer 30) at least partially covered by a protective coating or layer such as 286.
[383] The pharmaceutical package 210 optionally can comprise a vessel or vessel part such as 250; optionally a barrier coating or layer 30) such as 288 on the vessel or vessel part; a protective coating or layer such as 286 on the vessel, vessel part, or barrier coating or layer 30); and a pharmaceutical composition or preparation such as contained within the vessel.
[384] The barrier coating or layer 30) such as 288 can be an SiOx barrier coating or layer 30) applied as described in any embodiment of this specification or in U.S. Patent No. 7,985,188. For example, the barrier coating or layer 30) such as 288 of any embodiment can be applied at a thickness of at least 2 nm, or at least 4 nm, or at least 7 nm, or at least 10 nm, or at least 20 nm, or at least 30 nm, or at least 40 nm, or at least 50 nm, or at least 100 nm, or at least 150 nm, or at least 200 nm, or at least 300 nm, or at least 400 nm, or at least 500 nm, or at least 600 nm, or at least 700 nm, or at least 800 nm, or at least 900 nm. The barrier coating or layer 30) can be up to 1000
nm, or at most 900 nm, or at most 800 nm, or at most 700 nm, or at most 600 nm, or at most 500 nm, or at most 400 nm, or at most 300 nm, or at most 200 nm, or at most 100 nm, or at most 90 nm, or at most 80 nm, or at most 70 nm, or at most 60 nm, or at most 50 nm, or at most 40 nm, or at most 30 nm, or at most 20 nm, or at most 10 nm, or at most 5 nm thick. Specific thickness ranges composed of any one of the minimum thicknesses expressed above, plus any equal or greater one of the maximum thicknesses expressed above, are expressly contemplated. The thickness of the SiOx or other barrier coating or layer 30) can be measured, for example, by transmission electron microscopy (TEM), and its composition can be measured by X-ray photoelectron spectroscopy (XPS). The protective coating or layer described herein can be applied to a variety of pharmaceutical packages or other vessels made from plastic or glass, for example to plastic tubes, vials, and syringes, cartridges, or similar articles.
[385] The protective coating or layer such as 286 can be an SiOxCy protective coating or layer applied as described in any embodiment of this specification. For example, the protective coating or layer such as 286 of any embodiment optionally can comprise or consist essentially of a coating or layer of SiOxCy applied over the barrier coating or layer 30 to protect at least a portion of the barrier coating or layer 30) from the pharmaceutical preparation such as in FIGS. 24-26. The protective coating or layer such as 286 is provided, for example, by applying one of the described precursors on or in the vicinity of a substrate in a PECVD process, providing a protective coating or layer. The coating can be applied, for example, at a thickness of 1 to 5000 nm, or 10 to 1000 nm, or 10 to 500 nm, or 10 to 200 nm, or 20 to 100 nm, or 30 to 1000 nm, or 30 to 500 nm thick, or 30 to 1000 nm, or 20 to 100 nm, or 80 to 150 nm, and crosslinking or polymerizing (or both) the protective coating or layer, optionally in a PECVD process, to provide a protected surface.
[386] Although not intending to be bound according to the accuracy of the following theory, the inventors contemplate that the protective coating or layer, applied over an SiOx barrier layer on a vessel wall, functions at least in part by passivating the SiOx barrier layer surface against attack by the contents of the vessel, as well as providing a more resistant or sacrificial independent layer to isolate the SiOx barrier layer from the
contents of the vessel. It is thus contemplated that the protective coating or layer can be very thin, and even so improve the shelf life of the pharmaceutical package.
[387] A lubricity coating or layer can be applied after applying an SiOx barrier layer and/or a protective coating or layer to the inner or interior surface or to other parts of the pharmaceutical package, as described in U.S. Patent No. 7,985,188.
[388] Thus, the coating or layer 90 can comprise a barrier coating or layer 30) of SiOx and a protective coating or layer of SiwOxCy (which for all embodiments in this specification is equivalent to SiOxCy, since w = 1 ) and optionally in any embodiment further including a lubricity coating or layer, each characterized as defined in this specification. As another option, the barrier coating or layer 30) of SiOx can be deposited at a location more remote from the protective coating or layer, with at least one intervening coating or layer of another material.
[389] Another expedient contemplated here, for adjacent layers of SiOx and a lubricity and/or protective coating or layer, is a graded composite of SiOx and SiwOxCy, or its equivalent SiOxCy, as defined in the Definition Section. A graded composite can be separate layers of a lubricity and/or protective and/or barrier layer or coating with a transition or interface of intermediate composition between them, or separate layers of a lubricity and/or protective and/or hydrophobic layer and SiOx with an intermediate distinct protective coating or layer of intermediate composition between them, or a single coating or layer that changes continuously or in steps from a composition of a lubricity and/or protective and/or hydrophobic layer to a composition more like SiOx, going through the protective coating or layer in a normal direction.
[390] The grade in the graded composite can go in either direction. For example, the composition of SiOx can be applied directly to the substrate and graduate to a composition further from the surface of a protective coating or layer, and optionally can further graduate to another type of coating or layer, such as a hydrophobic coating or layer or a lubricity coating or layer. Additionally, in any embodiment an adhesion coating or layer, for example SiwOxCy, or its equivalent SiOxCy, optionally can be applied directly to the substrate before applying the barrier layer. A graduated protective coating or layer is particularly contemplated if a layer of one composition is better for
adhering to the substrate than another, in which case the better-adhering composition can, for example, be applied directly to the substrate. It is contemplated that the more distant portions of the graded protective coating or layer can be less compatible with the substrate than the adjacent portions of the graded protective coating or layer, since at any point the protective coating or layer is changing gradually in properties, so adjacent portions at nearly the same depth of the protective coating or layer have nearly identical composition, and more widely physically separated portions at substantially different depths can have more diverse properties. It is also contemplated that a protective coating or layer portion that forms a better barrier against transfer of material to or from the substrate can be directly against the substrate, to prevent the more remote protective coating or layer portion that forms a poorer barrier from being contaminated with the material intended to be barred or impeded by the barrier.
[391 ] The applied coatings or layers, instead of being graded, optionally can have sharp transitions between one layer and the next, without a substantial gradient of composition. Such protective coating or layer can be made, for example, by providing the gases to produce a layer as a steady state flow in a non-plasma state, then energizing the system with a brief plasma discharge to form a coating or layer on the substrate. If a subsequent protective coating or layer is to be applied, the gases for the previous protective coating or layer are cleared out and the gases for the next protective coating or layer are applied in a steady-state fashion before energizing the plasma and again forming a distinct layer on the surface of the substrate or its outermost previous protective coating or layer, with little if any gradual transition at the interface.
Syringe with Lubricity Coated Plunger and Bilayer Coated Barrel
[392] One non-limiting aspect of the invention is a syringe, for example any of the syringes described in this specification, including a barrel; a stopper, O-ring, plunger tip or piston 36; a barrier coating and pH protective layer on the barrel; and a lubricity and optionally solute barrier layer on the stopper, O-ring, plunger tip or piston. The barrel can be an injection molded barrel or wall 14 including a lumen 18, a vessel substrate defining at least a portion of the lumen 18, and an internal sliding surface 16 on the
vessel substrate adjacent to the lumen. The stopper, O-ring, plunger tip or piston 36 is operatively connected with the lumen and can include a substrate having an external sliding surface 268 slidable in the lumen at least substantially in contact with the internal sliding surface 16 and a surface exposed to the lumen. The barrier coating or layer is disposed on the internal sliding surface, with or without additional intervening layers. The pH protective layer comprises SiOxCy, where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3, disposed between the barrier coating or layer and the lumen. The barrier layer and pH protective layer combined are alternatively referred to as a "bilayer" or "bilayer coating." The parylene coating or layer is provided on the external sliding surface 268 of the stopper, O-ring, plunger tip or piston. The parylene coating is arranged to be effective to reduce the F, and Fm of the stopper, O-ring, plunger tip or piston respecting relative movement of the inner and outer sliding surfaces.
[393] Optionally in any embodiment, the syringe further comprises a tie coating or layer of SiOxCy as an intervening layer between the barrier coating or layer and the internal sliding surface.
[394] Optionally in any embodiment of the syringe, the stopper, O-ring, plunger tip or piston 36 comprises elastomeric material defining the external sliding surface.
[395] Optionally in any embodiment of the syringe, the parylene coating or layer is effective to reduce the leaching of solutes from the stopper, O-ring, plunger tip or piston 36.
[396] Optionally in any embodiment of the syringe, the parylene coating or layer comprises fluorinated parylene.
[397] Optionally in any embodiment of the syringe, the parylene coating or layer is deposited by vapor deposition.
[398] Optionally in any embodiment of the syringe, the parylene coating or layer is deposited by chemical vapor deposition.
[399] Optionally in any embodiment, of the syringe the parylene coating or layer comprises polytetrafluoroparaxylylene.
[400] Optionally in any embodiment of the syringe, the parylene coating or layer consists essentially of polytetrafluoroparaxylylene.
[401 ] Optionally in any embodiment of the syringe, the barrier coating or layer comprises SiOx, where x is from 1 .5 to 2.9.
[402] Optionally in any embodiment of the syringe, the barrier coating or layer consists essentially of SiOx, where x is from 1 .5 to 2.9.
[403] Optionally in any embodiment of the syringe, the parylene coating or layer is from at least 0.1 micrometers to at most 10 micrometers thick,
• optionally from at least 0.1 micrometers to at most 8 micrometers thick,
• optionally from at least 0.1 micrometers to at most 6 micrometers thick,
• optionally from at least 0.1 micrometers to at most 4 micrometers thick,
• optionally from at least 0.1 micrometers to at most 2 micrometers thick,
• optionally from at least 0.1 micrometers to at most 1 micrometers thick,
• optionally from at least 0.1 micrometers to at most 0.9 micrometers thick,
• optionally from at least 0.1 micrometers to at most 0.8 micrometers thick,
• optionally from at least 0.1 micrometers to at most 0.7 micrometers thick,
• optionally from at least 0.1 micrometers to at most 0.6 micrometers thick,
• optionally from at least 0.1 micrometers to at most 0.5 micrometers thick,
• optionally from at least 0.5 micrometers to at most 5 micrometers thick,
• optionally from at least 0.5 micrometers to at most 4 micrometers thick,
• optionally from at least 0.5 micrometers to at most 3 micrometers thick,
• optionally from at least 0.5 micrometers to at most 2 micrometers thick,
• optionally from at least 0.5 micrometers to at most 1 micrometer thick,
optionally about 2 micrometers thick.
[404] Optionally in any embodiment of the syringe, the barrier coating or layer is deposited by vapor deposition.
[405] Optionally in any embodiment of the syringe, the barrier coating or layer is deposited by chemical vapor deposition.
[406] Optionally in any embodiment of the syringe, the barrier coating or layer is deposited by plasma enhanced chemical vapor deposition.
[407] Optionally in any embodiment of the syringe, the pH protective coating or layer is deposited by vapor deposition.
[408] Optionally in any embodiment of the syringe, the pH protective coating or layer is deposited by chemical vapor deposition.
[409] Optionally in any embodiment of the syringe, the pH protective coating or layer is deposited by plasma enhanced chemical vapor deposition.
[410] Optionally in any embodiment of the syringe, the fluorinated parylene is applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor (182) in a cracking pipe (190) and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus (198) to form at least one of the internal and external sliding surfaces.
[41 1 ] Optionally in any embodiment of the syringe, the precursor for the fluorinated parylene comprises xylene or its ethyl, propyl, or butyl-substituted analog, fully halogenated on each pendant alkyl moiety.
[412] Optionally in any embodiment of the syringe, each pendant alkyl moiety is trihalogenated methyl.
[413] Optionally in any embodiment of the syringe, each pendant alkyl moiety is trifluoromethyl.
[414] Optionally in any embodiment of the syringe, the halogen is one nonfluoro halogen terminal moiety selected from chloro, bromo, or iodo and the balance fluoro.
[415] Optionally in any embodiment of the syringe, the alkyl moieties are bromodifluoromethyl.
[416] Optionally in any embodiment of the syringe, the precursor gasprecursor vapor is decomposed in the presence of a catalyst.
[417] Optionally in any embodiment of the syringe, the catalyst comprises copper, zinc, magnesium, titanium, cadmium, silver, indium, tin, aluminum, or a combination of two or more of these.
[418] Optionally in any embodiment of the syringe, the catalyst comprises zinc or a zinc halide, for example zinc bromide.
[419] Optionally in any embodiment of the syringe, the catalyst comprises copper or a copper halide, for example copper bromide.
[420] Optionally in any embodiment of the syringe, the precursor gasprecursor vapor is decomposed in the presence of an initiator different from the precursor.
[421 ] Optionally in any embodiment of the syringe, the initiator comprises xylene or its ethyl, propyl, or butyl-substituted analog, at least partially halogenated on each pendant alkyl moiety.
[422] Optionally in any embodiment of the syringe, the methyl pendant groups are di- or tri-halogen-substituted.
[423] Optionally in any embodiment of the syringe, the initiator comprises m-bis- (dibromomethyl)benzene.
[424] Optionally in any embodiment of the syringe, the initiator comprises p-bis- (dibromomethyl)benzene.
[425] Optionally in any embodiment of the syringe, the initiator comprises m-bis- (difluorobromo)benzene.
[426] Optionally in any embodiment of the syringe, the initiator comprises p-bis- (difluorobromo)benzene.
[427] Optionally in any embodiment of the syringe, the fluorinated parylene is applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor comprising p-bis(trifluoromethyl)benzene in a cracking pipe in the presence of an initiator comprising bis(difluorobromomethyl)benzene and a catalyst comprising zinc metal and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus (198) to form at least the external sliding surface.
[428] Optionally in any embodiment of the syringe, the Fi and Fm values for advance of the external sliding surface along the internal sliding surface are each from 1 to 20 N, alternatively from 3 to 18 N, optionally from 5 to 15 N after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
[429] Optionally in any embodiment of the syringe, the F, and Fm values for advance of the external sliding surface along the internal sliding surface do not increase more than 50 percent, alternatively more than 40 percent, alternatively more than 30 percent, alternatively more than 20 percent, alternatively more than 10 percent, alternatively at all, and optionally decrease 10%, optionally 20%, optionally 30%, after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
[430] Optionally in any embodiment of the syringe, the stopper, O-ring, plunger tip or piston 36 is injection molded.
[431 ] Optionally in any embodiment of the syringe, the parylene polymer comprises poly(tetrafluoro-p-xylylene), and the extractables obtainable from the injection molded substrate by isopropanol extraction are reduced by at least 10%, optionally at least 25%, optionally at least 30%, optionally at least 40%, optionally at least 47%, optionally at least 50%, optionally at least 60%, optionally at least 70%, optionally at least 80%, optionally at least 90%, optionally from 10% to 95%, optionally from 10% to 90%, optionally from 10% to 80%, optionally from 10% to 70%, optionally from 10% to 60%, optionally from 10% to 50%, optionally from 25% to 50%.
[432] Optionally in any embodiment of the syringe, the parylene polymer is applied as a coating on an elastomeric stopper, O-ring, plunger tip or piston 36 as a substrate and the Bonfiglioli container closure integrity result for the parylene polymer coated substrate is a vacuum decay of less than 50 mbar, alternatively less than 40 mbar, alternatively less than 30 mbar, alternatively less than 20 mbar, as an upper limit, and at least 3 mbar, alternatively at least 5 mbar, alternatively at least 7 mbar, alternatively at least 10 mbar, alternatively at least 12 mbar, as a lower limit.
[433] Optionally in any embodiment of the syringe, the parylene coating is 0.5-20 microns thick, optionally 0.5-10 microns thick, optionally 0.5-4.5 microns thick, optionally 1 to 5 microns thick, optionally 1 to 4.5 microns thick, optionally 1 -3 microns thick.
[434] Optionally in any embodiment of the syringe, the parylene coating is applied with a precision in reproducible coating thicknesses of +/- 1 -15%, optionally +/- 1 -10%, optionally +/- 1 to 5%, optionally +/- 2%.
[435] Optionally in any embodiment of the syringe, the parylene coating consists essentially of Parylene HTX.
[436] Optionally in any embodiment of the syringe, the parylene is provided in the form of a coating having a crystallinity of greater than 10%, optionally from 15% to 50%, optionally from 20 to 40%, optionally 20 to 30%.
Vessels Generally
[437] A vessel with a protective coating or layer as described herein and/or prepared according to a method described herein can be used for reception and/or storage and/or delivery of a compound or composition. The compound or composition can be sensitive, for example air-sensitive, oxygen-sensitive, sensitive to humidity and/or sensitive to mechanical influences. It can be a biologically active compound or composition, for example a pharmaceutical preparation or medicament like insulin or a composition comprising insulin. In another aspect, it can be a biological fluid, optionally a bodily fluid, for example blood or a blood fraction. In certain aspects of the present invention, the compound or composition can be a product to be administrated to a subject in need thereof, for example a product to be injected, like blood (as in transfusion of blood from a donor to a recipient or reintroduction of blood from a patient back to the patient) or insulin.
[438] A vessel with a protective coating or layer as described herein and/or prepared according to a method described herein can further be used for protecting a compound or composition contained in its interior space against mechanical and/or chemical effects of the surface of the vessel material. For example, it can be used for preventing or reducing precipitation and/or clotting or platelet activation of the compound or a component of the composition, for example insulin precipitation or blood clotting or platelet activation.
[439] It can further be used for protecting a compound or composition contained in its interior against the environment outside of the pharmaceutical package or other vessel, for example by preventing or reducing the entry of one or more compounds from the environment surrounding the vessel into the interior space of the vessel. Such environmental compound can be a gas or liquid, for example an atmospheric gas or liquid containing oxygen, air, and/or water vapor.
[440] A vessel with a protective coating or layer as described herein can also be evacuated and stored in an evacuated state. For example, the protective coating or layer allows better maintenance of the vacuum in comparison to a corresponding vessel without a protective coating or layer. In one aspect of this embodiment, the vessel with a protective coating or layer is a blood collection tube. The tube can also contain an agent for preventing blood clotting or platelet activation, for example EDTA or heparin.
[441 ] Any of the above-described embodiments can be made, for example, by providing as the vessel a length of tubing from about 1 cm to about 200 cm, optionally from about 1 cm to about 150 cm, optionally from about 1 cm to about 120 cm, optionally from about 1 cm to about 100 cm, optionally from about 1 cm to about 80 cm, optionally from about 1 cm to about 60 cm, optionally from about 1 cm to about 40 cm, optionally from about 1 cm to about 30 cm long, and processing it with a probe electrode as described below. Particularly for the longer lengths in the above ranges, it is contemplated that relative motion between the probe and the vessel can be useful during protective coating or layer formation. This can be done, for example, by moving the vessel with respect to the probe or moving the probe with respect to the vessel.
[442] In these embodiments, it is contemplated that the barrier coating or layer 30) can be thinner or less complete than would be preferred to provide the high gas barrier integrity needed in an evacuated blood collection tube. In these embodiments, it is contemplated that the protective coating or layer can be thinner or less complete than would be preferred to provide the long shelf life needed to store a liquid material in contact with the barrier layer for an extended period.
[443] As an optional feature of any of the foregoing embodiments the vessel has a central axis.
[444] As an optional feature of any of the foregoing embodiments the vessel wall is sufficiently flexible to be flexed at least once at 20 °C, without breaking the wall, over a range from at least substantially straight to a bending radius at the central axis of not more than 100 times as great as the outer diameter of the vessel.
[445] As an optional feature of any of the foregoing embodiments the bending radius at the central axis is not more than 90 times as great as, or not more than 80 times as great as, or not more than 70 times as great as, or not more than 60 times as great as, or not more than 50 times as great as, or not more than 40 times as great as, or not more than 30 times as great as, or not more than 20 times as great as, or not more than 10 times as great as, or not more than 9 times as great as, or not more than 8 times as great as, or not more than 7 times as great as, or not more than 6 times as great as, or not more than 5 times as great as, or not more than 4 times as great as, or not more than 3 times as great as, or not more than 2 times as great as, or not more than, the outer diameter of the vessel.
[446] As an optional feature of any of the foregoing embodiments the vessel wall can be a fluid-contacting surface made of flexible material.
[447] As an optional feature of any of the foregoing embodiments the vessel lumen can be the fluid flow passage of a pump.
[448] As an optional feature of any of the foregoing embodiments the vessel can be a blood bag adapted to maintain blood in good condition for medical use.
[449] As an optional feature of any of the foregoing embodiments the polymeric material can be a silicone elastomer or a thermoplastic polyurethane, as two examples, or any material suitable for contact with blood, or with insulin.
[450] In an optional embodiment, the vessel has an inner diameter of at least 2 mm, or at least 4 mm.
[451 ] As an optional feature of any of the foregoing embodiments the vessel is a tube.
[452] As an optional feature of any of the foregoing embodiments the lumen has at least two open ends.
Relative proportions of gases of any embodiment
[453] The process gas can contain this ratio of gases for preparing a lubricity and/or protective coating or layer:
• from 0.5 to 10 standard volumes of the precursor;
• from 1 to 100 standard volumes of a carrier or diluent gas,
• from 0.1 to 10 standard volumes of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 1 to 80 standard volumes of a carrier or diluent gas,
• from 0.1 to 2 standard volumes of an oxidizing agent. alternatively this ratio:
• from 2 to 4 standard volumes, of the precursor;
• from 1 to 100 standard volumes of a carrier or diluent gas,
• from 0.1 to 2 standard volumes of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 3 to 70 standard volumes, of a carrier or diluent gas,
• from 0.1 to 2 standard volumes of an oxidizing agent. alternatively this ratio:
• from 2 to 4 standard volumes, of the precursor;
• from 3 to 70 standard volumes of a carrier or diluent gas,
• from 0.1 to 2 standard volumes of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 1 to 100 standard volumes of a carrier or diluent gas,
• from 0.2 to 1 .5 standard volumes of an oxidizing agent. alternatively this ratio:
• zfrom 2 to 4 standard volumes, of the precursor;
• from 1 to 100 standard volumes of a carrier or diluent gas,
• from 0.2 to 1 .5 standard volumes of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 3 to 70 standard volumes of a carrier or diluent gas,
• from 0.2 to 1 .5 standard volumes of an oxidizing agent. alternatively this ratio:
• from 2 to 4 standard volumes of the precursor;
• from 3 to 70 standard volumes of a carrier or diluent gas,
• from 0.2 to 1 .5 standard volumes of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 1 to 100 standard volumes of a carrier or diluent gas,
• from 0.2 to 1 standard volumes of an oxidizing agent. alternatively this ratio:
• from 2 to 4 standard volumes of the precursor;
• from 1 to 100 standard volumes of a carrier or diluent gas,
• from 0.2 to 1 standard volumes of an oxidizing agent.
alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 3 to 70 standard volumes of a carrier or diluent gas,
• from 0.2 to 1 standard volumes of an oxidizing agent.
alternatively this ratio:
• 2 to 4 standard volumes, of the precursor;
• from 3 to 70 standard volumes of a carrier or diluent gas,
• from 0.2 to 1 standard volumes of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 5 to 100 standard volumes of a carrier or diluent gas,
• from 0.1 to 2 standard volumes of an oxidizing agent. alternatively this ratio:
• from 2 to 4 standard volumes, of the precursor;
• from 5 to 100 standard volumes of a carrier or diluent gas,
• from 0.1 to 2 standard volumes
• of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 10 to 70 standard volumes, of a carrier or diluent gas,
• from 0.1 to 2 standard volumes of an oxidizing agent. alternatively this ratio:
• from 2 to 4 standard volumes, of the precursor;
• from 10 to 70 standard volumes of a carrier or diluent gas,
• from 0.1 to 2 standard volumes of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 5 to 100 standard volumes of a carrier or diluent gas,
• from 0.5 to 1 .5 standard volumes of an oxidizing agent. alternatively this ratio:
• from 2 to 4 standard volumes, of the precursor;
• from 5 to 100 standard volumes of a carrier or diluent gas,
• from 0.5 to 1 .5 standard volumes of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 10 to 70 standard volumes, of a carrier or diluent gas,
• from 0.5 to 1 .5 standard volumes of an oxidizing agent. alternatively this ratio:
• from 2 to 4 standard volumes of the precursor;
• from 10 to 70 standard volumes of a carrier or diluent gas,
• from 0.5 to 1 .5 standard volumes of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 5 to 100 standard volumes of a carrier or diluent gas,
• from 0.8 to 1 .2 standard volumes of an oxidizing agent.
alternatively this ratio:
• from 2 to 4 standard volumes of the precursor;
• from 5 to 100 standard volumes of a carrier or diluent gas,
• from 0.8 to 1 .2 standard volumes of an oxidizing agent. alternatively this ratio:
• from 1 to 6 standard volumes of the precursor;
• from 10 to 70 standard volumes of a carrier or diluent gas,
• from 0.8 to 1 .2 standard volumes of an oxidizing agent. alternatively this ratio:
• 2 to 4 standard volumes, of the precursor;
• from 10 to 70 standard volumes of a carrier or diluent gas,
• from 0.8 to 1 .2 standard volumes of an oxidizing agent.
Precursor of any embodiment
[454] The organosilicon precursor has been described elsewhere in this description.
[455] The organosilicon compound can in certain aspects, particularly when a lubricity and/or protective coating or layer can be formed, comprise octamethylcyclotetrasiloxane (OMCTS). The organosilicon compound for any embodiment of said certain aspects optionally can consist essentially of octamethylcyclotetrasiloxane (OMCTS). The organosilicon compound can in certain aspects, particularly when a barrier coating or layer can be formed, be or comprise hexamethyldisiloxane.
[456] The reaction gas can also include a hydrocarbon. The hydrocarbon can comprise methane, ethane, ethylene, propane, acetylene, or a combination of two or more of these.
[457] The organosilicon precursor can be delivered at a rate of equal to or less than 10 seem, optionally equal to or less than 6 seem, optionally equal to or less than 2.5 seem, optionally equal to or less than 1 .5 seem, optionally equal to or less than 1 .25 seem. Larger pharmaceutical packages or other vessels or other changes in conditions or scale may require more or less of the precursor. The precursor can be provided at less than 1 Torr absolute pressure.
Carrier or diluent gas of any embodiment
[458] The carrier or diluent gas can comprise or consist of an inert gas, for example argon, helium, xenon, neon, another gas that is inert to the other constituents of the process gas under the deposition conditions, or any combination of two or more of these.
Oxidizing gas of any embodiment
[459] The oxidizing gas can comprise or consist of oxygen (02 and/or 03 (commonly known as ozone)), nitrous oxide, or any other gas that oxidizes the precursor during PECVD at the conditions employed. The oxidizing gas optionally can comprise about 1 standard volume of oxygen. The gaseous reactant or process gas can be at least substantially free of nitrogen.
III. PLASMA OF ANY EMBODIMENT
[460] The plasma of any PECVD embodiment can be formed in the vicinity of the substrate. The plasma can in certain cases, especially when preparing a barrier coating or layer 30), be a non-hollow-cathode plasma. In other certain cases, especially when preparing a lubricity coating or layer, a non-hollow-cathode plasma is not desired. The plasma can be formed from the gaseous reactant at reduced pressure. Sufficient plasma generation power input can be provided to induce protective coating or layer formation on the substrate.
IV. RF POWER OF ANY EMBODIMENT
[461 ] The precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes powered at a frequency of 10 kHz to 2.45 GHz, alternatively from about 13 to about 14 MHz.
[462] The precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes powered at radio frequency, optionally at a frequency of from 10 kHz to less than 300 MHz, optionally from 1 to 50 MHz, even optionally from 10 to 15 MHz, optionally at 13.56 MHz.
[463] The precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes supplied with electric power at from 0.1 to 25 W, optionally from 1 to 22 W, optionally from 1 to 10 W, even optionally from 1 to 5 W, optionally from 2 to 4 W, for example of 3 W, optionally from 3 to 17 W, even optionally from 5 to 14 W, for example 6 or 7.5 W, optionally from 7 to 1 1 W, for example of 8 W, from 0.1 to 500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300 W, optionally from 1 to 250 W, optionally from 1 to 200 W, even optionally from 10 to 150 W, optionally from 20 to 150 W, for example of 40 W, optionally from 40 to 150 W, even optionally from 60 to 150 W.
[464] The precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes supplied with electric power density at less than 10 W/ml of plasma volume, alternatively from 6 W/ml to 0.1 W/ml of plasma volume, alternatively from 5 W/ml to 0.1 W/ml of plasma volume, alternatively from 4 W/ml to 0.1 W/ml of plasma volume, alternatively from 2 W/ml to 0.2 W/ml of plasma volume, alternatively from 10 W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml.
[465] The plasma can be formed by exciting the reaction mixture with electromagnetic energy, alternatively microwave energy.
V. OTHER PROCESS OPTIONS OF ANY EMBODIMENT
[466] The applying step for applying a protective coating or layer to the substrate can be carried out by vaporizing the precursor and providing it in the vicinity of the substrate.
[467] The chemical vapor deposition employed can be PECVD and the deposition time can be from 1 to 30 sec, alternatively from 2 to 10 sec, alternatively from 3 to 9 sec. The purposes for optionally limiting deposition time can be to avoid overheating the substrate, to increase the rate of production, and to reduce the use of process gas and its constituents. The purposes for optionally extending deposition time can be to provide a thicker protective coating or layer for particular deposition conditions.
VI. PROTECTIVE COATING OR LAYER PROPERTIES OF ANY EMBODIMENT Hydrophobicity properties of any embodiment
[468] An embodiment can be carried out under conditions effective to form a hydrophobic protective coating or layer on the substrate. Optionally, the hydrophobic characteristics of the protective coating or layer can be set by setting the ratio of the O2 to the organosilicon precursor in the gaseous reactant, and/or by setting the electric power used for generating the plasma. Optionally, the protective coating or layer can have a lower wetting tension than the uncoated surface, optionally a wetting tension of from 20 to 72 dyne/cm, optionally from 30 to 60 dynes/cm, optionally from 30 to 40 dynes/cm, optionally 34 dyne/cm. Optionally, the protective coating or layer can be more hydrophobic than the uncoated surface.
Thickness of any embodiment
[469] Optionally, the protective coating or layer can have a thickness determined by transmission electron microscopy (TEM), of any amount stated in this disclosure.
Composition of any embodiment
[470] Optionally, the lubricity and/or protective coating or layer can be composed of SiwOxCyHz (or its equivalent SiOxCy) or SiwNxCyHz or its equivalent SiNxCy), each as defined previously. The atomic ratio of Si : O : C can be determined by XPS (X-ray photoelectron spectroscopy). Taking into account the H atoms, the protective coating or layer may thus in one aspect have the formula SiwOxCyHz, or its equivalent SiOxCy, for example where w is 1 , x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z is from about 2 to about 9.
[471 ] Typically, expressed as the formula SiwOxCy, the atomic ratios of Si, O, and C are, as several options:
Si 100 : O 50-150 : C 90-200 (i.e. w = 1 , x = 0.5 to 1 .5, y = 0.9 to 2);
Si 100 : O 70-130 : C 90-200 (i.e. w = 1 , x = 0.7 to 1 .3, y = 0.9 to 2)
Si 100 : O 80-120 : C 90-150 (i.e. w = 1 , x = 0.8 to 1 .2, y = 0.9 to 1 .5)
Si 100 : O 90-120 : C 90-140 (i.e. w = 1 , x = 0.9 to 1 .2, y = 0.9 to 1 .4), or
Si 100 : O 92-107 : C 1 16-133 (i.e. w = 1 , x = 0.92 to 1 .07, y = 1 .16 to 1 .33).
[472] Alternatively, the protective coating or layer can have atomic concentrations normalized to 100% carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS) of less than 50% carbon and more than 25% silicon. Alternatively, the atomic concentrations are from 25 to 45% carbon, 25 to 65% silicon, and 10 to 35% oxygen. Alternatively, the atomic concentrations are from 30 to 40% carbon, 32 to 52% silicon, and 20 to 27% oxygen. Alternatively, the atomic concentrations are from 33 to 37% carbon, 37 to 47% silicon, and 22 to 26% oxygen.
[473] Optionally, the atomic concentration of carbon in the protective coating or layer, normalized to 100% of carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS), can be greater than the atomic concentration of carbon in the atomic formula for the organosilicon precursor. For example, embodiments are contemplated in which the atomic concentration of carbon increases by from 1 to 80 atomic percent, alternatively from 10 to 70 atomic percent, alternatively
from 20 to 60 atomic percent, alternatively from 30 to 50 atomic percent, alternatively from 35 to 45 atomic percent, alternatively from 37 to 41 atomic percent.
[474] Optionally, the atomic ratio of carbon to oxygen in the protective coating or layer can be increased in comparison to the organosilicon precursor, and/or the atomic ratio of oxygen to silicon can be decreased in comparison to the organosilicon precursor.
[475] Optionally, the protective coating or layer can have an atomic concentration of silicon, normalized to 100% of carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS), less than the atomic concentration of silicon in the atomic formula for the feed gas. For example, embodiments are contemplated in which the atomic concentration of silicon decreases by from 1 to 80 atomic percent, alternatively by from 10 to 70 atomic percent, alternatively by from 20 to 60 atomic percent, alternatively by from 30 to 55 atomic percent, alternatively by from 40 to 50 atomic percent, alternatively by from 42 to 46 atomic percent.
[476] As another option, a protective coating or layer is contemplated that can be characterized by a sum formula wherein the atomic ratio C : O can be increased and/or the atomic ratio Si : O can be decreased in comparison to the sum formula of the organosilicon precursor.
Other protective coating or layer properties of any embodiment
[477] The protective coating or layer can have a density between 1 .25 and 1 .65 g/cm3, alternatively between 1 .35 and 1 .55 g/cm3, alternatively between 1 .4 and 1 .5 g/cm3, alternatively between 1 .4 and 1 .5 g/cm3, alternatively between 1 .44 and 1 .48 g/cm3, as determined by X-ray reflectivity (XRR). Optionally, the organosilicon compound can be octamethylcyclotetrasiloxane and the protective coating or layer can have a density which can be higher than the density of a protective coating or layer made from HMDSO as the organosilicon compound under the same PECVD reaction conditions.
[478] The protective coating or layer optionally can prevent or reduce the precipitation of a compound or component of a composition in contact with the protective coating or layer, in particular can prevent or reduce insulin precipitation or blood clotting, in comparison to the uncoated surface and/or to a barrier coated surface using HMDSO as precursor.
[479] The substrate can be a pharmaceutical package or other vessel, for protecting a compound or composition contained or received in the vessel with a protective coating or layer against mechanical and/or chemical effects of the surface of the uncoated substrate.
[480] The substrate can be a pharmaceutical package or other vessel, for preventing or reducing precipitation and/or clotting of a compound or a component of the composition in contact with the inner or interior surface of the vessel. The compound or composition can be a biologically active compound or composition, for example a medicament, for example the compound or composition can comprise insulin, wherein insulin precipitation can be reduced or prevented. Alternatively, the compound or composition can be a biological fluid, for example a bodily fluid, for example blood or a blood fraction wherein blood clotting can be reduced or prevented.
[481 ] The protective coating or layer optionally can have an RMS surface roughness value (measured by AFM) of from about 5 to about 9, optionally from about 6 to about 8, optionally from about 6.4 to about 7.8. The Ra surface roughness value of the protective coating or layer, measured by AFM, can be from about 4 to about 6, optionally from about 4.6 to about 5.8. The Rmax surface roughness value of the protective coating or layer, measured by AFM, can be from about 70 to about 160, optionally from about 84 to about 142, optionally from about 90 to about 130.
VII. PRODUCT MADE OF VESSEL PLUS CONTENTS, OPTIONAL FOR ANY EMBODIMENT
[482] In any embodiment, the substrate can be a vessel having an inner or interior surface defining a lumen and an exterior surface, the protective coating or layer can be
on the inner or interior surface of the pharmaceutical package or other vessel, and the vessel can contain a compound or composition in its lumen, for example citrate or a citrate containing composition, or for example insulin or an insulin containing composition. A prefilled syringe is especially considered which contains injectable or other liquid drugs like insulin.
EXAMPLES
[483] The following Examples are in part already disclosed in EP 2 251 455. In order to avoid unnecessary repetition, not all of the Examples in EP 2 251 455 A2 are repeated here, but explicit reference is herewith made to them.
Basic Protocols for Forming and Coating Syringe Barrels
[484] The pharmaceutical packages or other vessels tested in the subsequent working examples were formed and coated according to the following exemplary protocols, except as otherwise indicated in individual examples. Particular parameter values given in the following basic protocols, for example the electric power and gaseous reactant or process gas flow, are typical values. When parameter values were changed in comparison to these typical values, this will be indicated in the subsequent working examples. The same applies to the type and composition of the gaseous reactant or process gas.
[485] In some instances, the reference characters and Figures mentioned in the following protocols and additional details can be found in U.S. Patent No. 7,985,188.
Protocol for Coating Syringe Barrel Interior with SiOx
[486] The apparatus and protocol generally as found in U.S. Patent No. 7,985,188 were used for coating syringe barrel interiors with an SiOx barrier coating or layer 30), in some cases with minor variations. A similar apparatus and protocol were used for coating vials with an SiOx barrier coating or layer 30), in some cases with minor variations.
Protocol for Coating Syringe Barrel Interior with OMCTS protective coating or layer
[487] Syringe barrels already interior coated with a barrier coating or layer 30) of SiOx, as previously identified, are further interior coated with a protective coating or layer as previously identified, generally following the protocols of U.S. Patent No. 7,985,188 for applying the lubricity coating or layer, except with modified conditions in certain instances as noted in the working examples. The conditions given here are for a COC syringe barrel, and can be modified as appropriate for syringe barrels made of other materials. The apparatus as generally shown in FIGS. 8 and 9 is used to hold a syringe barrel with butt sealing at the base of the syringe barrel. Additionally a shield 28 is provided that seals the end of the syringe barrel (illustrated in FIG. 8).
[488] The syringe barrel is carefully moved into the sealing position over the extended probe or counter electrode 108 and pushed against a plasma screen. The plasma screen is fit snugly around the probe or counter electrode 108 insuring good electrical contact. The probe or counter electrode 108 is grounded to the casing of the RF matching network.
[489] The gas delivery port 1 10 is connected to a manual ball valve or similar apparatus for venting, a thermocouple pressure gauge and a bypass valve connected to the vacuum pumping line. In addition, the gas system is connected to the gas delivery port 1 10 allowing the gaseous reactant or process gas, octamethylcyclotetrasiloxane (OMCTS) (or the specific gaseous reactant or process gas reported for a particular
example) to be flowed through the gas delivery port 1 10 (under process pressures) into the interior of the syringe barrel.
[490] The gas system is comprised of a commercially available heated mass flow vaporization system that heats the OMCTS to about 100°C. The heated mass flow vaporization system is connected to liquid octamethylcyclotetrasiloxane (Alfa Aesar® Part Number A1 160, 98%). The OMCTS flow rate is set to the specific organosilicon precursor flow reported for a particular example. To ensure no condensation of the vaporized OMCTS flow past this point, the gas stream is diverted to the pumping line when it is not flowing into the interior of the COC syringe barrel for processing.
[491 ] Once the syringe barrel is installed, the vacuum pump valve is opened to the vessel holder 50 and the interior of the COC syringe barrel. A vacuum pump and blower comprise the vacuum pump system. The pumping system allows the interior of the COC syringe barrel to be reduced to pressure(s) of less than 100 mTorr while the gaseous reactant or process gases is flowing at the indicated rates.
[492] Once the base vacuum level is achieved, the vessel holder 50 assembly is moved into the electrode 160 assembly. The gas stream (OMCTS vapor) is flowed into the gas delivery port 1 10 (by adjusting the 3-way valve from the pumping line to the gas delivery port 1 10. Pressure inside the COC syringe barrel is approximately 140 mTorr as measured by a capacitance manometer (MKS) installed on the pumping line near the valve that controls the vacuum. In addition to the COC syringe barrel pressure, the pressure inside the gas delivery port 1 10 and gas system is also measured with the thermocouple vacuum gauge that is connected to the gas system. This pressure is typically less than 6 Torr.
[493] Once the gas is flowing to the interior of the COC syringe barrel, the RF power supply is turned on to its fixed power level. A 600 Watt RF power supply is used (at 13.56 MHz) at a fixed power level indicated in a specific example. The RF power supply is connected to an auto match which matches the complex impedance of the plasma (to be created in the vessel) to the output impedance of the RF power supply. The forward power is as stated and the reflected power is 0 Watts so that the stated power is delivered to the interior of the vessel. The RF power supply is controlled by a
laboratory timer and the power on time set to 10 seconds (or a different time stated in a given example).
[494] Upon initiation of the RF power, a uniform plasma is established inside the interior of the vessel. The plasma is maintained for the entire protective coating or layer time, until the RF power is terminated by the timer. The plasma produces a protective coating or layer on the interior of the vessel.
[495] After protective coating or layer, the gas flow is diverted back to the vacuum line and the vacuum valve is closed. The vent valve is then opened, returning the interior of the COC syringe barrel to atmospheric pressure (approximately 760 Torr). The treated vessel is then carefully removed from the vessel holder 50 assembly (after moving the vessel holder 50 assembly out of the electrode 160 assembly).
[496] A similar protocol is used, except using apparatus generally like that of FIG. 1 , for applying a protective coating or layer to vials.
Protocol for Total Silicon Measurement
[497] This protocol is used to determine the total amount of silicon coatings present on the entire vessel wall. A supply of 0.1 N potassium hydroxide (KOH) aqueous solution is prepared, taking care to avoid contact between the solution or ingredients and glass. The water used is purified water, 18 ΜΏ quality. A Perkin Elmer Optima Model 7300DV ICP-OES instrument is used for the measurement except as otherwise indicated.
[498] Each device (vial, syringe, tube, or the like) to be tested and its shield and crimp (in the case of a vial) or other closure are weighed empty to 0.001 g, then filled completely with the KOH solution (with no headspace), capped, crimped, and reweighed to 0.001 g. In a digestion step, each vial is placed in a sonicating water bath at 40 °C for a minimum of 8-10 hours. The digestion step is carried out to quantitatively remove the silicon coatings from the vessel wall into the KOH solution. After this digestion step, the vials are removed from the sonicating water bath and allowed to cool to room temperature. The contents of the vials are transferred into 15 ml ICP tubes.
The total Si concentration is run on each solution by ICP/OES following the operating procedure for the ICP/OES.
[499] The total Si concentration is reported as parts per billion of Si in the KOH solution. This concentration represents the total amount of silicon coatings that were on the vessel wall before the digestion step was used to remove it.
[500] The total Si concentration can also be determined for fewer than all the silicon layers on the vessel, as when an SiOx barrier layer is applied, an SiOxCy second layer (for example, a lubricity layer or a protective coating or layer) is then applied, and it is desired to know the total silicon concentration of just the SiOxCy layer. This determination is made by preparing two sets of vessels, one set to which only the SiOx layer is applied and the other set to which the same SiOx layer is applied, followed by the SiOxCy layer or other layers of interest. The total Si concentration for each set of vessels is determined in the same manner as described above. The difference between the two Si concentrations is the total Si concentration of the SiOxCy second layer.
Protocol for Measuring Dissolved Silicon in a Vessel
[501 ] In some of the working examples, the amount of silicon dissolved from the wall of the vessel by a test solution is determined, in parts per billion (ppb), for example to evaluate the dissolution rate of the test solution. This determination of dissolved silicon is made by storing the test solution in a vessel provided with an SiOx and/or SiOxCy coating or layer under test conditions, then removing a sample of the solution from the vessel and testing the Si concentration of the sample. The test is done in the same manner as the Protocol for Total Silicon Measurement, except that the digestion step of that protocol is replaced by storage of the test solution in the vessel as described in this protocol. The total Si concentration is reported as parts per billion of Si in the test solution
Protocol for Determining Average Dissolution Rate
[502] The average dissolution rates reported in the working examples are determined as follows. A series of test vessels having a known total total silicon measurement are filled with the desired test solution analogous to the manner of filling the vials with the KOH solution in the Protocol for Total Silicon Measurement. (The test solution can be a physiologically inactive test solution as employed in the present working examples or a physiologically active pharmaceutical preparation intended to be stored in the vessels to form a pharmaceutical package). The test solution is stored in respective vessels for several different amounts of time, then analyzed for the Si concentration in parts per billion in the test solution for each storage time. The respective storage times and Si concentrations are then plotted. The plots are studied to find a series of substantially linear points having the steepest slope.
[503] The plot of dissolution amount (ppb Si) versus days decreases in slope with time. It is believed that the dissolution rate is not flattening out because the Si layer has been fully digested by the test solution.
[504] For the PC194 test data in Table 10 below, linear plots of dissolution versus time data are prepared by using a least squares linear regression program to find a linear plot corresponding to the first five data points of each of the experimental plots. The slope of each linear plot is then determined and reported as representing the average dissolution rate applicable to the test, measured in parts per billion of Si dissolved in the test solution per unit of time.
Protocol for Determining Calculated Shelf Life
[505] The calculated shelf life values reported in the working examples below are determined by extrapolation of the total silicon measurements and average dissolution rates, respectively determined as described in the Protocol for Total Silicon Measurement and the Protocol for Determining Average Dissolution Rate. The assumption is made that under the indicated storage conditions the SiOxCy protective coating or layer will be removed at the average dissolution rate until the coating is
entirely removed. Thus, the total silicon measurement for the vessel, divided by the dissolution rate, gives the period of time required for the test solution to totally dissolve the SiOxCy coating. This period of time is reported as the calculated shelf life. Unlike commercial shelf life calculations, no safety factor is calculated. Instead, the calculated shelf life is the calculated time to failure.
[506] It should be understood that because the plot of ppb Si versus hours decreases in slope with time, an extrapolation from relatively short measurement times to relatively long calculated shelf lives is believed to be a "worst case" test that tends to underestimate the calculated shelf life actually obtainable.
SEM Procedure
[507] SEM Sample Preparation: Each syringe sample was cut in half along its length (to expose the inner or interior surface). The top of the syringe (Luer end) was cut off to make the sample smaller.
[508] The sample was mounted onto the sample holder with conductive graphite adhesive, then put into a Denton Desk IV SEM Sample Preparation System, and a thin (approximately 50 A) gold protective coating or layer was sputtered onto the inner or interior surface of the syringe. The gold protective coating or layer is required to eliminate charging of the surface during measurement.
[509] The sample was removed from the sputter system and mounted onto the sample stage of a Jeol JSM 6390 SEM (Scanning Electron Microscope). The sample was pumped down to at least 1 x 10"6 Torr in the sample compartment. Once the sample reached the required vacuum level, the slit valve was opened and the sample was moved into the analysis station.
[510] The sample was imaged at a coarse resolution first, then higher magnification images were accumulated. The SEM images provided in the Figures are 5 μηι edge-to- edge (horizontal and vertical).
AFM (Atomic Force Microscopy) Procedure.
[51 1 ] AFM images were collected using a NanoScope III Dimension 3000 machine (Digital Instruments, Santa Barbara, California, USA). The instrument was calibrated against a NIST traceable standard. Etched silicon scanning probe microscopy (SPM) tips were used. Image processing procedures involving auto-flattening, plane fitting or convolution were employed. One 10 μηι x 10 μηι area was imaged. Roughness analyses were performed and were expressed in: (1 ) Root-Mean-Square Roughness, RMS; 2 Mean Roughness, Ra; and (3) Maximum Height (Peak-to-Valley), Rmax, all measured in nm (see Table 5 and Figs. 18 to 20. For the roughness analyses, each sample was imaged over the 10 μηι x 10 μηι area, followed by three cross sections selected by the analyst to cut through features in the 10 μηι x 10 μηι images. The vertical depth of the features was measures using the cross section tool. For each cross section, a Root-Mean-Square Roughness (RMS) in nanmeters was reported. These RMS values along with the average of the three cross sections for each sample are listed in Table 5.
[512] Additional analysis of the 10 μηι x 10 μηι images represented by Figs. 18 to 20 (Examples Q, T and V) was carried out. For this analysis three cross sections were extracted from each image. The locations of the cross sections were selected by the analyst to cut through features in the images. The vertical depth of the features was measured using the cross section tool.
[513] The Digital Instruments Nanoscope III AFM/STM acquires and stores 3- dimensional representations of surfaces in a digital format. These surfaces can be analyzed in a variety of ways.
[514] The Nanoscope III software can perform a roughness analysis of any AFM or STM image. The product of this analysis is a single page reproducing the selected image in top view. To the upper right of the image is the "Image Statistics" box, which lists the calculated characteristics of the whole image minus any areas excluded by a stopband (a box with an X through it). Similar additional statistics can be calculated for a selected portion of the image and these are listed in the "Box Statistics" in the lower
right portion of the page. What follows is a description and explanation of these statistics.
[515] Image Statistics:
[516] Z Range (Rp): The difference between the highest and lowest points in the image. The value is not corrected for tilt in the plane of the image; therefore, plane fitting or flattening the data will change the value.
[517] Mean: The average of all of the Z values in the imaged area. This value is not corrected for the tilt in the plane of the image; therefore, plane fitting or flattening the data will change this value.
[518] RMS (Rq): This is the standard deviation of the Z values (or RMS roughness) in the image. It is calculated according to the formula:
[519] Rq= {∑(Z Zavg)2/N}
[520] where Zavg is the average Z value within the image; Zi is the current value of Z; and N is the number of points in the image. This value is not corrected for tilt in the plane of the image; therefore, plane fitting or flattening the data will change this value.
[521 ] Mean roughness (Ra): This is the mean value of the surface relative to the Center Plane and is calculated using the formula:
Ra=[1 /(LxLy)]JoLyioLx{f(x,y)}dxdy
where f(x,y) is the surface relative to the Center plane, and Lx and Ly are the dimensions of the surface.
[522] Max height (Rmax) : This is the difference in height between the highest and lowest points of the surface relative to the Mean Plane.
[523] Surface area: (Optical calculation): This is the area of the 3-dimensional surface of the imaged area. It is calculated by taking the sum of the areas of the triangles formed by 3 adjacent data points throughout the image.
[524] Surface area diff: (Optional calculation) This is the amount that the Surface area is in excess of the imaged area. It is expressed as a percentage and is calculated according to the formula:
[525] Surface area diff = 100[(Surface area/Si2-1 ]
[526] where Si is the length (and width) of the scanned area minus any areas excluded by stopbands.
[527] Center Plane: A flat plane that is parallel to the Mean Plane. The volumes enclosed by the image surface above and below the center plane are equal.
[528] Mean Plane: The image data has a minimum variance about this flat plane. It results from a first order least squares fit on the Z data.
Summary of Protective Measurements
[529] Table 8 shows a summary of the above OMCTS coatings or layers and their Fj and Fm values. It should be understood that the initial lubricity and/or protective coating or layer work (C-K; roughness not known) was to identify the lowest possible stopper, O-ring, plunger tip or piston force attainable. From subsequent market input, it was determined that the lowest achievable stopper, O-ring, plunger tip or piston force was not necessarily most desirable, for reasons explained in the generic description (for example premature release). Thus, the PECVD reaction parameters were varied to obtain a stopper, O-ring, plunger tip or piston force of practical market use.
Working Example A: Parylene Process
[530] Parylene-coated Stelmi C2574 plunger tip samples were tested for their lubricity properties in syringes. The Stelmi tips were made of a bromine-substituted polymer composition, respectively coated as follows:
• Sample A: Stelmi tips coated 2 microns thick by heat-initiated chemical vapor deposition with Parylene C.
• Sample B: Stelmi tips coated 2 microns thick by heat-initiated chemical vapor deposition with Parylene HT®, shown in Figs. 7 and 1 5, respectively compared to PDMS and PTFE.
• Sample C: Stelmi tips coated 0.2 microns thick by heat-initiated chemical vapor deposition with Parylene HT®.
The syringes used were thermoplastic syringes having an internal barrier coating and coating and pH protective coating applied by PECVD as described in this specification (the two coatings being referred to below as a "bilayer coating").
[531 ] An initial screen was carried out by hand insertion of the coated Stelmi plunger tips, installed on plunger rods, into bilayer coated syringe barrels. The 2 micron Parylene HT® coated tips were easiest to insert in the bilayer coated syringe barrels, and were judged by the experimenter to be similar, regarding ease of insertion, to polytetrafluoroethylene coated tips. The other three (0.2 micron Parylene HT®, 0.2 micron Parylene C, 2 micron Parylene C) were not insertable without extreme force and smearing of the tip ribs.
[532] The Sample B syringes, using plungers coated 2 microns thick with Parylene HT®, were assembled and stored without movement of the plunger (i.e. with the plunger "parked") for various lengths of time, then tested for static force (breakout force) on an Instron unit at the end of their respective park times. This was repeated for each of the (10) replicate test samples. The static force (Newtons, N) was plotted versus time (sec) on a log-log scale, providing a linear plot. The plot is the plot identified in FIG. 7 as "2 urn Parylene(HT)-Coated Plunger" (etc.). The slope and intercept of the plot was then calculated and extrapolated to two years (about 6.3 x 107 sec). The extrapolated breakout force was 4.1 N, which is an acceptable breakout force for a 1 ml medical syringe used for injection of patients. The plot is the descending plot shown in FIG.. 15.
[533] Comparative testing was carried out, using the same type of bilayer coated syringe and a Stelmi C2574 plunger tip, coated with a 10-micron coating of PTFE using chemical vapor deposition. The result was plotted in FIG. 15 (log F, vs. log time), and is the ascending plot showing a very slight increase in initiation force over time
[534] Comparative testing was carried out, using the same type of bilayer coated syringe and an unmodified Stelmi C2574 plunger tip, with the syringe conventionally lubricated with silicone oil. The data obtained is plotted on Fig. 7, marked as "Bi-layer plastic syringe with silicone oil" (etc.). The extrapolated (2-year) breakout force was 29.7 N, which means a much higher force was required to break out the conventionally lubricated plunger than was needed for the 2 urn Parylene HT®-Coated Plunger.
[535] Comparative testing was carried out, using a commercially available glass syringe and an unmodified Stelmi C2574 plunger tip, again with the syringe conventionally lubricated with silicone oil. The extrapolated (2-year) force was 12.7 N, which means a higher force was required to break out the conventionally lubricated plunger in a glass syringe than was needed for the 2 urn Parylene HT®-Coated Plunger.
[536] It is surprising that the Parylene HT® coated plunger had a much lower breakout force than the Parylene C coated plunger, since the Wolgemuth article cited in this specification states, at page 45, "Parylene N, C, and Parylene HT® offer similar lubricity capabilities...." It is also surprising that a Parylene coated plunger provides a lower breakout force than the industry standard - a glass barrel syringe lubricated with silicone oil.
[537] Additional testing was done to measure the Fm, or maintenance force to maintain plunger travel in the syringe barrel after breakout for the Sample B syringes, using plungers coated 2 microns thick with Parylene HT®, and extrapolate the results to a two-year park time. The Fm was 4.7 N, thus nearly the same as the F, or breakout force. This low, nearly equal breakout and maintenance force means that the syringes had a very smooth action, with little tendency to cause the hypodermic needle to jerk at the beginning of administration of the contents of the syringe during an injection. These are highly desirable properties of a syringe.
Working Example B:
Parylene or halogenated polymer Coated Plunger Providing a Lower Plunger Breakout Force That is More Consistent Throughout Shelf Life
[538] This testing was done to show the advantages to be obtained by coating the plunger of a syringe with a parylene or halogenated polymer, as described for embodiments of this invention.
[539] 1 ml thermoplastic staked syringes, cartridges, or similar articles (i.e. with permanently attached needles) were provided with Stelmi plungers having elastomeric plunger tips, threaded plunger rods, and barrels.
[540] The syringe barrels were coated with a PECVD SiOx barrier coating or layer and a PECVD protective coating or layer on the interior surfaces. These coatings or layers are referred to in the legend on FIG. 3 as a "Bilayer."
[541 ] Separately, the plunger tips were coated using the GVD Corporation hot wire or filament chemical vapor deposition (HWCVD) equipment and a method similar to those described in U.S. Publ. Appl. 2012/0003497. The coating was applied 10 microns (micrometers) thick with a parylene or halogenated polymer characterized as polytetrafluoroethylene (PTFE), at a maximum temperature of the tip of 100°C, over a period of 2 hours, allowing intermediate time for the plunger tips to cool to maintain the maximum temperature. There was no evidence of melting or distortion to the tips.
[542] Each plunger was assembled on the plunger rod until it bottomed out on the plunger rod shoulder. The plunger assembly was then inserted into the syringe barrel to the appropriate depth and allowed to dwell or park undisturbed for 100 sec, one hour, three hours, or 24 hours (86,400 seconds).
[543] The syringes, cartridges, or similar articles were tested for static force (breakout force) on an Instron unit at the end of their respective park times. This was repeated for each of the (10) replicate test samples. The static force (Newtons, N) was plotted versus time (sec) on a log-log scale, providing a linear plot. The plot is the nearly horizontal plot identified in FIG. 3 as "Bi-layer with PFTE" (etc.). The slope and intercept of the plot was then calculated (slope 0.0049, intercept 0.8364) and extrapolated to two years (about 6.3 x 107 sec). The extrapolated breakout force was 7.5 N, which is an acceptable breakout force for a 1 ml medical syringe used for injection of patients.
Comparative Examples
[544] Parallel testing was done with three other comparative samples.
[545] One comparative example was carried out as described above in the working example, except that the PTFE coating on the plunger tip was only 1 micron thick. This experiment did not yield a linear plot or nearly as low breakout forces, so it was regarded as unsuccessful.
[546] A second comparative example was carried out as described in the working example above, except that instead of applying a PTFE coating the bilayer coated plastic syringe was siliconized conventionally by applying silicone oil to lubricate it. The resulting plot and extrapolation are shown in FIG. 3 with the legend, "bilayer coated plastic syringe with silicone oil" (etc). As shown the slope was 0.1767, the intercept was 0.0939, and the two-year extrapolation of breakout force was 29.7 N. It was surprising that the substitution of silicone oil for the PTFE coating had such a drastic effect on the slope of the plot and thus the increase in breakout force with an increase in park time.
[547] A third comparative example was carried out as described in the working example above, except that a glass syringe and no bi-layer coating was used, and instead of applying a PTFE coating the glass syringe was siliconized conventionally by applying silicone oil to lubricate it. The resulting plot and extrapolation are shown in FIG. 3 with the legend, "glass syringe with silicone oil" (etc). As shown the slope was 0.2072, the intercept was 0.51 18, and the two-year extrapolation of breakout force was 12.7 N.
[548] The data show that a 10 micron thick PTFE coating is effective at maintaining a consistent plunger force over a 24 hour period, with almost horizontal slope, while the comparative examples had a substantial upward slope showing a substantial increase of breakout force with park time. The data also show that a 1 micron thick PTFE is not as effective a lubricity layer as the 10 micron PTFE coating.
[549] This invention thus addresses and (based on extrapolation of short-term data) largely solves the problem of providing a lubricity coating that maintains a consistent breakloose force over the pre-filled syringe shelf life - approximately 2-3 years.
Example Z: Protective coating or layer Extractables
[550] This testing is done on syringes, cartridges, or similar articles to show the effect of the protective coating or layer on silicon extractables.
[551 ] Silicon extractables from syringes, cartridges, or similar articles were measured using ICP-MS analysis as described in the Protocol for Measuring Dissolved
Silicon in a Vessel. The syringes, cartridges, or similar articles were evaluated in both static and dynamic situations. The Protocol for Measuring Dissolved Silicon in a Vessel, modified as follows, describes the test procedure:
[552] · Syringe 12 filled with 2 ml of 0.9% saline solution
[553] · Syringe 12 placed in a stand - stored at 50 °C for 72 hours.
[554] · After 72 hours saline solution test for dissolved silicon
[555] · Dissolved silicon measured before and after saline solution expelled through syringe 12.
[556] The extractable Silicon Levels from a silicon oil coated glass syringe and a Lubricity and/or protective coated and SiOx coated COC syringe 12 are shown in Table 7. Precision of the ICP-MS total silicon measurement is +/- 3%.
Comparative Example AA: Dissolution of SiOx Coating Versus pH
[557] The Protocol for Measuring Dissolved Silicon in a Vessel is followed, except as modified here. Test solutions - 50 mM buffer solutions at pH 3, 6, 7, 8, 9, and 12 are prepared. Buffers are selected having appropriate pKa values to provide the pH values being studied. A potassium phosphate buffer is selected for pH 3, 7, 8 and 12, a sodium citrate buffer is utilized for pH 6 and tris buffer is selected for pH 9. 3 ml of each test solution is placed in borosilicate glass 5 ml pharmaceutical vials and SiOx coated 5 ml thermoplastic pharmaceutical vials. The vials are all closed with standard coated stoppers and crimped. The vials are placed in storage at 20 - 25 °C and pulled at various time points for inductively coupled plasma spectrometer (ICP) analysis of Si content in the solutions contained in the vials, in parts per billion (ppb) by weight, for different storage times.
[558] The Protocol for Determining Average Dissolution Rate Si content is used to monitor the rate of glass dissolution, except as modified here. The data is plotted to determine an average rate of dissolution of borosilicate glass or SiOx coating at each pH condition. Representative plots at pH 6 through 8 are FIGS 27-29.
[559] The rate of Si dissolution in ppb is converted to a predicted thickness (nm) rate of Si dissolution by determining the total weight of Si removed, then using a surface area calculation of the amount of vial surface (1 1 .65 cm2) exposed to the solution and a density of SiOx of 2.2 g/cm3. FIG. 30 shows the predicted initial thickness of the SiOx coating required, based on the conditions and assumptions of this example (assuming a residual SiOx coating of at least 30 nm at the end of the desired shelf life of two years, and assuming storage at 20 to 25 °C). As FIG. 30 shows, the predicted initial thickness of the coating is about 36 nm at pH 5, about 80 nm at pH 6, about 230 nm at pH 7, about 400 nm at pH 7.5, about 750 nm at pH 8, and about 2600 nm at pH 9.
[560] The coating thicknesses in FIG. 30 represent atypically harsh case scenarios for pharma and biotech products. Most biotech products and many pharma products are stored at refrigerated conditions and none are typically recommended for storage above room temperature. As a general rule of thumb, storage at a lower temperature reduces the thickness required, all other conditions being equivalent.
[561 ] The following conclusions are reached, based on this test. First, the amount of dissolved Si in the SiOx coating or glass increases exponentially with increasing pH. Second, the SiOx coating dissolves more slowly than borosilicate glass at a pH lower than 8. The SiOx coating shows a linear, monophasic dissolution over time, whereas borosilicate glass tends to show a more rapid dissolution in the early hours of exposure to solutions, followed by a slower linear dissolution. This may be due to surface accumulation of some salts and elements on borosilicate during the forming process relative to the uniform composition of the SiOx coating. This result incidentally suggests the utility of an SiOx coating on the wall of a borosilicate glass vial to reduce dissolution of the glass at a pH lower than 8. Third, PECVD applied barrier coatings for vials in which pharmaceutical preparations are stored will need to be adapted to the specific pharmaceutical preparation and proposed storage conditions (or vice versa), at least in some instances in which the pharmaceutical preparation interacts with the barrier coating significantly.
Example BB
[562] An experiment is conducted with vessels coated with SiOx coating + OMCTS lubricity layer, to test the lubricity layer for its functionality as a protective coating or layer. The vessels are 5 mL vials (the vials are normally filled with product to 5 mL; their capacity without headspace, when capped, is about 7.5 mL) composed of cyclic olefin co-polymer (COC, Topas® 6013M-07).
[563] Sixty vessels are coated on their interior surfaces with an SiOx coating produced in a plasma enhanced chemical vapor deposition (PECVD) process using a HMDSO precursor vapor according to the Protocol for Coating Tube Interior with SiOx set forth above, except that equipment suitable for coating a vial is used. The following conditions are used.
• HMDSO flow rate: 0.47 seem
• Oxygen flow rate: 7.5 seem
• RF power: 70 Watts
• Coating time: 12 seconds (includes a 2-sec RF power ramp-up time)
[564] Next the SiOx coated vials are coated over the SiOx with an SiOxCy coating produced in a PECVD process using an OMCTS precursor vapor according to the Protocol for Coating COC Syringe Barrel Interior with OMCTS Lubricity Coating set forth above, except that the same coating equipment is used as for the SiOx coating. Thus, the special adaptations in the protocol for coating a syringe 12 are not used. The following conditions are used.
• OMCTS flow rate: 2.5 seem
• Argon flow rate: 10 seem
• Oxygen flow rate: 0.7 seem
• RF power: 3.4 Watts
• Coating time: 5 seconds
[565] Eight vials are selected and the total deposited quantity of PECVD coating (SiOx + SiOxCy) is determined with a Perkin Elmer Optima Model 7300DV ICP-OES
instrument, using the Protocol for Total Silicon Measurement set forth above. This measurement determines the total amount of silicon in both coatings, and does not distinguish between the respective SiOx and SiOxCy coatings. The results are shown below.
Quantity of SiOx + Lubricity layer on Vials
[567] In the following work, except as indicated otherwise in this example, the Protocol for Determining Average Dissolution Rate is followed. Two buffered pH test solutions are used in the remainder of the experiment, respectively at pH 4 and pH 8 to test the effect of pH on dissolution rate. Both test solutions are 50 mM buffers using potassium phosphate as the buffer, diluted in water for injection (WFI) (0.1 urn sterilized, filtered). The pH is adjusted to pH 4 or 8, respectively, with concentrated nitric acid.
[568] 25 vials are filled with 7.5 ml per vial of pH 4 buffered test solution and 25 other vials are filled with 7.5 ml per vial of pH 4 buffered test solution (note the fill level is to the top of the vial - no head space). The vials are closed using prewashed butyl stoppers and aluminum crimps. The vials at each pH are split into two groups. One group at each pH containing 12 vials is stored at 4°C and the second group of 13 vials is stored at 23 °C
[569] The vials are sampled at Days 1 , 3, 6, and 8. The Protocol for Measuring Dissolved Silicon in a Vessel is used, except as otherwise indicated in this example. The analytical result is reported on the basis of parts per billion of silicon in the buffered
test solutions of each vial. A dissolution rate is calculated in terms of parts per billion per day as described above in the Protocol for Determining Average Dissolution Rate. The results at the respective storage temperatures follow:
[570] The observations of Si dissolution versus time for the OMCTS-based coating at pH8 and pH 4 indicate the pH 4 rates are higher at ambient conditions. Thus, the pH 4 rates are used to determine how much material would need to be initially applied to leave a coating of adequate thickness at the end of the shelf life, taking account of the amount of the initial coating that would be dissolved. The results of this calculation are:
Shelf Life Calculation
[571 ] Based on this calculation, the OMCTS lubricity layer needs to be about 2.5 times thicker - resulting in dissolution of 33945 ppb versus the 14,371 ppb representing the entire mass of coating tested - to achieve a 3-year calculated shelf life.
Example CC
[572] The results of Comparative Example AA and Example BB above can compared as follows, where the "lubricity layer" is the coating of SiOxCy referred to Example BB.
[573] This data shows that the silicon dissolution rate of SiOx alone is reduced by more than 2 orders of magnitude at pH 8 in vials also coated with SiOxCy coatings.
[574] Another comparison is shown by the following data from several different experiments carried out under similar accelerated dissolution conditions, of which the 1 - day data is also presented in Fig. 31 .
Silicon Dissolution with pH 8 at 40°C
(ug/L)
Vial Coating
1 2 3 10
4 days 7 days 15 days
Description day days days days
A. SiOx made 165 21 1 226 252 435 850 1 ,364 with HMDSO
Plasma +
SiwOxCy or its
equivalent
SiOxCy made
with OMCTS
Plasma
B. SiwOxCy or 109 107 76 69 74 158 198 its equivalent
SiOxCy made
with OMCTS
Plasma
Silicon Dissolution with pH 8 at 40°C
(ug/L)
Vial Coating
1 2 3 10
4 days 7 days 15 days
Description day days days days
C. SiOx made 2,504 4,228 5,226 5,650 9,292 10,177 9,551 with HMDSO
Plasma
D. SiOx made 1 ,607 1 ,341 3,927 10,182 18,148 20,446 21 ,889 with HMDSO
Plasma +
SiwOxCy or its
equivalent
SiOxCy made
with HMDSO
Plasma
E. SiwOxCy or 1 ,515 1 ,731 1 ,813 1 ,743 2,890 3,241 3,812 its equivalent
SiOxCy made
with HMDSO
Plasma
[575] Fig. 31 and Row A (SiOx with OMCTS coating) versus C (SiOx without OMCTS coating) show that the OMCTS lubricity layer is also an effective protective coating or layer to the SiOx coating at pH 8. The OMCTS coating reduced the one-day dissolution rate from 2504 ug/L ("u" or μ or the Greek letter "mu" as used herein are identical, and are abbreviations for "micro") to 165 ug/L. This data also shows that an HMDSO-based SiwOxCy (or its equivalent SiOxCy) overcoat (Row D) provided a far higher dissolution rate than an OMCTS-based SiwOxCy (or its equivalent SiOxCy) overcoat (Row A). This data shows that a substantial benefit can be obtained by using a cyclic precursor versus a linear one.
Example DD
[576] Samples 1 -6 as listed in Table 9 were prepared as described in Example AA, with further details as follows.
[577] A cyclic olefin copolymer (COC) resin was injection molded to form a batch of 5ml vials. Silicon chips were adhered with double-sided adhesive tape to the internal walls of the vials. The vials and chips were coated with a two layer coating by plasma enhanced chemical vapor deposition (PECVD). The first layer was composed of SiOx with barrier properties as defined in the present disclosure, and the second layer was an SiOxCy protective coating or layer.
[578] A precursor vapor mixture comprising OMCTS, argon, and oxygen was introduced inside each vial. The gas inside the vial was excited between capacitively coupled electrodes by a radio-frequency (13.56 MHz) power source as described in connection with FIGS. 1 , 2, 1 1 -15, and 25. The monomer flow rate (Fm) in units of seem, oxygen flow rate (F0) in units of seem, argon flowrate in seem, and power (W) in units of watts are shown in Table 9.
[579] A composite parameter, W/FM in units of kJ/kg, was calculated from process parameters W, Fm, F0 and the molecular weight, M in g/mol, of the individual gas species. W/FM is defined as the energy input per unit mass of polymerizing gases. Polymerizing gases are defined as those species that are incorporated into the growing coating such as, but not limited to, the monomer and oxygen. Non-polymerizing gases, by contrast, are those species that are not incorporated into the growing coating, such as but not limited to argon, helium and neon.
[580] In this test, PECVD processing at high W/FM is believed to have resulted in higher monomer fragmentation, producing organosiloxane coatings with higher crosslink density. PECVD processing at low W/FM, by comparison, is believed to have resulted in lower monomer fragmentation producing organosiloxane coatings with a relatively lower cross-link density.
[581 ] The relative cross-link density of samples 5, 6, 2, and 3 was compared between different coatings by measuring FTIR absorbance spectra. The spectra of samples 5, 6, 2, and 3 are provided in Figs. 34-37. In each spectrum, the ratio of the peak absorbance at the symmetric stretching mode (1000-1040 cm"1) versus the peak absorbance at the asymmetric stretching mode (1060-1 100 cm"1) of the Si-O-Si bond was measured, and the ratio of these two measurements was calculated, all as shown
in Table 9. The respective ratios were found to have a linear correlation to the composite parameter W/FM as shown in Fig. 32.
[582] A qualitative relation - whether the coating appeared oily (shiny, often with irridescence) or non-oily (non-shiny) when applied on the silicon chips - was also found to correlate with the W/FM values in Table 9. Oily appearing coatings deposited at lower W/FM values, as confirmed by Table 9, are believed to have a lower crosslink density, as determined by their lower sym/asym ratio, relative to the non-oily coatings that were deposited at higher W/FM and a higher cross-link density. The only exception to this general rule of thumb was sample 2 in Table 9. It is believed that the coating of sample 2 exhibited a non-oily appearance because it was was too thin to see. Thus, an oilyness observation was not reported in Table 9 for sample 2. The chips were analyzed by FTIR in transmission mode, with the infrared spectrum transmitted through the chip and sample coating, and the transmission through an uncoated null chip subtracted.
[583] Non-oily organosiloxane layers produced at higher W/FM values, which protect the underlying SiOx coating from aqueous solutions at elevated pH and temperature, were preferred because they provided lower Si dissolution and a longer shelf life, as confirmed by Table 9. For example, the calculated silicon dissolution by contents of the vial at a pH of 8 and 40 °C was reduced for the non-oily coatings, and the resulting shelf life was 1381 days in one case and 1 147 days in another, as opposed to the much shorter shelf lives and higher rates of dissolution for oily coatings. Calculated shelf life was determined as shown for Example AA. The calculated shelf life also correlated linearly to the ratio of symmetric to asymmetric stretching modes of the Si-O- Si bond in organosiloxane protective coating or layers.
[584] Sample 6 can be particularly compared to Sample 5. An organosiloxane, pH protective coating or layer was deposited according to the process conditions of sample 6 in Table 9. The coating was deposited at a high W/FM. This resulted in a non-oily coating with a high Si-O-Si sym/asym ratio of 0.958, which resulted in a low rate of dissolution of 84.1 ppb/day (measured by the Protocol for Determining Average Dissolution Rate) and long shelf life of 1 147 days (measured by the Protocol for
Determining Calculated Shelf Life). The FTIR spectra of this coating is shown in Figure
35, which exhibits a relatively similar asymmetric Si-O-Si peak absorbance compared to the symmetric Si-O-Si peak absorbance. This is an indication of a higher cross-link density coating, which is a preferred characteristic for pH protection and long shelf life.
[585] An organosiloxane pH protective coating or layer was deposited according to the process conditions of sample 5 in Table 9. The coating was deposited at a moderate W/FM. This resulted in an oily coating with a low Si-O-Si sym/asym ratio of 0.673, which resulted in a high rate of dissolution of 236.7 ppb/day (following the Protocol for Determining Average Dissolution Rate) and shorter shelf life of 271 days (following the Protocol for Determining Calculated Shelf Life). The FTIR spectrum of this coating is shown in FIG. 34, which exhibits a relatively high asymmetric Si-O-Si peak absorbance compared to the symmetric Si-O-Si peak absorbance. This is an indication of a lower cross-link density coating, which is contemplated to be an unfavorable characteristic for pH protection and long shelf life.
[586] Sample 2 can be particularly compared to Sample 3. A protective coating or layer was deposited according to the process conditions of sample 2 in Table 9. The coating was deposited at a low W/FM. This resulted in a coating that exhibited a low Si- O-Si sym/asym ratio of 0.582, which resulted in a high rate of dissolution of 174ppb/day and short shelf life of 107 days. The FTIR spectrum of this coating is shown in Figure
36, which exhibits a relatively high asymmetric Si-O-Si peak absorbance compared to the symmetric Si-O-Si peak absorbance. This is an indication of a lower cross-link density coating, which is an unfavorable characteristic for pH protection and long shelf life.
[587] An organosiloxane, pH protective coating or layer was deposited according to the process conditions of sample 3 in Table 9. The coating was deposited at a high W/FM. This resulted in a non-oily coating with a high Si-O-Si sym/asym ratio of 0.947, which resulted in a low rate of Si dissolution of 79.5ppb/day (following the Protocol for Determining Average Dissolution Rate) and long shelf life of 1381 days (following the Protocol for Determining Calculated Shelf Life). The FTIR spectrum of this coating is shown in Figure 37, which exhibits a relatively similar asymmetric Si-O-Si peak
absorbance compared to the symmetric Si-O-Si peak absorbance. This is an indication of a higher cross-link density coating, which is a preferred characteristic for pH protection and long shelf life.
Example EE
[588] An experiment similar to Example BB was carried out, modified as indicated in this example and in Table 10 (where the results are tabulated). 100 5 mL COP vials were made and coated with an SiOx barrier layer and an OMCTS-based protective coating or layer as described previously, except that for Sample PC194 only the protective coating or layer was applied. The coating quantity was again measured in parts per billion extracted from the surfaces of the vials to remove the entire protective coating or layer, as reported in Table 10.
[589] In this example, several different coating dissolution conditions were employed. The test solutions used for dissolution contained either 0.02 or 0.2 wt.% polysorbate-80 surfactant, as well as a buffer to maintain a pH of 8. Dissolution tests were carried out at either 23 °C or 40 °C.
[590] Multiple syringes, cartridges, or similar articles were filled with each test solution, stored at the indicated temperature, and analyzed at several intervals to determine the extraction profile and the amount of silicon extracted. An average dissolution rate for protracted storage times was then calculated by extrapolating the data obtained according to the Protocol for Determining Average Dissolution Rate. The results were calculated as described previously and are shown in Table 10. Of particular note, as shown on Table 10, were the very long calculated shelf lives of the filled packages provided with a PC 194 protective coating or layer:
[591 ] 21045 days (over 57 years) based on storage at a pH of 8, 0.02 wt.% polysorbate-80 surfactant, at 23 °C;
[592] 38768 days (over 100 years) based on storage at a pH of 8, 0.2 wt.% polysorbate-80 surfactant, at 23 °C;
[593] 8184 days (over 22 years) based on storage at a pH of 8, 0.02 wt.% polysorbate-80 surfactant, at 40 °C; and
[594] 14732 days (over 40 years) based on storage at a pH of 8, 0.2 wt.% polysorbate-80 surfactant, at 40 °C.
[595] Referring to Table 10, the longest calculated shelf lives corresponded with the use of an RF power level of 150 Watts and a corresponding high W/FM value. It is believed that the use of a higher power level causes higher cross-link density of the protective coating or layer.
Example FF
[596] Another series of experiments similar to those of Example EE are run, showing the effect of progressively increasing the RF power level on the FTIR absorbance spectrum of the protective coating or layer. The results are tabulated in Table 1 1 , which in each instance shows a symmetric / assymmetric ratio greater than 0.75 between the maximum amplitude of the Si-O-Si symmetrical stretch peak normally located between about 1000 and 1040 cm"1 , and the maximum amplitude of the Si-O-Si assymmetric stretch peak normally located between about 1060 and about 1 100 cm"1. Thus, the symmetric / assymmetric ratio is 0.79 at a power level of 20 W, 1 .21 or 1 .22 at power levels of 40, 60, or 80 W, and 1 .26 at 100 Watts under otherwise comparable conditions.
[597] The 150 Watt data in Table 1 1 is taken under somewhat different conditions than the other data, so it is not directly comparable with the 20 - 100 Watt data discussed above. The FTIR data of samples 6 and 8 of Table 1 1 was taken from the upper portion of the vial and the FTIR data of samples 7 and 9 of Table 1 1 was taken from the lower portion of the vial. Also, the amount of OMCTS was cut in half for samples 8 and 9 of Table 1 1 , compared to samples 6 and 7. Reducing the oxygen level while maintaining a power level of 150 W raised the symmetric / asymmetric ratio still further, as shown by comparing samples 6 and 7 to samples 8 and 9 in Table 1 1 .
[598] It is believed that, other conditions being equal, increasing the symmetric / asymmetric ratio increases the shelf life of a vessel filled with a material having a pH exceeding 5.
[599] Table 12 shows the calculated O-Parameters and N-Parameters (as defined in U.S. Pat. No. 8,067,070) for the experiments summarized in Table 1 1 . As Table 12 shows, the O-Parameters ranged from 0.134 to 0.343, and the N-Parameters ranged from 0.408 to 0.623 - all outside the ranges claimed in U.S. Pat. No. 8,067,070.
TABLE 8: Summary Table of OMCTS protective coating or layer from Tables 1 , 2, 3 and 5
TABLE 9
Process Parameters Si Dissolution @ pH8/40eC FTI R Absorbance
Si-O-Si
Si-O-Si asym
Rate of sym stretch stretch Ratio Si-O-
Flow Rate o2 W/FM Total Si Shelf life Dissolution (1000- (1060- Si
Samples OMCTS Ar Flow Rate Power (W) (kJ/kg) (ppb) (days) (ppb/day) 1040cm"1) 1 100cm"1) (sym/asym) Oilyness
1 3 10 0.5 14 21613 43464 385 293.18 0.153 0.219 0.700 YES
2 3 20 0.5 2 3088 7180 107 174.08 0.01 1 0.020 0.582 NA
3 1 20 0.5 14 62533 42252.17 1381 79.53 0.093 0.098 0.947 NO
4 2 15 0.5 8 18356 27398 380 187.63 0.106 0.141 0.748 YES
5 3 20 0.5 14 21613 24699 271 236.73 0.135 0.201 0.673 YES
6 1 10 0.5 14 62533 37094 1 147 84.1 0.134 0.140 0.958 NO
TABLE 10
TABLE 11
TABLE 12
Parylene Coating Theory
[600] The following theory of operation is provided to indicate the inventors' conception of how the invention works. The scope and validity of the claims do not depend on the accuracy or completeness of this theory.
[601 ] The classic molecular layer chemistries are self-assembled monolayers (SAMs). SAMs are long-chain alkyl chains, which interact with surfaces based on sulfur- metal interaction (alkylthiolates) or a sol-gel type reaction with a hydroxylated oxide surface (trichlorosilyl alkyls or trialkoxy alkyls). However, unless a gold or oxide surface is provided and carefully treated and the alkyl chain is long, these SAMs form disordered monolayers, which do not pack well. This lack of packing causes issues of, for example, sticktion in micro electro-mechanical system (MEMS) devices.
[602] The observation that Parylene could form ordered molecular layers (MLs) came with contact angle measurements, where MLs thicker than 10 A had an equilibrium contact angle of 80 degrees (same as bulk Parylene N) but those thinner had a reduced contact angle. This is also confirmed with electrical measurements (bias- temperature stress measurements) using metal-insulator-semiconductor capacitors (MISCAPs). In short, Parylene coatings with no functional groups are pin-hole free at -10 A. This results because the Parylene repeat units have a phenyl ring. Because of the high electronic polarizability of the phenyl ring, adjacent repeat units order themselves in the XY-plane. As a result of this interaction, Parylene MLs are surface independent, except for transition metals (where they don't deposit). This finding of Parylene as molecular layers is very powerful for industrial applications because of the robustness of the process and that the MLs are deposited at room temperature.
[603] It is the combination of low temperature coating (amenable to organic articles, plastics, elastomers), high self-orientation capability (independent of substrate), and low surface energy (for fluorinated Parylene) which provides unique potential for application of stopper, O-ring, plunger tip, and piston coatings, as well as barrel coatings, vial coatings, and vial stopper coatings, offering excellent lubricity, container closure, and low extractables.
Additional Parylene Examples
Parylene dimer-type coating of tips via thermal CVD- General Procedure 1
[604] The standard Gorham process as disclosed in U.S. Pat. No. 3,342,754 (incorporated here by reference) and elsewhere, regardless of the cyclophane starting chemistry, can be utilized for Parylene coating. Parylene and its precursors are cyclophanes. A cyclophane is a hydrocarbon consisting of an aromatic unit (typically a benzene ring) and an aliphatic chain that forms a bridge between two non-adjacent positions of the aromatic ring. The coating hardware can range from that described in Gorham et.al. to equipment defined in www.scscoating.com.
[605] The solid cyclophane dimer is placed into a loading boat, which is then inserted into the vaporizer. Under a base pressure of 1-100 mTorr, the dimer is heated between 100-150 °C causing either sublimation or vaporization. This dimer vapor is passed into to a pyrolysis heater zone (temperature: 650-700 °C). In this pyrolysis zone (typically a quartz tube), the cyclophane dimer is thermally cracked (split) into two xylylidene monomer intermediates, which are transported to a room temperature deposition chamber. The intermediate condenses on the article to be coated and polymerizes into the Parylene coating. Depending on the vapor pressure of the specific cyclophane, typical Parylene deposition rates are about 0.2 mils (5 microns) per hour.
[606] Optionally, pretreatment of the article surface can be done, including plasma gas (argon, oxygen, nitrogen, water vapor), carbon dioxide powder, and other surface treatment/modification methods to clean and/or roughen and/or prime the surface for improved Parylene coating adhesion. See, e.g., W.F. Gorham (1966). "A New, General Synthetic Method for the Preparation of Linear Poly-p-xylylenes". J. Polym. Sci. A 4 (12): 3027.
Parylene Monomor Coating of Tips Via Pyrolytic Chemical Vapor Deposition - General Procedure 2.
[607] The procedure, materials, and apparatus generally as described in U.S. Pat. No. 5,268,202, You et al., Example 1 , incorporated here by reference, are used to deposit a Parylene HT coating on a thermoplastic resin substrate.
Stratamet Thin Film Corporation Parylene HT Monomer Coating of Tips
[608] A procedure similar to General Procedure 2 is followed, for example by Stratamet Thin Film Corporation, except that in the Stratamet process the catalyst optionally can comprise a heated solid zinc metal matrix and the precursor optionally can comprise BrCF2-C6H4-CF2Br, either used alone or as an initiator with 1 ,4- bis(trifluoromethyl)benzene (CAS No. 455-19-2).
EXAMPLE P1- Parylene C coatings from 2,2'-dichloro[2.2]paracyclophane- Prophetic
[609] Using each of the Parylene procedures above, Stelmi plunger tips (1 ml Long Plunger (Gray), two coating runs are performed depositing 0.5 and 2 microns of Parylene C coating, respectively.
Example P2- Parylene HT® coatings from octafluoro-[2.2]paracyclophane- Prophetic
[610] Using the general Parylene procedure above, Stelmi plunger tips (1 ml Long Plunger (Gray) Lot G01 1 /50825), two coating runs are performed depositing 0.5 and 2 microns of Parylene HT® coating, respectively.
Example P3- Fluorinated Parylene coatings- prophetic
[61 1 ] Using the general Parylene procedure above on plunger tips, coating runs are performed depositing 0.05, 0.2, 0.5, 0.8, 1 , 1 .5, 2, 3, and 5 microns of Parylene CF and a Parylene dimer containing one to eight fluorine atoms on the two aromatic rings and, independently, one to eight fluorine atoms on the four methylene carbons, bonded to the Parylene dimer molecule coating, respectively.
[612] Parylene CF is also known as VT-4, generic name (Kisco product).
Example P4 - PTFE-type coating of tips via thermal CVD -General Procedure
[613] Depositions are performed in a custom-built vacuum chamber onto Stelmi plunger tip substrates. The pressure within the chamber is controlled by a butterfly valve connected to an MKS type 252 exhaust valve controller. Substrates are placed on a stage maintained at a low temperature (15 ± 5 °C) by the circulation of chilled water through internal coils.
[614] Precursor and/or radical initiator breakdown is achieved by means of a resistively heated 0.038-cm-diameter Nichrome wire (80% nickel, 20% chromium; Omega Engineering). The frame holding the filament wire is equipped with springs to compensate for thermal expansion of the wire upon heating. The distance between the filament wire and the substrate is less than 3 centimeters. The filament temperature is measured by a 2.2-pm infrared pyrometer. The spectral emissivity is estimated to be 0.85 based on direct-contact thermocouple experiments.
[615] The flow of hexafluoropropylene oxide (HFPO) gas into the chamber is controlled by an MKS model 1295C mass flow controller (MFC). The tert-butylperoxide (TBPO) and co-monomers, as utilized, are vaporized in a stainless steel heated vessel. The lines leading from the vessel to the vacuum chamber are maintained at 130 ± 5 °C. The flow of vapor from the vessel into the chamber is regulated by a needle valve.
[616] Prior to the deposition of copolymer film, the filament wire is preconditioned by being heated at a constant voltage of 86.5 V and under a flow of HFPO into the reactor at 30 seem for 20 min at a chamber pressure of 1 Torr. Following this treatment, the power to the filament is turned down over a 5-min span, and the chamber is pumped up to atmospheric pressure to facilitate cleaning and placement of the plunger tips on the stage.
[617] Depositions are performed at a filament temperature of 620 °C and a chamber pressure of 1 Torr. The precursor flow rate is 20 seem for HFPO. The duration of these depositions ranges between 10 minutes and 120 minutes. The deposition rate of PTFE is in the range of 5-10 microns per hour.
[618] Optionally, pretreatment of the article surface can be done, including plasma gas (argon, oxygen, nitrogen, water vapor), carbon dioxide powder, and other surface treatment/modification methods to clean and/or roughen and/or prime the surface for improved Parylene coating adhesion.
Example P5 - Polytetrafluoroethylene (PTFE) coating from perfluoroproyplene oxide (PFPO) - prophetic
[619] Using the general PTFE coating procedure above, Stelmi plunger tips (1 ml Long Plunger (Gray)), coating runs are performed depositing 0.1 , 1 , 5, 10, and 15 microns of coating, respectively.
Example P6- PTFE-co-(perfluoromonomer) coatings - prophetic
[620] Using the general PTFE coating procedure above on plunger tips including the co-monomer, hexafluoropropylene (HFP), coating runs are performed depositing 0.05, 0.2, 0.5, 0.8, 1 , 1 .5, 2, 3, 5 and 10 microns of a TFE-HFP (tetrafluoroethylene- hexafluoropropylene) copolymer.
Example P7- PTFE crosslinked coatings - prophetic
[621 ] Using the general PTFE coating procedure above on plunger tips including the co-monomer, divinylbenzene (DVB), coating runs are performed depositing 0.05, 0.2, 0.5, 0.8, 1 , 1 .5, 2, 3, 5 and 10 microns of a crosslinked TFE-DVB copolymer.
Example P8- Oriented PTFE coatings- Prophetic
[622] Tips are initially coated using perfluorooctylmethacrylate monomer and tert- butyl peroxide (TBPO), with the TBPO vapors exposed to temperatures (a) less than 270 °C and (b) greater than 300 °C. This results in orientation of the perfluorooctyl groups of the polymer perfluorooctylmethacrylate parallel and perpendicular (normal) to the substrate (tip) surface, respectively. Then, using the general PTFE coating procedure above on plunger tips coating runs are performed depositing 0.05, 0.2, 0.5, 0.8, 1 , 1 .5, 2, 3, 5 and 10 microns of a TFE polymer.
Example P9 - Composite Parylene - PTFE Coating - prophetic
[623] Utilizing a commercial CVD coater (SCS Coatings Labcoater 2), modified with a mass flow controller (MFC) and stainless tubing into a separate pyrolysis tube, Parylene N dimer is placed into the vaporizer chamber and hexafluoropropylene oxide (HFPO) into the feed side of the MFC. Syringe elastomeric plunger tips (Stelmi 6720) and/or molded cyclic olefin polymer (COP) plastic 1 ml staked needle syringe barrels are placed into the deposition chamber.
[624] The vacuum pump is operated at a nominal base pressure of 0.001 torr, with working pressures and temperatures of the Parylene delivery zones (vaporizer, pyrolysis) at 150°C and 680 °C, respectively, with the HFPO pyrolysis tube maintained at 250°C with a feed rate in the range of 0.1 to 10 seem, with the deposition zone maintained at 25 °C.
[625] The process is run for 20 minutes resulting in a coating on the articles. The articles, when tested for water wettability indicate a contact angle of greater than 90 degrees. The articles, when tested for lubricity via an Instron plunger force test, indicate an initiation/maintenance force of less than 25 Newtons that does not change over a week's time with the plunger/barrel placement. When tested for extractables with isopropanol, the coated plunger tips demonstrate lower extractables than uncoated tips. The articles, when tested for total silicon release from an SiOx coated syringe barrel, demonstrate a lower silicon dissolution rate than an uncoated syringe barrel.
Example P10 - (Coated Plunger Lubricity- Inventive)
[626] Stelmi plungers (chlorobutyl rubber composite) were coated with 1 .5-2 microns of Poly[1 ,4-phenylene(1 ,1 ,2,2-tetrafluoro-1 ,2-ethanediyl)] (Synonyms: Poly[p- phenylene (tetrafluoroethylene)](8CI); AF 4; Parylene AF 4; Parylene F (Kisco); Parylene HT (SCSCoatings); Poly(tetrafluoro-p-xylylene);(Poly(a,a,a',a'-tetrafluoro-p- xylylene)) .
[627] The coated plungers were then inserted into corresponding syringe barrels about 1 .5 centimeters from the plunger bottom with a threaded plunger rod. The
syringe barrels were SiOx/p-OMCTS bilayer coated 1 ml_ staked needle syringe COP barrels.
[628] Each rod-plunger/syringe barrel assembly was then placed on an Instron tensile testing machine and the force to Initiate Movement (Fi) and Maintain movement (Fm) of the plunger through the barrel were recorded. The average of 10 replicates is reported below.
Example P11 - (Uncoated Plunger Lubricity- Comparative)
[629] Example P10 was repeated except using untreated plunger tips. The averages of 10 replicates of Example P10 and 10 replicates of Example P1 1 were recorded as follows:
Syringe Plunger-Barrel Lubricity - Coated Plunger
(Newtons) F, Fm
Parylene HT (Inventive Example P10) 7.2 6.9
Uncoated (Comparative Example P1 1 ) >40 >40
Example P12 - (Coated Barrel Lubricity- Inventive, Prophetic)
[630] SiOx barrier layer interior coated 1 ml_ staked needle COP syringe barrels are further interior coated with 5-6 microns of Poly[1 ,4-(2-chloro)-phenylene(1 ,2-ethanediyl)] (Synonym: Parylene C). Stelmi plungers (chlorobutyl rubber composite) are inserted into the barrels about 1 .5 centimeters from the plunger bottom with a threaded plunger rod. The rod-plunger/syringe barrel assembly is then placed on an Instron tensile force tester, and the force to Initiate Movement (Fi) and Maintain movement (Fm) through the barrel is recorded. The predicted average of 10 replicates is reported below.
Example P13 - (Coated Barrel Lubricity- Inventive, Prophetic)
[631 ] Example P12 is repeated, except that the coating is 1 -2 microns of Poly[1 ,4- phenylene(1 ,1 ,2,2-tetrafluoro-1 ,2-ethanediyl)] (Synonyms: Poly[p-phenylene(tetrafluoro- ethylene)](8CI); AF 4; Parylene AF 4; Parylene F (Kisco); Parylene HT (SCSCoatings);
Poly(tetrafluoro-p-xylylene); Parylene HTX; Poly(a,a,a',a'-tetrafluoro-p-xylylene)). The predicted average of 10 replicates is reported below.
Syringe Plunger-Barrel Lubricity- Coated Barrel
(predicted Newtons) m
Parylene C (Inventive Example P12)
Poly[1 ,4-phenylene(1 ,1 ,2,2-tetrafluoro-1 ,2-ethanediyl)]
(Inventive Example P13)
Uncoated (Comparative Example P1 1 )
Example P14 - (Coated Barrel SiOx Dissolution Inhibition- Inventive, Prophetic)
[632] The interior plastic surfaces of SiOx-coated 1 ml_ staked needle COP syringe barrels are coated with 5-6 microns of Poly[1 ,4-(2-chloro)-phenylene(1 ,2-ethanediyl)] (Synonyms: Parylene C). The barrel is filled with pH=8 (NaOH) water and covered with aluminum foil. The samples are allowed to age for 3 days. The aqueous fluid contents are expelled and total silicon measured using an ICP measurement method. The predicted results are stated below.
Example P15 - (Coated Barrel SiOx Dissolution Inhibition- Inventive, Prophetic)
[633] The interior plastic surface of SiOx-coated 1 ml_ staked needle COP syringe barrels are coated with 1 -2microns of Poly[1 ,4-phenylene(1 ,1 ,2, 2-tetrafluoro-1 ,2- ethanediyl)] (Synonyms: Poly[p-phenylene(tetrafluoroethylene)](8CI); AF 4; Parylene AF 4; Parylene F (Kisco); Parylene HT (SCSCoatings); Poly(tetrafluoro-p-xylylene); Parylene HTX; Poly(a,a,a',a'-tetrafluoro-p-xylylene)). The barrel is filled with pH=8 (NaOH) water and covered with aluminum foil. The samples are allowed to age for 3 days. The aqueous fluid contents are expelled and total silicon measured using an ICP measurement method. The predicted results are stated below.
Example P16 - (Uncoated Barrel SiOx Dissolution Inhibition- Comparative, Prophetic)
[634] Example P15 is repeated, except without applying the Parylene coating. The predicted results are stated below.
Table 3. Barrel SiOx Dissolution Rate - Coated Barrel
Predicted Total Si (ppm, 3 days)
Parylene C (Inventive Example P14) < 100
Parylene HTX (Inventive Example P15) < 100
Uncoated (Comparative Example P16 > 1000
Example P17 - 2 micron Parylene HT-coated Stelmi 6901 Plunger- Lubricity
[635] Stelmi 6901 plunger tips were coated utilizing a pretreatment step of argon/oxygen plasma and trimethoxysilylpropylmethylacrylate [Dow Corning A174] vapor exposure, followed by application of a two micron parylene HT* coating (all performed by SCSCoating (7645 Woodland Drive Indianapolis, IN 46278 ). [*] Parylene HT is the SCS designation for Parylene AF4 [-CF2-C6H4-CF2-]n.
[636] Lubricity Test- 2 micron Parylene HT coated Stelmi 6901 plunger tips were attached to a plunger rod, then inserted (about 2 centimeters from the top opening with a spacer) into an SiOx/pOMCTS bilayer coated 1 ml_ staked needle syringe barrel. At various time intervals, from within two hours of tip insertion to 7 days from tip insertion, the plunger force was measured utilizing an Instron for recording the force (in Newtons) to move the plunger/rod down to the stop of the bottom of the syringe barrel at a fixed rate [Details are provided in earlier specifications]. Replicates of 10 systems were tested at five intervals over a 7 day interval. Two different Stelmi tip batches were coated (small batch/ large batch), three different siox/pOMCTS bilayer syringes were utilized, and one uncoated syringe, and two different filling conditions (unfilled (dry) and water-for-injection (WFI)).
[637] The average of the 10 replicates were determined and are reported in the following table:
Table - 2 micron Parylene HT Plunger Force Determination
Several features stand out with regard to the lubricity of Parylene HT, offering
(a) low initiation (Fi) and maintanence (Fm) forces; well below a targeted threshold of 15 Newtons,
(b) Fi and Fm forces are comparable; desirable to maintain uniform delivery rates,
(c) Fi and Fm forces are projected to be unchanging over an extrapolated time of up to 2 years; desirable for product consistency.
Example P18- 2 micron Parylene HT-coated Stelmi 6901 Plunger- Extractable Barrier
[638] The Stelmi 6901 coated tips were tested for plunger extractables level using water, pH8 buffered water, and isopropanol (I PA).
Only I PA resulted in extractables of uncoated 6901 Stelmi pluungers above the
Analytical Detection Threshold of 1 ,680,000 Abundance Units (Figure 59 below).
Comparing the 2 micron Parylene HT-coated 6901 Stelmi tip resulted in a 25-50% reduction in extractable levels.
Table. Comparison of Uncoated and 2 micron Parylene HT-coated Stelmi 6901 Plungers to IPA Extraction.
Abundance Units
Species (retention time = minutes) Sample C?i H4n (14.5) C?i HigCI (16) Broad band (20-35)
Uncoated Stelmi 6901 2.4E7 1 .5E7 4E6
2 micron Parylene HT-coated telmi 6901 1 .8E7 8E6 2E6
Reduction 25% 47% 50%
Note: "E" followed by a number n indicates that the number preceding the "E" is multiplied by 10". For example, "2.4E7" = 2.4 x 107 = 24,000,000.
Example P19- 2 micron Parylene HTX-coated Stelmi 6901 Plunger- Lubricity
[639] Stelmi 6720 plunger tips were coated with two microns Parylene HTX coating using the Stratamet process. Parylene HTX is the STF designation for Parylene AF4 [-CF2-C6H4-CF2-]n compostion.
Lubricity Test- 2 micron Parylene HTX coated Stelmi 6720 plunger tips were attached to a plunger rod, then inserted (about 2 centimeters from the top opening with a spacer) into an uncoated 1 ml_ staked needle syringe barrel. At various time intervals, from within two hours of tip insertion to 7 days from tip insertion, the plunger force was measured utilizing an Instron for recording the force (in Newtons) to move the plunger/rod down to the stop of the bottom of the syringe barrel at a fixed rate. Replicates of 5 systems were tested at five intervals over a 7 day interval.
[640] The average of the 5 replicates were determined (Table) and the F, results were plotted on a log-log plot versus park time (FIG. 14).
Table - 2 micron Parylene HTX Plunger Force Determination
Example P20- 2 micron Parylene HT-coated Stelmi 6901 Plunger versus uncoated Stelmi 6901- CCI
[641 ] Bonfiglioli CCI testing on plunger inserted barrels was performed. 2 micron Parylene HT indicated good container closure integrity (CCI) relative to uncoated Stelmi tips, as shown in FIG. 13.
GENERAL INFORMATION
[642] Parylene is a generic term often used to describe a class of poly-p-xylenes which may be derived from a dimer of the structure:
[643] wherein X is typically a hydrogen atom or a halogen atom. The most commonly used forms of these dimers include:
[644] Octafluoro-[2,2]paracyclophane (hereinafter "AF4") is a fluorine substituted version of the above dimer having the structure:
[645] While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; the invention is not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art and practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.
Claims
1 . A container comprising:
• a barrel or wall including a lumen, a vessel substrate defining at least a portion of the lumen, and an internal sliding surface on the vessel substrate adjacent to the lumen; and
• a stopper, O-ring, plunger tip or piston within the lumen comprising a substrate having an external sliding surface slidable in the lumen at least substantially in contact with the internal sliding surface;
wherein the internal sliding surface, the external sliding surface, or both is made at least in part of a parylene or a vapor-deposited halogenated polymer.
2. The invention of claim 1 , in which the at least one sliding surface is made at least in part of a parylene or halogenated polymer.
3. The invention of any preceding claim, in which the internal sliding surface is made at least in part of a parylene or halogenated polymer.
4. The invention of any preceding claim, in which the external sliding surface is made at least in part of a parylene or halogenated polymer.
5. The invention of any preceding claim, in which the internal sliding surface and the external sliding surface are made at least in part of the same or different parylene or halogenated polymers.
6. (canceled)
7. A method of making the article of any preceding claim, in which the parylene or halogenated polymer is deposited directly or with intervening layers to define the external sliding surface, the internal sliding surface, or both.
8. The invention of any preceding claim, in which the parylene or halogenated polymer is deposited by vapor deposition.
9. The invention of any preceding claim, in which the parylene or halogenated polymer optionally comprises polytetrafluoroethylene.
10. The invention of any preceding claim, in which the parylene or halogenated polymer optionally comprises linear polytetrafluoroethylene.
1 1 . The invention of any preceding claim, in which the parylene or halogenated polymer consists essentially of polytetrafluoroethylene.
12. The invention of any preceding claim, in which the parylene or halogenated polymer consists essentially of linear polytetrafluoroethylene.
13. The invention of any preceding claim, in which the parylene or halogenated polymer optionally comprises a fluorine substituted derivative of poly(paraxylylene).
14. The invention of any preceding claim, in which the parylene or halogenated polymer comprises polytetrafluoroparaxylylene.
15. The invention of any preceding claim, in which the parylene or halogenated polymer consists essentially of polytetrafluoroparaxylylene.
16. The invention of any preceding claim, in which the parylene or halogenated polymer optionally comprises a composite of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene).
17. The invention of any preceding claim, in which the parylene or halogenated polymer optionally comprises:
• polytetrafluoroethylene particles or a layer defining at least one of the internal and external sliding surfaces, and
• a fluorine substituted derivative of poly(paraxylylene) between the polytetrafluoroethylene particles or layer and the substrate.
18. The invention of any preceding claim, in which the parylene or halogenated polymer comprises polytetrafluoroethylene particles or a layer effective to improve the lubricity between the internal sliding surface and the external sliding surface.
19. The invention of any preceding claim, in which the parylene or halogenated polymer of at least one of the internal and external sliding surfaces comprises a composite layer of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene.
20. The invention of claim 19, in which the composite layer is formed by sequential deposition of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene).
21 . The invention of claim 19, in which the composite layer is formed at least in part by overlapping deposition of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene).
22. The invention of claim 21 , in which during the overlapping deposition a gradient composition is formed transitioning from predominantly the previously deposited composition, optionally the fluorine substituted derivative of poly(paraxylylene), to predominantly the later deposited composition, optionally polytetrafluoroethylene.
23. The invention of claim 19, in which the composite layer is formed by substantially simultanous deposition of polytetrafluoroethylene and a fluorine substituted derivative of poly(paraxylylene).
24. The invention of any preceding claim, in which the parylene or halogenated polymer is:
• opt onal iy 1 rom at least 0 01 micrometer to at most 100 micrometers thick,
• opt onal iy 1 rom at least 0 05 micrometers to at most 90 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 80 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 70 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 60 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 50 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 40 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 30 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 20 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 15 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 12 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 10 micrometers thick
• opt onal iy 1 rom at least 0 1 micrometers to at most 8 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 6 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 4 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 2 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 1 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 0.9 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 0.8 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 0.7 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 0.6 micrometers thick,
• opt onal iy 1 rom at least 0 1 micrometers to at most 0.5 micrometers thick,
• optionally from at least 0.5 micrometers to at most 5 micrometers thick,
• optionally from at least 0.5 micrometers to at most 4 micrometers thick,
• optionally from at least 0.5 micrometers to at most 3 micrometers thick,
• optionally from at least 0.5 micrometers to at most 2 micrometers thick,
• optionally from at least 0.5 micrometers to at most 1 micrometer thick,
• optionally about 10 micrometers thick,
• optionally about 2 micrometers thick.
25. The invention of any preceding claim, in which the parylene or halogenated polymer is applied by vapor deposition.
26. The invention of any preceding claim, in which the parylene or halogenated polymer is applied by chemical vapor deposition.
27. The invention of any preceding claim, in which the parylene or halogenated polymer is applied by chemical vapor deposition of dimeric tetrafluoroparaxylylene.
28. The invention of any preceding claim, in which the parylene or halogenated polymer is applied by chemical vapor deposition of polytetrafluoroethylene.
29. The invention of any preceding claim, in which the parylene or halogenated polymer is a parylene polymer including a halogen element bonded to a carbon atom, either in the aromatic ring or ethylene chain.
30. The invention of any preceding claim, in which the parylene or halogenated polymer comprises a polymer having the structure:
T-[CXmHn-C6XoUp-CXqHr]s-V
in which: each X is a halogen atom, each T and V is a terminal group, each CXmHn and CXqHr moiety is a methylene or substituted methylene moiety, each -C6X0UP- moiety is a benzene or substituted benzene nucleus, each U is hydrogen or lower alkyl, in which lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, i-butyl, or t-butyl, m & q are independently 0-2, o is 0-4, n & r are independently (2-m) and (2-q), p is (4-o), and s is from 3 to 100,000, optionally from 10 to 100,000, optionally from 10-10,000.
31 . The invention of any preceding claim, in which the parylene or halogenated polymer is applied by hot filament chemical vapor deposition.
32. The invention of any preceding claim, in which the parylene or halogenated polymer is applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor vapor in a cracking pipe and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus to form at least one of the internal and external sliding surfaces.
33. The invention of any preceding claim, in which the precursor for the parylene or halogenated polymer comprises xylene or its ethyl, propyl, or butyl- substituted analog, fully halogenated on each pendant alkyl moiety.
34. The invention of claim 33, in which each pendant alkyl moiety is trihalogenated methyl.
35. The invention of claim 33 or 34, in which each pendant alkyl moiety is trifluoromethyl.
36. The invention of claim 33 or 34, in which the halogen is one nonfluoro halogen terminal moiety selected from chloro, bromo, or iodo and the balance fluoro.
37. The invention of claim 36, in which the alkyl moieties are bromodifluoromethyl.
38. The invention of any claim 32 to 37, in which the precursor vapor is decomposed in the presence of a catalyst.
39. The invention of claim 38, in which the catalyst comprises copper, zinc, magnesium, titanium, cadmium, silver, indium, tin, aluminum, or a combination of two or more of these.
40. The invention of claim 38 or 39, in which the catalyst comprises zinc or a zinc halide, for example zinc bromide.
41 . The invention of claim 38 or 39, in which the catalyst comprises copper or a copper halide, for example copper bromide.
42. The invention of any claim 32 to 41 , in which the precursor vapor is decomposed in the presence of an initiator different from the precursor.
43. The invention of claim 42, in which the initiator comprises xylene or its ethyl, propyl, or butyl-substituted analog, at least partially halogenated on each pendant alkyl moiety.
44. The invention of claim 43, in which the methyl pendant groups are di- or tri-halogen-substituted.
45. The invention of claim 44, in which the initiator comprises m-bis- (dibromomethyl)benzene.
46. The invention of claim 44, in which the initiator comprises p-bis- (dibromomethyl)benzene.
47. The invention of claim 44, in which the initiator comprises m-bis- (difluorobromo)benzene.
48. The invention of claim 44, in which the initiator comprises p-bis- (difluorobromo)benzene.
49. The invention of claim 32, in which the parylene or halogenated polymer is applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor comprising p-bis(trifluoromethyl)benzene in a cracking pipe in the presence of an initiator comprising bis(difluorobromomethyl)benzene and a catalyst comprising zinc metal and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus to form at least the external sliding surface.
50. The invention of any preceding claim, in which the stopper, O-ring, plunger tip or piston consists essentially of an elastomeric seal having an injection molded external sliding surface directly coated by chemical vapor deposition with the parylene or halogenated polymer.
51 . The invention of any preceding claim, in which the F, and Fm values for advance of the external sliding surface along the internal sliding surface are each from 1 to 20 N, alternatively from 3 to 18 N, optionally from 5 to 15 N after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
52. The invention of any preceding claim, in which the Fi and Fm values for advance of the external sliding surface along the internal sliding surface do not increase more than 50 percent, alternatively more than 40 percent, alternatively more than 30 percent, alternatively more than 20 percent, alternatively more than 10 percent, alternatively at all, and optionally decrease 10%, optionally 20%, optionally 30%, after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
53. The invention of any preceding claim, in which a substrate supporting the parylene or halogenated polymer is injection molded, the parylene or halogenated polymer is applied to the supporting substrate by chemical vapor deposition, and the presence of the parylene or halogenated polymer reduces the extractables obtainable from the injection molded substrate.
54. The invention of claim 53, in which the parylene or halogenated polymer comprises poly(tetrafluoro-p-xylylene), and the extractables obtainable from the injection molded substrate by isopropanol extraction are reduced by at least 10%, optionally at least 25%, optionally at least 30%, optionally at least 40%, optionally at least 47%, optionally at least 50%, optionally at least 60%, optionally at least 70%, optionally at least 80%, optionally at least 90%, optionally from 10% to 95%, optionally from 10% to 90%, optionally from 10% to 80%, optionally from 10% to 70%, optionally from 10% to 60%, optionally from 10% to 50%, optionally from 25% to 50%.
55. The invention of any preceding claim, in which the parylene or halogenated polymer is applied as a coating on an elastomeric stopper, O-ring, plunger tip or piston 36 as a substrate and the Bonfiglioli container closure integrity result for the parylene or halogenated polymer coated substrate is a vacuum decay of less than 50 mbar, alternatively less than 40 mbar, alternatively less than 30 mbar, alternatively less than 20 mbar, as an upper limit, and at least 3 mbar, alternatively at least 5 mbar, alternatively at least 7 mbar, alternatively at least 10 mbar, alternatively at least 12 mbar, as a lower limit.
56. The invention of any preceding claim, in which the parylene or halogenated polymer coating is 0.5-20 microns thick, optionally 0.5-10 microns thick, optionally 0.5-4.5 microns thick, optionally 1 to 5 microns thick, optionally 1 to 4.5 microns thick, optionally 1 -3 microns thick.
57. The invention of any preceding claim, in which the parylene or halogenated polymer coating is applied with a precision in reproducible coating thicknesses of +/- 1 -15%, optionally +/- 1 -10%, optionally +/- 1 to 5%, optionally +/- 2%.
58. The invention of any preceding claim, in which the parylene or halogenated polymer coating consists essentially of Parylene HTX.
59. The invention of any preceding claim, in which the parylene or halogenated polymer is provided in the form of a coating having a crystallinity of greater than 10%, optionally from 15% to 50%, optionally from 20 to 40%, optionally 20 to 30%.
60. The invention of any preceding claim 26 - 49, in which during deposition the chemical vapor deposition apparatus comprises the barrel (14) functioning as its own reaction vessel.
61 . The method according to claim 32 or 60, in which the temperature in the cracking pipe (190) is controlled at from 150°C to 1300°C during decomposition in the cracking pipe.
62. The method according to any preceding claim 32 to 61 , in which during the decomposing step a difluorocarbene precursor vapor (184) is decomposed in the cracking pipe (190) to generate difluorocarbene free radicals.
63. The method according to claim 62, in which a polytetrafluoroethylene coating film is formed on the substrate due to polymerization of the difluorocarbene free radicals.
64. The method according to any preceding claim 62 to 63, in which the difluorocarbene precursor vapor is one or more of hexafluoroepoxypropane, trifluoromethane and difluorochloromethane.
65. The method according to any preceding claim 62 to 64, in which the difluorocarbene precursor vapor is fed at the flow rate of 5-600 seem.
66. The method according to any preceding claim 32 to 65, in which the cracking pipe has an inlet and an outlet, the outlet of the cracking pipe and the treated substrate are connected via a conduit, and the minimum distance through the conduit between the outlet 1 of the cracking pipe and the treated substrate is from 1 to 60 cm, alternatively from 1 to 50 cm, alternatively from 1 to 40 cm, alternatively from 1 to 30 cm, alternatively from 1 to 20 cm, alternatively from 10 to 60 cm, alternatively from 10 to 50 cm, alternatively from 10 to 40 cm, alternatively from 10 to 30 cm, alternatively from 10 to 20 cm, alternatively from 20 to 60 cm, alternatively from 20 to 50 cm, alternatively from 20 to 40 cm, alternatively from 20 to 30 cm, alternatively from 30 to 60 cm, alternatively from 30 to 50 cm, alternatively from 30 to 40 cm.
67. The method according to any preceding claim 32 to 66, in which the polymerization reaction is performed at a temperature controlled to be below 100°C at the substrate.
68. The method according to any preceding claim 32 to 66, in which the polymerization reaction is performed at a temperature controlled to be below 90 °C at the substrate.
69. The method according to any preceding claim 32 to 66, in which the polymerization reaction is performed at a temperature controlled to be below 80 °C at the substrate.
70. The method according to any preceding claim 32 to 66, in which the polymerization reaction is performed at a temperature controlled to be below 70 °C at the substrate.
71 . The method according to any preceding claim 32 to 66, in which the polymerization reaction is performed at a temperature controlled to be below 60 °C at the substrate.
72. The method according to any preceding claim 32 to 66, in which the polymerization reaction is performed at a temperature controlled to be below 50 °C at the substrate.
73. The method according to any preceding claim 32 to 72, in which the polymerization reaction is performed under a reaction environment selected from vacuum environment or an environment filled with a filler gas.
74. The method according to according to any preceding claim 32 to 73, in which the filler gas is nitrogen and has a pressure within 10 standard atmosphere pressures.
75. The method according to according to any preceding claim 62 to 74, in which other acid gases are generated when the difluorocarbene precursor vapor is decomposed in a cracking pipe to generate difluorocarbene free radicals, and the other acid gases are frozen by a cold trap Dewar bottle or absorbed with a basic solution.
76. The method according to any preceding claim 32 to 61 , in which during the decomposing step a dimeric tetrafluoroparaxylylene precursor vapor is decomposed in the cracking pipe to generate tetrafluoroparaxylylene free radicals.
77. The method according to claim 76, in which a poly tetrafluoroparaxylylene coating film is formed on the substrate due to polymerization of the tetrafluoroparaxylylene free radicals.
78. The method according to any preceding claim 76 to 77, in which the dimeric tetrafluoroparaxylylene precursor vapor is fed at the flow rate of 5-600 seem.
79. The method according to any preceding claim 32 to 78, in which the cracking pipe has an inlet and an outlet, the outlet of the cracking pipe and the treated substrate are connected via a conduit, and the minimum distance through the conduit between the outlet of the cracking pipe and the treated substrate is from 1 to 60 cm, alternatively from 1 to 50 cm, alternatively from 1 to 40 cm, alternatively from 1 to 30 cm, alternatively from 1 to 20 cm, alternatively from 10 to 60 cm, alternatively from 10 to 50 cm, alternatively from 10 to 40 cm, alternatively from 10 to 30 cm, alternatively from 10 to 20 cm, alternatively from 20 to 60 cm, alternatively from 20 to 50 cm, alternatively from 20 to 40 cm, alternatively from 20 to 30 cm, alternatively from 30 to 60 cm, alternatively from 30 to 50 cm, alternatively from 30 to 40 cm.
80. The method according to any preceding claim 32 to 79, in which the polymerization reaction is performed at a temperature controlled to be below 100°C at the substrate.
81 . The method according to any preceding claim 32 to 79, in which the polymerization reaction is performed at a temperature controlled to be below 90 °C at the substrate.
82. The method according to any preceding claim 32 to 79, in which the polymerization reaction is performed at a temperature controlled to be below 80 °C at the substrate.
83. The method according to any preceding claim 32 to 79, in which the polymerization reaction is performed at a temperature controlled to be below 70 °C at the substrate.
84. The method according to any preceding claim 32 to 79, in which the polymerization reaction is performed at a temperature controlled to be below 60 °C at the substrate.
85. The method according to any preceding claim 32 to 79, in which the polymerization reaction is performed at a temperature controlled to be below 50 °C at the substrate.
86. The method according to any preceding claim 32 to 85, in which the polymerization reaction is performed under a reaction environment selected from vacuum environment or an environment filled with a filler gas.
86. The method according to according to claim 8657, in which the filler gas is nitrogen and has a pressure within 10 standard atmosphere pressures.
87. The method according to according to any preceding claim 62 to 86, in which effluent gases are frozen by a cold trap Dewar bottle or absorbed with a basic solution.
88. The invention of any preceding claim, in which the parylene or halogenated polymer is applied by chemically modifying a precursor, while on or in the vicinity of the fluid receiving interior surface.
89. The invention of claim 88, in which the precursor comprises:
• dimeric tetrafluoroparaxylylene,
• difluorocarbene,
• monomeric tetrafluoroethylene,
• oligomeric tetrafluoroethylene having the formula F2C=CF(CF2)xF in which x is from 1 to 100, optionally 2 to 50, optionally 2-20, optionally 2-10,
• sodium chlorodifluoroacetate,
• chlorodifluoromethane,
• bromodifluoromethane,
• hexafluoropropylene oxide,
• 1 H,1 H,2H,2H-perfluorodecyl acrylate (FDA),
• a bromofluoroalkane in which the alkane moiety has from 1 to 6 carbon atoms,
• an iodofluoroalkane in which the alkane moiety has from 1 to 6 carbon atoms, or
• a combination of any two or more of these.
90. The invention of any preceding claim, in which the internal sliding surface, the external sliding surface, or both is applied by heated wire chemical vapor deposition (HWCVD).
91 . A syringe comprising:
An injection molded barrel or wall including a lumen, a vessel substrate defining at least a portion of the lumen, and an internal sliding surface on the vessel substrate adjacent to the lumen; a stopper, O-ring, plunger tip or piston operatively connected with the lumen comprising a substrate having an external sliding surface slidable in the lumen at least substantially in contact with the internal sliding surface and a surface exposed to the lumen; a barrier coating or layer disposed on the internal sliding surface, with or without additional intervening layers; a pH protective layer of SiOxCy, where x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3, disposed between the barrier coating or layer and the lumen; a parylene coating or layer on the external sliding surface of the stopper, O-ring, plunger tip or piston, the parylene coating being effective to reduce the Fi and Fm of the stopper, O-ring, plunger tip or piston.
92. The syringe of claim 91 , further comprising a tie coating or layer of SiOxCy as an intervening layer between the barrier coating or layer and the internal sliding surface.
93. The syringe of claim 91 or 92, in which the stopper, O-ring, plunger tip or piston comprises elastomeric material defining the external sliding surface.
94. The syringe of claim 91 , 92, or 93, in which the parylene coating or layer is effective to reduce the leaching of solutes from the stopper, O-ring, plunger tip or piston.
95. The syringe of claim 91 , 92, 93, or 94, in which the parylene coating or layer comprises fluorinated parylene.
96. The syringe of any preceding claim 91 to 95, in which the parylene coating or layer is deposited by vapor deposition.
97. The syringe of any preceding claim 91 to 96, in which the parylene coating or layer is deposited by chemical vapor deposition.
98. The syringe of any preceding claim 91 to 97, in which the parylene coating or layer comprises polytetrafluoroparaxylylene.
99. The syringe of any preceding claim 91 to 98, in which the parylene coating or layer consists essentially of polytetrafluoroparaxylylene.
100. The syringe of any preceding claim 91 to 99, in which the barrier coating or layer comprises siox, where x is from 1 .5 to 2.9.
101 . The syringe of any preceding claim 91 to 100, in which the barrier coating or layer consists essentially of SiOx, where x is from 1 .5 to 2.9.
102. The syringe of any preceding claim 91 to 101 , in which the parylene coating or layer is: from at least 0.1 micrometers to at most 10 micrometers thick, optionally from at least 0.1 micrometers to at most 8 micrometers thick, optionally from at least 0.1 micrometers to at most 6 micrometers thick, optionally from at least 0.1 micrometers to at most 4 micrometers thick,
optiona rom at least 0.1 micrometers to at most 2 micrometers thick, optiona rom at least 0.1 micrometers to at most 1 micrometers thick, optiona rom at least 0.1 micrometers to at most 0.9 micrometers thick, optiona rom at least 0.1 micrometers to at most 0.8 micrometers thick, optiona rom at least 0.1 micrometers to at most 0.7 micrometers thick, optiona rom at least 0.1 micrometers to at most 0.6 micrometers thick, optiona rom at least 0.1 micrometers to at most 0.5 micrometers thick, optiona rom at least 0.5 micrometers to at most 5 micrometers thick, optiona rom at least 0.5 micrometers to at most 4 micrometers thick, optiona rom at least 0.5 micrometers to at most 3 micrometers thick, optiona rom at least 0.5 micrometers to at most 2 micrometers thick, optiona y from at least 0.5 micrometers to at most 1 micrometer thick, optionally about 2 micrometers thick.
103. The syringe of any preceding claim 91 to 102, in which the barrier coating or layer is deposited by vapor deposition.
104. The syringe of any preceding claim 91 to 103, in which the barrier coating or layer is deposited by chemical vapor deposition.
105. The syringe of any preceding claim 91 to 104, in which the barrier coating or layer is deposited by plasma enhanced chemical vapor deposition.
106. The syringe of any preceding claim 91 to 105, in which the pH protective coating or layer is deposited by vapor deposition.
107. The syringe of any preceding claim 91 to 106, in which the pH protective coating or layer is deposited by chemical vapor deposition.
108. The syringe of any preceding claim 91 to 107, in which the pH protective coating or layer is deposited by plasma enhanced chemical vapor deposition.
109. The syringe of any preceding claim 95 to 108, in which the fluorinated parylene is applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor in a cracking pipe and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus to form at least one of the internal and external sliding surfaces.
1 10. The syringe of any preceding claim 95 to 1 19, in which the precursor for the fluorinated parylene comprises xylene or its ethyl, propyl, or butyl-substituted analog, fully halogenated on each pendant alkyl moiety.
1 1 1 . The syringe of any preceding claim 95 to 1 10, in which each pendant alkyl moiety is trihalogenated methyl.
1 12. The syringe of any preceding claim 95 to 1 1 1 , in which each pendant alkyl moiety is trifluoromethyl.
1 13. The syringe of any preceding claim 95 to 1 12, in which the halogen is one nonfluoro halogen terminal moiety selected from chloro, bromo, or iodo and the balance fluoro.
1 14. The syringe of any preceding claim 95 to 1 13, in which the alkyl moieties are bromodifluoromethyl.
1 15. The syringe of any preceding claim 95 to 1 14, in which the precursor vapor is decomposed in the presence of a catalyst.
1 16. The syringe of any preceding claim 95 to 1 15, in which the catalyst comprises copper, zinc, magnesium, titanium, cadmium, silver, indium, tin, aluminum, or a combination of two or more of these.
1 17. The syringe of any preceding claim 95 to 1 16, in which the catalyst comprises zinc or a zinc halide, for example zinc bromide.
1 18. The syringe of any preceding claim 95 to 1 17, in which the catalyst comprises copper or a copper halide, for example copper bromide.
1 19. The syringe of any preceding claim 95 to 1 18, in which the precursor vapor is decomposed in the presence of an initiator different from the precursor.
120. The syringe of any preceding claim 95 to 1 19, in which the initiator comprises xylene or its ethyl, propyl, or butyl-substituted analog, at least partially halogenated on each pendant alkyl moiety.
121 . The syringe of any preceding claim 95 to 120, in which the methyl pendant groups are di- or tri-halogen-substituted.
122. The syringe of any preceding claim 95 to 121 , in which the initiator comprises m-bis-(dibromomethyl)benzene.
123. The syringe of any preceding claim 95 to 122, in which the initiator comprises p-bis-(dibromomethyl)benzene.
124. The syringe of any preceding claim 95 to 123, in which the initiator comprises m-bis-(difluorobromo)benzene.
125. The syringe of any preceding claim 95 to 124, in which the initiator comprises p-bis-(difluorobromo)benzene.
126. The syringe of any preceding claim 95 to 125, in which the fluorinated parylene is applied by pyrolysis chemical vapor deposition, carried out by decomposing a precursor comprising p-bis(trifluoromethyl)benzene in a cracking pipe in the presence of an initiator comprising bis(difluorobromomethyl)benzene and a catalyst comprising zinc metal and contacting the generated decomposition product with a substrate in a chemical vapor deposition apparatus to form at least the external sliding surface.
127. The syringe of any preceding claim 91 to 126, in which the Fi and Fm values for advance of the external sliding surface along the internal sliding surface are each from 1 to 20 N, alternatively from 3 to 18 N, optionally from 5 to 15 N after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
128. The syringe of any preceding claim 91 to 127, in which the Fi and Fm values for advance of the external sliding surface along the internal sliding surface do not increase more than 50 percent, alternatively more than 40 percent, alternatively more than 30 percent, alternatively more than 20 percent, alternatively more than 10
percent, alternatively at all, and optionally decrease 10%, optionally 20%, optionally 30%, after a park time of at least one day, optionally one week, optionally one month, alternatively three months, alternatively six months, alternatively 12 months, alternatively 18 months, alternatively 24 months.
129. The syringe of any preceding claim 91 to 128, in which the stopper, O- ring, plunger tip or piston is injection molded.
130. The syringe of any preceding claim 91 to 129, in which the parylene polymer comprises poly(tetrafluoro-p-xylylene), and the extractables obtainable from the injection molded substrate by isopropanol extraction are reduced by at least 10%, optionally at least 25%, optionally at least 30%, optionally at least 40%, optionally at least 47%, optionally at least 50%, optionally at least 60%, optionally at least 70%, optionally at least 80%, optionally at least 90%, optionally from 10% to 95%, optionally from 10% to 90%, optionally from 10% to 80%, optionally from 10% to 70%, optionally from 10% to 60%, optionally from 10% to 50%, optionally from 25% to 50%.
131 . The syringe of any preceding claim 91 to 130, in which the parylene polymer is applied as a coating on an elastomeric stopper, O-ring, plunger tip or piston as a substrate and the Bonfiglioli container closure integrity result for the parylene polymer coated substrate is a vacuum decay of less than 50 mbar, alternatively less than 40 mbar, alternatively less than 30 mbar, alternatively less than 20 mbar, as an upper limit, and at least 3 mbar, alternatively at least 5 mbar, alternatively at least 7 mbar, alternatively at least 10 mbar, alternatively at least 12 mbar, as a lower limit.
132. The syringe of any preceding claim 91 to 131 , in which the parylene coating is 0.5-20 microns thick, optionally 0.5-10 microns thick, optionally 0.5-4.5 microns thick, optionally 1 to 5 microns thick, optionally 1 to 4.5 microns thick, optionally 1 -3 microns thick.
133. The syringe of any preceding claim 91 to 132, in which the parylene coating is applied with a precision in reproducible coating thicknesses of +/- 1 -15%, optionally +/- 1 -10%, optionally +/- 1 to 5%, optionally +/- 2%.
134. The syringe of any preceding claim 91 to 133, in which the parylene coating consists essentially of Parylene HTX.
135. The syringe of any preceding claim 91 to 134, in which the parylene is provided in the form of a coating having a crystallinity of greater than 10%, optionally from 15% to 50%, optionally from 20 to 40%, optionally 20 to 30%.
136. The invention of any preceding claim, in which the relation between: y -the breakout static force in Newtons for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface, and x - the parking time T in seconds of the article before breaking loose over a period of two years, is given by the equation:
(log)y = m (log) x + b in which m is between about 0 and 0.17,
• optionally between about 0 and 0.16,
• optionally between about 0 and 0.15,
• optionally between about 0 and 0.14,
• optionally between about 0 and 0.13,
• optionally between about 0 and 0.12,
• optionally between about 0 and 0.1 1 ,
• optionally between about 0 and 0.10,
• optionally between about 0 and 0.09,
opt onal iy between about 0 and 0.08, opt onal iy between about 0 and 0.07, opt onal iy between about 0 and 0.06, opt onal iy between about 0 and 0.05, opt onal iy between about 0 and 0.04, opt onal iy between about 0 and 0.03, opt onal iy between about 0 and 0.02, opt onal iy between about 0 and 0.01 , opt onal iy between about -0 1 and 0.17, opt onal iy between about -0 1 and 0.16, opt onal iy between about -0 1 and 0.15, opt onal iy between about -0 1 and 0.14, opt onal iy between about -0 1 and 0.13, opt onal iy between about -0 1 and 0.12, opt onal iy between about -0 1 and 0.1 1 , opt onal iy between about -0 1 and 0.10, opt onal iy between about -0 1 and 0.09, opt onal iy between about -0 1 and 0.08, opt onal iy between about -0 1 and 0.07, opt onal iy between about -0 1 and 0.06, opt onal iy between about -0 1 and 0.05, opt onal iy between about -0 1 and 0.04, opt onal iy between about -0 1 and 0.03, opt onal iy between about -0 1 and 0.02, opt onal iy between about -0 1 and 0.01 , opt onal iy between about 0.1 and 0.17, opt onal iy between about 0.2 and 0.17, opt onal iy between about 0.1 and 0.16,
opt onal ly between about 0.2 and 0.16,
opt onal ly between about 0.1 and 0.15,
opt onal ly between about 0.2 and 0.15,
opt onal ly between about 0.1 and 0.14,
opt onal ly between about 0.2 and 0.14,
opt onal ly between about 0.1 and 0.13,
opt onal ly between about 0.2 and 0.13,
opt onal ly between about 0.1 and 0.12,
opt onal ly between about 0.2 and 0.12, and b is from -0.5 to -0.2.
137. The invention of any preceding claim, in which the ratio between the log of the break loose static force in Newtons for breaking the piston or plunger sliding surface loose from the internal wall, as a function of the log of the parking time T in seconds of the article before breaking loose, is from -0.2 to +0.2, preferably from -0.1 to +0.1 , more preferably from -0.05 to +0.05, for example about 0.
138. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of one month.
139. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of two months.
140. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of three months.
141 . The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of four months.
142. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of five months.
143. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of six months.
144. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of seven months.
145. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of eight months.
146. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of nine months.
147. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of 10 months.
148. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of 1 1 months.
149. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of 12 months.
150. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of 13 months.
151 . The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of 14 months.
152. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of 15 months
153. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of 16 months.
154. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of 17 months.
155. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of 18 months.
156. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal wall is from 7 to 28 N after a parking time of 19 months.
157. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of 20 months.
158. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of 21 months.
159. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of 22 months.
160. The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of 23 months.
161 . The invention of any preceding claim, in which the breakout static force for breaking the stopper, O-ring, plunger tip or piston sliding surface loose from the internal sliding surface is from 7 to 28 N after a parking time of 24 months.
162. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20 N after a parking time of one month.
163. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20 N after a parking time of two months.
164. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20 N after a parking time of three months.
165. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20 N after a parking time of four months.
166. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20 N after a parking time of five months.
167. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of six months.
168. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of seven months.
169. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of eight months.
170. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20 N after a parking time of nine months.
171 . The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 10 months.
172. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 1 1 months.
173. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 12 months.
174. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 13 months.
175. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 14 months.
176. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 15 months
177. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 16 months.
178. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 17 months.
179. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 18 months.
180. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 19 months.
181 . The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 20 months.
182. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 21 months.
183. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 22 months.
184. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 23 months.
185. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is from 2 to 20N after a parking time of 24 months.
186. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of one month.
187. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of two months.
188. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of three months.
189. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of four months.
190. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of five months.
191 . The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of six months.
192. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of seven months.
193. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of eight months.
194. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of nine months.
195. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 10 months.
196. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 1 1 months.
197. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 12 months.
198. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 13 months.
199. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 14 months.
200. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 15 months
201 . The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 16 months.
202. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 17 months.
203. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 18 months.
204. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 19 months.
205. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 20 months.
206. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 21 months.
207. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 22 months.
208. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 23 months.
209. The invention of any preceding claim, in which the dynamic force for maintaining sliding of the stopper, O-ring, plunger tip or piston sliding surface along the internal sliding surface is within 15% of, alternatively within 10% of, alternatively within 5% of, alternatively substantially the same as, the static breakout force necessary to start the plunger moving after a parking time of 24 months.
210. The invention of any preceding claim, further comprising a barrier coating or layer of SiOx, where x is from 1 .5 to 2.9, disposed on the internal sliding surface, with or without additional intervening layers.
21 1 . The invention of claim 136, in which the fluoropolymer layer functions as a pH protective coating or layer disposed on the barrier coating or layer, with or without additional intervening layers, the protective fluoropolymer coating or layer being effective to decrease the silicon dissolution rate of the internal sliding surface.
212. The invention of any preceding claim, which is a syringe.
213. The invention of claim 212, in which the syringe comprises a plunger.
214. The invention of claim 213, in which the plunger comprises a plunger tip defining the sliding surface.
215. The invention of claim 214, in which the plunger tip comprises elastomeric material.
216. The invention of claim 215, in which the elastomeric material consists essentially of chlorinated butyl rubber.
217. The invention of claim 215 or 216, in which the elastomeric material further comprises a filler or reinforcing agent.
218. The invention of claim 215, 216, or 217, in which the elastomeric material further comprises a filler or reinforcing agent which is talc, calcium carbonate, chalk, calcium sulfate, clay, kaolin, silica, glass, fumed silica, mica, wollastonite, feldspar, aluminum silicate, calcium silicate, alumina, hydrated alumina such as alumina trihydrate, glass microspheres, ceramic microspheres, thermoplastic microspheres, barite, wood flour, glass fibers, carbon fibers, marble dust, cement dust, magnesium oxide, magnesium hydroxide, antimony oxide, zinc oxide, barium sulfate, titanium dioxide, titanates and combinations thereof, carbon black, aluminum oxide, silica (for example hydrophobic fumed silica), coated calcium carbonate, bentonite, or a combination of any two or more of these.
219. The invention of any preceding claim, in which the barrel comprises a polyolefin or a polyester.
220. The invention of any preceding claim, in which the barrel comprises a polyolefin, optionally polypropylene, cyclic olefin polymer, or cyclic olefin copolymer.
221 . The invention of any preceding claim, in which the barrel comprises a polyester, optionally polyethylene terephthalate.
222. The invention of any preceding claim, in which the barrel comprises glass, optionally borosilicate glass.
223. The invention of any preceding claim, in which the breakout force is from 5 to 29 N,
• alternatively from 5 to 28 N,
• alternatively from 5 to 27 N,
• alternatively from 5 to 26 N,
• alternatively from 5 to 25 N,
• alternatively from 5 to 24 N,
Iternatively from 5 to 23 N, Iternatively from 5 to 22 N, a Iternatively from 5 to 21 N, a Iternatively from 5 to 20 N, a Iternatively from 5 to 19 N, a ternatively from 5 to 18 N, a ternatively from 5 to 17 N, a ternatively from 5 to 16 N, a ternatively from 5 to 15 N, a ternatively from 5 to 14 N, a ternatively from 5 to 13 N, al Iternatively from 5 to 12 N, al Iternatively from 5 to 1 1 N, al Iternatively from 5 to 10 N, a Iternatively from 5 to 9 N, a Iternatively from 5 to 8 N, a Iternatively from 5 to 7 N, a ternatively from 5 to 6 N, a ternatively from 7 to 28 N, a ternatively from 7 to 27 N, a Iternatively from 7 to 26 N, a Iternatively from 7 to 25 N, a Iternatively from 7 to 24 N, a Iternatively from 7 to 23 N, a Iternatively from 7 to 22 N, a Iternatively from 7 to 21 N, a ternatively from 7 to 20 N, a ternatively from 7 to 19 N,
Iternatively from 7 to 18 N, Iternatively from 7 to 17 N, a Iternatively from 7 to 16 N, a Iternatively from 7 to 15 N, a Iternatively from 7 to 14 N, al Iternatively from 7 to 13 N, al Iternatively from 7 to 12 N, al Iternatively from 7 to 1 1 N, a Iternatively from 7 to 10 N, a Iternatively from 7 to 9 N, a Iternatively from 7 to 8 N, al Iternatively from 8 to 28 N, al Iternatively from 9 to 28 N, al Iternatively from 10 to 28 N, a Iternatively from 1 1 to 28 N, a Iternatively from 12 to 28 N, a Iternatively from 13 to 28 N, al Iternatively from 14 to 28 N, al Iternatively from 15 to 28 N, a Iternatively from 16 to 28 N, a Iternatively from 17 to 28 N, a Iternatively from 18 to 28 N, a Iternatively from 19 to 28 N, a Iternatively from 20 to 28 N, al Iternatively from 21 to 28 N, a Iternatively from 22 to 28 N, a Iternatively from 23 to 28 N, a Iternatively from 24 to 28 N,
alternatively from 25 to 28 N,
alternatively from 26 to 28 N,
alternatively from 27 to 28 N,
alternatively from 8 to 27 N,
alternatively from 9 to 26 N,
alternatively from 10 to 25 N,
alternatively from 1 1 to 24 N,
alternatively from 12 to 23 N,
alternatively from 13 to 22 N,
alternatively from 14 to 21 N,
alternatively from 15 to 20 N,
alternatively from 16 to 19 N,
alternatively from 17 to 18 N,
alternatively from 6 to 8 N,
alternatively from 5 to 8 N,
alternatively from 4 to 8 N,
alternatively from 3 to 8 N,
alternatively from 2 to 8 N,
alternatively from 1 to 8 N,
after two years of parking time.
224. The invention of any preceding claim, which is a cartridge.
225. The invention of claim 224, which is an autoinjector cartridge.
226. The invention of any preceding claim, further comprising a barrier coating or layer of SiOx, wherein x is from 1 .5 to 2.9, from 2 to 1000 nm thick on the article barrel, the barrier coating or layer being effective to reduce the ingress of atmospheric gas into the lumen compared to a article barrel without a barrier coating or layer.
227. The invention of any preceding claim, in which the barrier coating or layer is on the internal sliding surface.
228. The invention of any preceding claim, in which the internal sliding surface yields measurable dissolved silicon when contacted with 0.1 N aqueous potassium hydroxide at 40 °C, and the fluoropolymer layer functions as a pH protective coating or layer having an interior surface facing the lumen, the protective coating or layer being effective to increase the calculated shelf life of the article (total Si / Si dissolution rate).
229. The invention of any preceding claim, further comprising a fluid composition contained in the lumen and having a pH between 5 and 9, wherein the calculated shelf life of the article is more than six months at a storage temperature of 4°C.
230. The invention of claim 228 or 229, in which the rate of erosion of the protective coating or layer on the internal sliding surface, if directly contacted by a fluid composition having a pH at some point between 5 and 9, is less than the rate of erosion of the internal sliding surface without the protective coating or layer, if directly contacted by the fluid composition.
231 . The invention of any preceding claim, in which the fluid composition has a pH between 5 and 6.
232. The invention of any preceding claim, in which the fluid composition has a pH between 6 and 7.
233. The invention of any preceding claim, in which the fluid composition has a pH between 7 and 8.
234. The invention of any preceding claim, in which the fluid composition has a pH between 8 and 9.
235. The invention of any preceding claim, in which the fluid composition has a pH between 6.5 and 7.5.
236. The invention of any preceding claim, in which the fluid composition has a pH between 7.5 and 8.5.
237. The invention of any preceding claim, in which the fluid composition has a pH between 8.5 and 9.
238. The invention of any preceding claim, in which the fluid composition is a liquid at 20 °C and 760 mm Hg. atmospheric pressure.
239. The invention of any preceding claim, in which the fluid composition is an aqueous liquid.
240. The invention of any preceding claim, in which the barrier coating or layer is from 4 nm to 500 nm thick.
241 . The invention of any preceding claim, in which the barrier coating or layer is from 7 nm to 400 nm thick.
242. The invention of any preceding claim, in which the barrier coating or layer is from 10 nm to 300 nm thick.
243. The invention of any preceding claim, in which the barrier coating or layer is from 20 nm to 200 nm thick.
244. The invention of any preceding claim, in which the barrier coating or layer is from 30 nm to 100 nm thick.
245. The invention of any preceding claim, in which the protective coating or layer comprises a fluoropolymer layer.
246. The invention of any preceding claim, in which the protective coating or layer consists essentially of a fluoropolymer layer.
247. The invention of any preceding claim, in which the protective coating or layer as applied is between 10 and 1000 nm thick.
248. The invention of any preceding claim, in which the protective coating or layer as applied is between 50 and 800 nm thick.
249. The invention of any preceding claim, in which the protective coating or layer as applied is between 100 and 700 nm thick.
250. The invention of any preceding claim, in which the protective coating or layer as applied is between 300 and 600 nm thick.
251 . The invention of any preceding claim, in which the protective coating or layer contacting the fluid composition is between 1 0 and 1000 nm thick two years after the invention is assembled.
252. The invention of any preceding claim, in which the protective coating or layer contacting the fluid composition is between 20 and 700 nm thick two years after the invention is assembled.
253. The invention of any preceding claim, in which the protective coating or layer contacting the fluid composition is between 50 and 500 nm thick two years after the invention is assembled.
254. The invention of any preceding claim, in which the protective coating or layer contacting the fluid composition is between 1 00 and 400 nm thick two years after the invention is assembled.
255. The invention of any preceding claim, in which the protective coating or layer contacting the fluid composition is between 1 50 and 300 nm thick two years after the invention is assembled.
256. The invention of any preceding claim, in which the rate of erosion of the protective coating or layer, if directly contacted by a fluid composition having a pH of 8, is less than 20% of the rate of erosion of the internal sliding surface without the protective coating or layer, if directly contacted by the same fluid composition under the same conditions.
257. The invention of any preceding claim, in which the rate of erosion of the protective coating or layer, if directly contacted by a fluid composition having a pH of 8, is less than 15% of the rate of erosion of the internal sliding surface without the protective coating or layer, if directly contacted by the same fluid composition under the same conditions.
258. The invention of any preceding claim, in which the rate of erosion of the protective coating or layer, if directly contacted by a fluid composition having a pH of 8, is less than 10% of the rate of erosion of the internal sliding surface without the protective coating or layer, if directly contacted by the same fluid composition under the same conditions.
259. The invention of any preceding claim, in which the rate of erosion of the protective coating or layer, if directly contacted by a fluid composition having a pH of 8, is less than 7% of the rate of erosion of the internal sliding surface without the protective coating or layer, if directly contacted by the same fluid composition under the same conditions.
260. The invention of any preceding claim, in which the rate of erosion of the protective coating or layer, if directly contacted by a fluid composition having a pH of 8, is from 5% to 20% of the rate of erosion of the internal sliding surface without the protective coating or layer, if directly contacted by the same fluid composition under the same conditions.
261 . The invention of any preceding claim, in which the rate of erosion of the protective coating or layer, if directly contacted by a fluid composition having a pH of 8, is from 5% to 15% of the rate of erosion of the internal sliding surface without the protective coating or layer, if directly contacted by the same fluid composition under the same conditions.
262. The invention of any preceding claim, in which the rate of erosion of the protective coating or layer, if directly contacted by a fluid composition having a pH of 8, is from 5% to 10% of the rate of erosion of the internal sliding surface without the protective coating or layer, if directly contacted by the same fluid composition under the same conditions.
263. The invention of any preceding claim, in which the rate of erosion of the protective coating or layer, if directly contacted by a fluid composition having a pH of 8, is from 5% to 7% of the rate of erosion of the internal sliding surface without the protective coating or layer, if directly contacted by the same fluid composition under the same conditions.
264. The invention of any preceding claim, in which the protective coating or layer is at least coextensive with the barrier coating or layer.
265. The invention of any preceding claim, having a shelf life, after the invention is assembled, of at least one year.
266. The invention of any preceding claim, having a shelf life, after the invention is assembled, of at least two years.
267. The invention of any preceding claim, having a shelf life, after the invention is assembled, of at least three years.
268. The invention of any preceding claim, having a shelf life, after the invention is assembled, of at least four years.
269. The invention of any preceding claim, having a shelf life, after the invention is assembled, of at least five years.
270. The invention of any preceding claim, having a shelf life, after the invention is assembled, of at least six years.
271 . The invention of any preceding claim, having a shelf life, after the invention is assembled, of at least seven years.
272. The invention of any preceding claim, having a shelf life, after the invention is assembled, of at least eight years.
273. The invention of any preceding claim, having a shelf life, after the invention is assembled, of at least nine years.
274. The invention of any preceding claim, having a shelf life, after the invention is assembled, of at most ten years.
275. The invention of any preceding claim, in which the shelf life is determined at 3°C.
276. The invention of any preceding claim, in which the shelf life is determined at 4°C.
277. The invention of any preceding claim, in which the shelf life is determined at 20 °C.
278. The invention of any preceding claim, in which the shelf life is determined at 23 °C.
279. The invention of any preceding claim, in which the shelf life is determined at 40 °C.
280. The invention of any preceding claim, in which the pH of the fluid composition is between 5 and 6 and the thickness of the protective coating or layer is at least 80 nm at the end of the shelf life.
281 . The invention of any preceding claim, in which the pH of the fluid composition is between 6 and 7 and the thickness of the protective coating or layer is at least 80 nm at the end of the shelf life.
282. The invention of any preceding claim, in which the pH of the fluid composition is between 7 and 8 and the thickness of the protective coating or layer is at least 80 nm at the end of the shelf life.
283. The invention of any preceding claim, in which the pH of the fluid composition is between 8 and 9 and the thickness of the protective coating or layer is at least 80 nm at the end of the shelf life.
284. The invention of any preceding claim, in which the pH of the fluid composition is between 5 and 6 and the thickness of the protective coating or layer is at least 150 nm at the end of the shelf life.
285. The invention of any preceding claim, in which the pH of the fluid composition is between 6 and 7 and the thickness of the protective coating or layer is at least 150 nm at the end of the shelf life.
286. The invention of any preceding claim, in which the pH of the fluid composition is between 7 and 8 and the thickness of the protective coating or layer is at least 150 nm at the end of the shelf life.
287. The invention of any preceding claim, in which the pH of the fluid composition is between 8 and 9 and the thickness of the protective coating or layer is at least 150 nm at the end of the shelf life.
288. The invention of any preceding claim, in which the fluid composition removes the protective coating or layer at a rate of 1 nm or less of protective coating or layer thickness per 44 hours of contact with the fluid composition.
289. The invention of any preceding claim, in which the fluid composition removes the protective coating or layer at a rate of 1 nm or less of protective coating or layer thickness per 88 hours of contact with the fluid composition.
290. The invention of any preceding claim, in which the fluid composition removes the protective coating or layer at a rate of 1 nm or less of protective coating or layer thickness per 175 hours of contact with the fluid composition.
291 . The invention of any preceding claim, in which the fluid composition removes the protective coating or layer at a rate of 1 nm or less of protective coating or layer thickness per 250 hours of contact with the fluid composition.
292. The invention of any preceding claim, in which the fluid composition removes the protective coating or layer at a rate of 1 nm or less of protective coating or layer thickness per 350 hours of contact with the fluid composition.
293. The invention of any preceding claim, in which the protective coating or layer is effective to provide a lower frictional resistance than the uncoated interior surface.
294. The invention of claim 293 wherein the frictional resistance is reduced by at least 25% in comparison to the uncoated interior surface.
295. The invention of claim 293 wherein the frictional resistance is reduced by at least 45% in comparison to the uncoated interior surface.
296. The invention of claim 293 wherein the frictional resistance is reduced by at least 60% in comparison to the uncoated interior surface.
297. The invention of any preceding claim, in which the protective coating or layer is effective to reduce the frictional resistance between a portion of the wall contacted by the fluid composition and a relatively sliding part after the invention is assembled.
298. The invention of any preceding claim, in which the protective coating or layer is effective to reduce the frictional resistance between the wall and a relatively sliding part at least two years after the invention is assembled.
299. The invention of any preceding claim, in which the silicon dissolution rate of the fluoropolymer layer and underlying structure, by a 50 mM potassium phosphate buffer diluted in water for injection, adjusted to pH 8 with concentrated nitric acid, and containing 0.2 wt. % polysorbate-80 surfactant from the vessel is less than 170 ppb/day.
300. The invention of claim 299, in which the silicon dissolution rate is less than 160 ppb/day.
301 . The invention of claim 299, in which the silicon dissolution rate is less than 140 ppb/day.
302. The invention of claim 299, in which the silicon dissolution rate is less than 120 ppb/day.
303. The invention of claim 299, in which the silicon dissolution rate is less than 100 ppb/day.
304. The invention of claim 299, in which the silicon dissolution rate is less than 90 ppb/day.
305. The invention of claim 299, in which the silicon dissolution rate is less than 80 ppb/day.
306. The invention of any preceding claim, in which the total silicon content of the protective coating and underlying structure, upon dissolution into 0.1 N potassium hydroxide aqueous solution at 40 °C from the vessel, is less than 66 ppm.
307. The invention of claim 306, in which the total silicon content is less than 60 ppm.
308. The invention of claim 306, in which the total silicon content is less than 50 ppm.
309. The invention of claim 306, in which the total silicon content is less than 40 ppm.
310. The invention of claim 306, in which the total silicon content is less than 30 ppm.
31 1 . The invention of claim 306, in which the total silicon content is less than 20 ppm.
312. The invention of any preceding claim, in which the calculated shelf life (total Si / Si dissolution rate) is more than 1 year.
313. The invention of any preceding claim, in which the calculated shelf life (total Si / Si dissolution rate) is more than 18 months.
314. The invention of any preceding claim, in which the calculated shelf life (total Si / Si dissolution rate) is more than 2 years.
315. The invention of any preceding claim, in which the calculated shelf life (total Si / Si dissolution rate) is more than 2½ years.
316. The invention of any preceding claim, in which the calculated shelf life (total Si / Si dissolution rate) is more than 3 years.
317. The invention of any preceding claim, in which the calculated shelf life (total Si / Si dissolution rate) is less than 4 years.
318. The invention of any preceding claim, in which the calculated shelf life (total Si / Si dissolution rate) is less than 5 years.
319. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of more than 22,000 kJ/kg of mass of polymerizing gases in the PECVD reaction chamber.
320. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of more than 30,000 kJ/kg of mass of polymerizing gases in the PECVD reaction chamber.
321 . The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of more than 40,000 kJ/kg of mass of polymerizing gases in the PECVD reaction chamber.
322. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of more than 50,000 kJ/kg of mass of polymerizing gases in the PECVD reaction chamber.
323. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of more than 60,000 kJ/kg of mass of polymerizing gases in the PECVD reaction chamber.
324. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of more than 62,000 kJ/kg of mass of polymerizing gases in the PECVD reaction chamber.
325. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of more than 70,000 kJ/kg of mass of polymerizing gases in the PECVD reaction chamber.
326. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of more than 80,000 kJ/kg of mass of polymerizing gases in the PECVD reaction chamber.
327. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of less than 100,000 kJ/kg of mass of polymerizing gases in the PECVD reaction chamber.
328. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of less than 90,000 kJ/kg of mass of polymerizing gases in the PECVD reaction chamber.
329. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of from 0.1 to 500 W.
330. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of from 0.1 to 400 W.
331 . The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of from 1 to 250 W.
332. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of from 1 to 200 W.
333. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of from 10 to 150 W.
334. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of from 20 to 150 W.
335. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of from 40 to 150 W.
336. The invention of any preceding claim, in which the protective coating or layer is applied by PECVD at a power level of from 60 to 150 W.
337. The invention of any preceding claim, in which the ratio of the electrode power to the plasma volume is from 1 W/ml to 100 W/ml.
338. The invention of claim 337, in which the ratio of the electrode power to the plasma volume is from 5 W/ml to 75 W/ml.
339. The invention of claim 337, in which the ratio of the electrode power to the plasma volume is from 6 W/ml to 60 W/ml.
340. The invention of claim 337, in which the ratio of the electrode power to the plasma volume is from 10 W/ml to 50 W/ml.
341 . The invention of claim 337, in which the ratio of the electrode power to the plasma volume is from 20 W/ml to 40 W/ml.
342. The invention of any preceding claim, in which the protective coating or layer has an RMS surface roughness value (measured by AFM) of from about 5 to about 9.
343. The invention of any preceding claim, in which the protective coating or layer has an RMS surface roughness value (measured by AFM) of from about 6 to about 8.
344. The invention of any preceding claim, in which the protective coating or layer has an RMS surface roughness value (measured by AFM) of from about 4 to about 6.
345. The invention of any preceding claim, in which the protective coating or layer has an RMS surface roughness value (measured by AFM) of from about 4.6 to about 5.8.
346. The invention of any preceding claim, in which the protective coating or layer has an Rmax surface roughness value of the protective coating or layer, measured by AFM, from about 70 to about 160.
347. The invention of any preceding claim, in which the protective coating or layer has an Rmax surface roughness value of the protective coating or layer, measured by AFM, from about 84 to about 142.
348. The invention of any preceding claim, in which the protective coating or layer has an Rmax surface roughness value of the protective coating or layer, measured by AFM, from about 90 to about 130.
Drug Claims
349. The invention of any preceding claim, in which the fluid composition comprises a member selected from the group consisting of:
Inhalation Anesthetics
Aliflurane
Chloroform
Cyclopropane
Desflurane (Suprane)
Diethyl Ether
Enflurane (Ethrane)
Ethyl Chloride
Ethylene
Halothane (Fluothane)
Isoflurane (Forane, Isoflo)
Isopropenyl vinyl ether
Methoxyflurane
methoxyflurane,
Methoxypropane
Nitrous Oxide
Roflurane
Sevoflurane (Sevorane, Ultane, Sevoflo)
Teflurane
Trichloroethylene
Vinyl Ether
Xenon
Injectable Drugs
Ablavar (Gadofosveset Trisodium Injection) Abarelix Depot
Abobotulinumtoxin A Injection (Dysport)
ABT-263
ABT-869
ABX-EFG
Accretropin (Somatropin Injection)
Acetadote (Acetylcysteine Injection)
Acetazolamide Injection (Acetazolamide Injection) Acetylcysteine Injection (Acetadote)
Actemra (Tocilizumab Injection)
Acthrel (Corticorelin Ovine Triflutate for Injection)
Actummune
Activase
Acyclovir for Injection (Zovirax Injection)
Adacel
Adalimumab
Adenoscan (Adenosine Injection)
Adenosine Injection (Adenoscan)
Adrenaclick
AdreView (lobenguane I 123 Injection for Intravenous Use) Afluria
Ak-Fluor (Fluorescein Injection)
Aldurazyme (Laronidase)
Alglucerase Injection (Ceredase)
Alkeran Injection (Melphalan Hcl Injection)
Allopurinol Sodium for Injection (Aloprim)
Aloprim (Allopurinol Sodium for Injection)
Alprostadil
Alsuma (Sumatriptan Injection)
ALTU-238
Amino Acid Injections
Aminosyn
Apidra
Apremilast
Alprostadil Dual Chamber System for Injection (Caverject Im
AMG 009
AMG 076
AMG 102
AMG 108
AMG 1 14
AMG 162
AMG 220
AMG 221
AMG 222
AMG 223
AMG 317
AMG 379
AMG 386
AMG 403
AMG 477
AMG 479
AMG 517
AMG 531
AMG 557
AMG 623
AMG 655
AMG 706
AMG 714
AMG 745
AMG 785
AMG 81 1
AMG 827
AMG 837
AMG 853
AMG 951
Amiodarone HCI Injection (Amiodarone HCI Injection) Amobarbital Sodium Injection (Amytal Sodium) Amytal Sodium (Amobarbital Sodium Injection) Anakinra
Anti-Abeta
Anti-Beta7
Anti-Beta20
Anti-CD4
Anti-CD20
Anti-CD40
Anti-IFNalpha
Anti-IL13
Anti-OX40L
Anti-oxLDS
Anti-NGF
Anti-NRP1
Arixtra
Amphadase (Hyaluronidase Inj)
Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection) Anaprox
Anzemet Injection (Dolasetron Mesylate Injection)
Apidra (Insulin Glulisine [rDNA origin] Inj)
Apomab
Aranesp (darbepoetin alfa)
Argatroban (Argatroban Injection)
Arginine Hydrochloride Injection (R-Gene 10)
Aristocort
Aristospan
Arsenic Trioxide Injection (Trisenox)
Articane HCI and Epinephrine Injection (Septocaine)
Arzerra (Ofatumumab Injection)
Asclera (Polidocanol Injection)
Ataluren
Ataluren-DMD
Atenolol Inj (Tenormin I.V. Injection)
Atracurium Besylate Injection (Atracurium Besylate Injection)
Avastin
Azactam Injection (Aztreonam Injection)
Azithromycin (Zithromax Injection)
Aztreonam Injection (Azactam Injection)
Baclofen Injection (Lioresal Intrathecal)
Bacteriostatic Water (Bacteriostatic Water for Injection)
Baclofen Injection (Lioresal Intrathecal)
Bal in Oil Ampules (Dimercarprol Injection)
BayHepB
BayTet
Benadryl
Bendamustine Hydrochloride Injection (Treanda)
Benztropine Mesylate Injection (Cogentin)
Betamethasone Injectable Suspension (Celestone Soluspan)
Bexxar
Bicillin C-R 900/300 (Penicillin G Benzathine and Penicillin G Procaine Injection)
Blenoxane (Bleomycin Sulfate Injection)
Bleomycin Sulfate Injection (Blenoxane)
Boniva Injection (Ibandronate Sodium Injection)
Botox Cosmetic (OnabotulinumtoxinA for Injection)
BR3-FC
Bravelle (Urofollitropin Injection)
Bretylium (Bretylium Tosylate Injection )
Brevital Sodium (Methohexital Sodium for Injection)
Brethine
Briobacept
BTT-1023
Bupivacaine HCI
Byetta
Ca-DTPA (Pentetate Calcium Trisodium Inj)
Cabazitaxel Injection (Jevtana)
Caffeine Alkaloid (Caffeine and Sodium Benzoate Injection)
Calcijex Injection (Calcitrol)
Calcitrol (Calcijex Injection)
Calcium Chloride (Calcium Chloride Injection 10%)
Calcium Disodium Versenate (Edetate Calcium Disodium Injection)
Campath (Altemtuzumab)
Camptosar Injection (Irinotecan Hydrochloride)
Canakinumab Injection (Maris)
Capastat Sulfate (Capreomycin for Injection)
Capreomycin for Injection (Capastat Sulfate)
Cardiolite (Prep kit for Technetium Tc99 Sestamibi for Injection)
Carticel
Cathflo
Cefazolin and Dextrose for Injection (Cefazolin Injection)
Cefepime Hydrochloride
Cefotaxime
Ceftriaxone
Cerezyme
Carnitor Injection
Caverject
Celestone Soluspan
Celsior
Cerebyx (Fosphenytoin Sodium Injection)
Ceredase (Alglucerase Injection)
Ceretec (Technetium Tc99m Exametazime Injection)
Certolizumab
CF-101
Chloramphenicol Sodium Succinate (Chloramphenicol Sodium Succinate Injection)
Chloramphenicol Sodium Succinate Injection (Chloramphenicol Sodium Succinate) Cholestagel (Colesevelam HCL)
Choriogonadotropin Alfa Injection (Ovidrel)
Cimzia
Cisplatin (Cisplatin Injection)
Clolar (Clofarabine Injection)
Clomiphine Citrate
Clonidine Injection (Duraclon)
Cogentin (Benztropine Mesylate Injection)
Colistimethate Injection (Coly-Mycin M)
Coly-Mycin M (Colistimethate Injection)
Com path
Conivaptan Hcl Injection (Vaprisol)
Conjugated Estrogens for Injection (Premarin Injection)
Copaxone
Corticorelin Ovine Triflutate for Injection (Acthrel)
Corvert (Ibutilide Fumarate Injection)
Cubicin (Daptomycin Injection)
CF-101
Cyanokit (Hydroxocobalamin for Injection)
Cytarabine Liposome Injection (DepoCyt)
Cyanocobalamin
Cytovene (ganciclovir)
D.H.E. 45
Dacetuzumab
Dacogen (Decitabine Injection)
Dalteparin
Dantrium IV (Dantrolene Sodium for Injection)
Dantrolene Sodium for Injection (Dantrium IV)
Daptomycin Injection (Cubicin)
Darbepoietin Alfa
DDAVP Injection (Desmopressin Acetate Injection)
Decavax
Decitabine Injection (Dacogen)
Dehydrated Alcohol (Dehydrated Alcohol Injection)
Denosumab Injection (Prolia)
Delatestryl
Delestrogen
Delteparin Sodium
Depacon (Valproate Sodium Injection)
Depo Medrol (Methylprednisolone Acetate Injectable Suspension
DepoCyt (Cytarabine Liposome Injection)
DepoDur (Morphine Sulfate XR Liposome Injection)
Desmopressin Acetate Injection (DDAVP Injection)
Depo-Estradiol
Depo-Provera 104mg/ml
Depo-Provera 150mg/ml
Depo-Testosterone
Dexrazoxane for Injection, Intravenous Infusion Only (Totect) Dextrose / Electrolytes
Dextrose and Sodium Chloride Inj (Dextrose 5% in 0.9% Sodium Dextrose
Diazepam Injection (Diazepam Injection)
Digoxin Injection (Lanoxin Injection)
Dilaudid-HP (Hydromorphone Hydrochloride Injection)
Dimercarprol Injection (Bal in Oil Ampules)
Diphenhydramine Injection (Benadryl Injection)
Dipyridamole Injection (Dipyridamole Injection)
DMOAD
Docetaxel for Injection (Taxotere)
Dolasetron Mesylate Injection (Anzemet Injection)
Doribax (Doripenem for Injection)
Doripenem for Injection (Doribax)
Doxercalciferol Injection (Hectorol Injection)
Doxil (Doxorubicin Hcl Liposome Injection)
Doxorubicin Hcl Liposome Injection (Doxil)
Duraclon (Clonidine Injection)
Duramorph (Morphine Injection)
Dysport (Abobotulinumtoxin A Injection)
Ecallantide Injection (Kalbitor)
EC-Naprosyn (naproxen)
Edetate Calcium Disodium Injection (Calcium Disodium Versenate)
Edex (Alprostadil for Injection)
Engerix
Edrophonium Injection (Enlon)
Eliglustat Tartate
Eloxatin (Oxaliplatin Injection)
Emend Injection (Fosaprepitant Dimeglumine Injection)
Enalaprilat Injection (Enalaprilat Injection)
Enlon (Edrophonium Injection)
Enoxaparin Sodium Injection (Lovenox)
Eovist (Gadoxetate Disodium Injection)
Enbrel (etanercept)
Enoxaparin
Epicel
Epinepherine
Epipen
Epipen Jr.
Epratuzumab
Erbitux
Ertapenem Injection (Invanz)
Erythropoieten
Essential Amino Acid Injection (Nephramine)
Estradiol Cypionate
Estradiol Valerate
Etanercept
Exenatide Injection (Byetta)
Evlotra
Fabrazyme (Adalsidase beta)
Famotidine Injection
FDG (Fludeoxyglucose F 18 Injection)
Feraheme (Ferumoxytol Injection)
Feridex I.V. (Ferumoxides Injectable Solution)
Fertinex
Ferumoxides Injectable Solution (Feridex I.V.)
Ferumoxytol Injection (Feraheme)
Flagyl Injection (Metronidazole Injection)
Fluarix
Fludara (Fludarabine Phosphate)
Fludeoxyglucose F 18 Injection (FDG)
Fluorescein Injection (Ak-Fluor)
Follistim AQ Cartridge (Follitropin Beta Injection)
Follitropin Alfa Injection (Gonal-f RFF)
Follitropin Beta Injection (Follistim AQ Cartridge)
Folotyn (Pralatrexate Solution for Intravenous Injection)
Fondaparinux
Forteo (Teriparatide (rDNA origin) Injection)
Fostamatinib
Fosaprepitant Dimeglumine Injection (Emend Injection) Foscarnet Sodium Injection (Foscavir)
Foscavir (Foscarnet Sodium Injection) Fosphenytoin Sodium Injection (Cerebyx) Fospropofol Disodium Injection (Lusedra) Fragmin
Fuzeon (enfuvirtide)
GA101
Gadobenate Dimeglumine Injection (Multihance) Gadofosveset Trisodium Injection (Ablavar) Gadoteridol Injection Solution (ProHance) Gadoversetamide Injection (OptiMARK)
Gadoxetate Disodium Injection (Eovist)
Ganirelix (Ganirelix Acetate Injection)
Gardasil
GC1008
GDFD
Gemtuzumab Ozogamicin for Injection (Mylotarg) Genotropin
Gentamicin Injection
GENZ-1 12638
Golimumab Injection (Simponi Injection)
Gonal-f RFF (Follitropin Alfa Injection)
Granisetron Hydrochloride (Kytril Injection)
Gentamicin Sulfate
Glatiramer Acetate
Glucagen
Glucagon
HAE1
Haldol (Haloperidol Injection)
Havrix
Hectorol Injection (Doxercalciferol Injection)
Hedgehog Pathway Inhibitor
Heparin
Herceptin
hG-CSF
Humalog
Human Growth Hormone
Humatrope
HuMax
Humegon
Humira
Humulin
Ibandronate Sodium Injection (Boniva Injection)
Ibuprofen Lysine Injection (NeoProfen)
Ibutilide Fumarate Injection (Corvert)
Idamycin PFS (Idarubicin Hydrochloride Injection)
Idarubicin Hydrochloride Injection (Idamycin PFS)
Maris (Canakinumab Injection)
Imipenem and Cilastatin for Injection (Primaxin I.V.)
Imitrex
Incobotulinumtoxin A for Injection (Xeomin)
Increlex (Mecasermin [rDNA origin] Injection)
Indocin IV (Indomethacin Inj)
Indomethacin Inj (Indocin IV)
Infanrix
Innohep
Insulin
Insulin Aspart [rDNA origin] Inj (NovoLog)
Insulin Glargine [rDNA origin] Injection (Lantus) Insulin Glulisine [rDNA origin] Inj (Apidra)
Interferon alfa-2b, Recombinant for Injection (Intron A)
Intron A (Interferon alfa-2b, Recombinant for Injection)
Invanz (Ertapenem Injection)
Invega Sustenna (Paliperidone Palmitate Extended- Release Injectable Suspension) Invirase (saquinavir mesylate)
lobenguane I 123 Injection for Intravenous Use (AdreView)
lopromide Injection (Ultravist)
loversol Injection (Optiray Injection)
Iplex (Mecasermin Rinfabate [rDNA origin] Injection)
Iprivask
Irinotecan Hydrochloride (Camptosar Injection)
Iron Sucrose Injection (Venofer)
Istodax (Romidepsin for Injection)
Itraconazole Injection (Sporanox Injection)
Jevtana (Cabazitaxel Injection)
Jonexa
Kalbitor (Ecallantide Injection)
KCL in D5NS (Potassium Chloride in 5% Dextrose and Sodium Chloride Injection) KCL in D5W
KCL in NS
Kenalog 10 Injection (Triamcinolone Acetonide Injectable Suspension)
Kepivance (Palifermin)
Keppra Injection (Levetiracetam)
Keratinocyte
KFG
Kinase Inhibitor
Kineret (Anakinra)
Kinlytic (Urokinase Injection)
Kinrix
Klonopin (clonazepam)
Kytril Injection (Granisetron Hydrochloride)
lacosamide Tablet and Injection (Vimpat)
Lactated Ringer's
Lanoxin Injection (Digoxin Injection)
Lansoprazole for Injection (Prevacid I.V.)
Lantus
Leucovorin Calcium (Leucovorin Calcium Injection)
Lente (L)
Leptin
Levemir
Leukine Sargramostim
Leuprolide Acetate
Levothyroxine
Levetiracetam (Keppra Injection)
Lovenox
Levocarnitine Injection (Carnitor Injection)
Lexiscan (Regadenoson Injection)
Lioresal Intrathecal (Baclofen Injection)
Liraglutide [rDNA] Injection (Victoza)
Lovenox (Enoxaparin Sodium Injection)
Lucentis (Ranibizumab Injection)
Lumizyme
Lupron (Leuprolide Acetate Injection)
Lusedra (Fospropofol Disodium Injection)
Maci
Magnesium Sulfate (Magnesium Sulfate Injection)
Mannitol Injection (Mannitol IV)
Marcaine (Bupivacaine Hydrochloride and Epinephrine Injection)
Maxipime (Cefepime Hydrochloride for Injection)
MDP Multidose Kit of Technetium Injection (Technetium Tc99m Medronate Injection) Mecasermin [rDNA origin] Injection (Increlex)
Mecasermin Rinfabate [rDNA origin] Injection (Iplex) Melphalan Hcl Injection (Alkeran Injection)
Methotrexate
Menactra
Menopur (Menotropins Injection)
Menotropins for Injection (Repronex)
Methohexital Sodium for Injection (Brevital Sodium)
Methyldopate Hydrochloride Injection, Solution (Methyldopate Hcl)
Methylene Blue (Methylene Blue Injection)
Methylprednisolone Acetate Injectable Suspension (Depo Medrol)
MetMab
Metoclopramide Injection (Reglan Injection)
Metrodin (Urofollitropin for Injection)
Metronidazole Injection (Flagyl Injection)
Miacalcin
Midazolam (Midazolam Injection)
Mimpara (Cinacalet)
Minocin Injection (Minocycline Inj)
Minocycline Inj (Minocin Injection)
Mipomersen
Mitoxantrone for Injection Concentrate (Novantrone)
Morphine Injection (Duramorph)
Morphine Sulfate XR Liposome Injection (DepoDur)
Morrhuate Sodium (Morrhuate Sodium Injection)
Motesanib
Mozobil (Plerixafor Injection)
Multihance (Gadobenate Dimeglumine Injection)
Multiple Electrolytes and Dextrose Injection
Multiple Electrolytes Injection
Mylotarg (Gemtuzumab Ozogamicin for Injection)
Myozyme (Alglucosidase alfa)
Nafcillin Injection (Nafcillin Sodium)
Nafcillin Sodium (Nafcillin Injection)
Naltrexone XR Inj (Vivitrol)
Naprosyn (naproxen)
NeoProfen (Ibuprofen Lysine Injection)
Nandrol Decanoate
Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection)
NEO-GAA
NeoTect (Technetium Tc 99m Depreotide Injection)
Nephramine (Essential Amino Acid Injection)
Neulasta (pegfilgrastim)
Neupogen (Filgrastim)
Novolin
Novolog
NeoRecormon
Neutrexin (Trimetrexate Glucuronate Inj)
NPH (N)
Nexterone (Amiodarone HCI Injection)
Norditropin (Somatropin Injection)
Normal Saline (Sodium Chloride Injection)
Novantrone (Mitoxantrone for Injection Concentrate)
Novolin 70/30 Innolet (70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin Injection)
NovoLog (Insulin Aspart [rDNA origin] Inj)
Nplate (romiplostim)
Nutropin (Somatropin (rDNA origin) for Inj)
Nutropin AQ
Nutropin Depot (Somatropin (rDNA origin) for Inj)
Octreotide Acetate Injection (Sandostatin LAR)
Ocrelizumab
Ofatumumab Injection (Arzerra)
Olanzapine Extended Release Injectable Suspension (Zyprexa Relprevv)
Omnitarg
Omnitrope (Somatropin [ rDNA origin] Injection)
Ondansetron Hydrochloride Injection (Zofran Injection)
OptiMARK (Gadoversetamide Injection)
Optiray Injection (loversol Injection)
Orencia
Osmitrol Injection in Aviva (Mannitol Injection in Aviva Plastic Vessel)
Osmitrol Injection in Viaflex (Mannitol Injection in Viaflex Plastic Vessel)
Osteoprotegrin
Ovidrel (Choriogonadotropin Alfa Injection)
Oxacillin (Oxacillin for Injection)
Oxaliplatin Injection (Eloxatin)
Oxytocin Injection (Pitocin)
Paliperidone Palmitate Extended-Release Injectable Suspension (Invega Sustenna) Pamidronate Disodium Injection (Pamidronate Disodium Injection)
Panitumumab Injection for Intravenous Use (Vectibix)
Papaverine Hydrochloride Injection (Papaverine Injection)
Papaverine Injection (Papaverine Hydrochloride Injection)
Parathyroid Hormone
Paricalcitol Injection Fliptop Vial (Zemplar Injection)
PARP Inhibitor
Pediarix
PEGIntron
Peginterferon
Pegfilgrastim
Penicillin G Benzathine and Penicillin G Procaine
Pentetate Calcium Trisodium Inj (Ca-DTPA)
Pentetate Zinc Trisodium Injection (Zn-DTPA)
Pepcid Injection (Famotidine Injection)
Pergonal
Pertuzumab
Phentolamine Mesylate (Phentolamine Mesylate for Injection)
Physostigmine Salicylate (Physostigmine Salicylate (injection))
Physostigmine Salicylate (injection) (Physostigmine Salicylate)
Piperacillin and Tazobactam Injection (Zosyn)
Pitocin (Oxytocin Injection)
Plasma-Lyte 148 (Multiple Electrolytes Inj)
Plasma-Lyte 56 and Dextrose (Multiple Electrolytes and Dextrose Injection
Plastic Vessel)
PlasmaLyte
Plerixafor Injection (Mozobil)
Polidocanol Injection (Asclera)
Potassium Chloride
Pralatrexate Solution for Intravenous Injection (Folotyn)
Pramlintide Acetate Injection (Symlin)
Premarin Injection (Conjugated Estrogens for Injection)
Prep kit for Technetium Tc99 Sestamibi for Injection (Cardiolite)
Prevacid I.V. (Lansoprazole for Injection)
Primaxin I.V. (Imipenem and Cilastatin for Injection)
Prochymal
Procrit
Progesterone
ProHance (Gadoteridol Injection Solution)
Prolia (Denosumab Injection)
Promethazine HCI Injection (Promethazine Hydrochloride Injection)
Propranolol Hydrochloride Injection (Propranolol Hydrochloride Injection) Quinidine Gluconate Injection (Quinidine Injection)
Quinidine Injection (Quinidine Gluconate Injection)
R-Gene 10 (Arginine Hydrochloride Injection)
Ranibizumab Injection (Lucentis)
Ranitidine Hydrochloride Injection (Zantac Injection)
Raptiva
Reclast (Zoledronic Acid Injection)
Recombivarix HB
Regadenoson Injection (Lexiscan)
Reglan Injection (Metoclopramide Injection)
Remicade
Renagel
Renvela (Sevelamer Carbonate)
Repronex (Menotropins for Injection)
Retrovir IV (Zidovudine Injection)
rhApo2L/TRAIL
Ringer's and 5% Dextrose Injection (Ringers in Dextrose)
Ringer's Injection (Ringers Injection)
Rituxan
Rituximab
Rocephin (ceftriaxone)
Rocuronium Bromide Injection (Zemuron)
Roferon-A (interferon alfa-2a)
Romazicon (flumazenil)
Romidepsin for Injection (Istodax)
Saizen (Somatropin Injection)
Sandostatin LAR (Octreotide Acetate Injection)
Sclerostin Ab
Sensipar (cinacalcet)
Sensorcaine (Bupivacaine HCI Injections)
Septocaine (Articane HCI and Epinephrine Injection)
Serostim LQ (Somatropin (rDNA origin) Injection)
Simponi Injection (Golimumab Injection)
Sodium Acetate (Sodium Acetate Injection)
Sodium Bicarbonate (Sodium Bicarbonate 5% Injection)
Sodium Lactate (Sodium Lactate Injection in AVIVA)
Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)
Somatropin (rDNA origin) for Inj (Nutropin)
Sporanox Injection (Itraconazole Injection)
Stelara Injection (Ustekinumab)
Stemgen
Sufenta (Sufentanil Citrate Injection)
Sufentanil Citrate Injection (Sufenta )
Sumavel
Sumatriptan Injection (Alsuma)
Symlin
Symlin Pen
Systemic Hedgehog Antagonist
Synvisc-One (Hylan G-F 20 Single Intra-articular Injection) Tarceva
Taxotere (Docetaxel for Injection)
Technetium Tc 99m
Telavancin for Injection (Vibativ)
Temsirolimus Injection (Torisel)
Tenormin I.V. Injection (Atenolol Inj)
Teriparatide (rDNA origin) Injection (Forteo)
Testosterone Cypionate
Testosterone Enanthate
Testosterone Propionate
Tev-Tropin (Somatropin, rDNA Origin, for Injection)
tgAAC94
Thallous Chloride
Theophylline
Thiotepa (Thiotepa Injection)
Thymoglobulin (Anti-Thymocyte Globulin (Rabbit)
Thyrogen (Thyrotropin Alfa for Injection)
Ticarcillin Disodium and Clavulanate Potassium Galaxy (Timentin Injection)
Tigan Injection (Trimethobenzamide Hydrochloride Injectable)
Timentin Injection (Ticarcillin Disodium and Clavulanate Potassium Galaxy)
TNKase
Tobramycin Injection (Tobramycin Injection)
Tocilizumab Injection (Actemra)
Torisel (Temsirolimus Injection)
Totect (Dexrazoxane for Injection, Intravenous Infusion Only )
Trastuzumab-DM1
Travasol (Amino Acids (Injection))
Treanda (Bendamustine Hydrochloride Injection)
Trelstar (Triptorelin Pamoate for Injectable Suspension)
Triamcinolone Acetonide
Triamcinolone Diacetate
Triamcinolone Hexacetonide Injectable Suspension (Aristospan Injection 20 mg)
Triesence (Triamcinolone Acetonide Injectable Suspension)
Trimethobenzamide Hydrochloride Injectable (Tigan Injection)
Trimetrexate Glucuronate Inj (Neutrexin)
Triptorelin Pamoate for Injectable Suspension (Trelstar)
Twinject
Trivaris (Triamcinolone Acetonide Injectable Suspension)
Trisenox (Arsenic Trioxide Injection)
Twinrix
Typhoid Vi
Ultravist (lopromide Injection)
Urofollitropin for Injection (Metrodin)
Urokinase Injection (Kinlytic)
Ustekinumab (Stelara Injection)
Ultralente (U)
Valium (diazepam)
Valproate Sodium Injection (Depacon)
Valtropin (Somatropin Injection)
Vancomycin Hydrochloride (Vancomycin Hydrochloride Injection) Vancomycin Hydrochloride Injection (Vancomycin Hydrochloride) Vaprisol (Conivaptan Hcl Injection)
VAQTA
Vasovist (Gadofosveset Trisodium Injection for Intravenous Use)
Vectibix (Panitumumab Injection for Intravenous Use)
Venofer (Iron Sucrose Injection)
Verteporfin Inj (Visudyne)
Vibativ (Telavancin for Injection)
Victoza (Liraglutide [rDNA] Injection)
Vimpat (lacosamide Tablet and Injection)
Vinblastine Sulfate (Vinblastine Sulfate Injection)
Vincasar PFS (Vincristine Sulfate Injection)
Victoza
Vincristine Sulfate (Vincristine Sulfate Injection)
Visudyne (Verteporfin Inj)
Vitamin B-12
Vivitrol (Naltrexone XR Inj)
Voluven (Hydroxyethyl Starch in Sodium Chloride Injection) Xeloda
Xenical (orlistat)
Xeomin (Incobotulinumtoxin A for Injection)
Xolair
Zantac Injection (Ranitidine Hydrochloride Injection)
Zemplar Injection (Paricalcitol Injection Fliptop Vial)
Zemuron (Rocuronium Bromide Injection)
Zenapax (daclizumab)
Zevalin
Zidovudine Injection (Retrovir IV)
Zithromax Injection (Azithromycin)
Zn-DTPA (Pentetate Zinc Trisodium Injection)
Zofran Injection (Ondansetron Hydrochloride Injection)
Zingo
Zoledronic Acid for Inj (Zometa)
Zoledronic Acid Injection (Reclast)
Zometa (Zoledronic Acid for Inj)
Zosyn (Piperacillin and Tazobactam Injection)
Zyprexa Relprevv (Olanzapine Extended Release Injectable Suspension)
Liquid Drugs (Non-lnjectable)
Ability
AccuNeb (Albuterol Sulfate Inhalation Solution)
Actidose Aqua (Activated Charcoal Suspension)
Activated Charcoal Suspension (Actidose Aqua)
Advair
Agenerase Oral Solution (Amprenavir Oral Solution)
Akten (Lidocaine Hydrochloride Ophthalmic Gel)
Alamast (Pemirolast Potassium Ophthalmic Solution)
Albumin (Human) 5% Solution (Buminate 5%)
Albuterol Sulfate Inhalation Solution
Alinia
Alocril
Alphagan
Alrex
Alvesco
Amprenavir Oral Solution
Analpram-HC
Arformoterol Tartrate Inhalation Solution (Brovana)
Aristospan Injection 20 mg (Triamcinolone Hexacetonide Injectable Suspension)
Asacol
Asmanex
Astepro
Astepro (Azelastine Hydrochloride Nasal Spray)
Atrovent Nasal Spray (Ipratropium Bromide Nasal Spray)
Atrovent Nasal Spray .06
Augmentin ES-600
Azasite (Azithromycin Ophthalmic Solution)
Azelaic Acid (Finacea Gel)
Azelastine Hydrochloride Nasal Spray (Astepro)
Azelex (Azelaic Acid Cream)
Azopt (Brinzolamide Ophthalmic Suspension)
Bacteriostatic Saline
Balanced Salt
Bepotastine
Bactroban Nasal
Bactroban
Beclovent
Benzac W
Betimol
Betoptic S
Bepreve
Bimatoprost Ophthalmic Solution
Bleph 10 (Sulfacetamide Sodium Ophthalmic Solution 10%)
Brinzolamide Ophthalmic Suspension (Azopt)
Bromfenac Ophthalmic Solution (Xibrom)
Bromhist
Brovana (Arformoterol Tartrate Inhalation Solution)
Budesonide Inhalation Suspension (Pulmicort Respules)
Cambia (Diclofenac Potassium for Oral Solution)
Capex
Carac
Carboxine-PSE
Carnitor
Cayston (Aztreonam for Inhalation Solution)
Cellcept
Centany
Cerumenex
Ciloxan Ophthalmic Solution (Ciprofloxacin HCL Ophthalmic Solution) Ciprodex
Ciprofloxacin HCL Ophthalmic Solution (Ciloxan Ophthalmic Solution)
Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)
CoLyte (PEG Electrolytes Solution)
Combiven
Comtan
Condylox
Cordran
Cortisporin Ophthalmic Suspension
Cortisporin Otic Suspension
Cromolyn Sodium Inhalation Solution (Intal Nebulizer Solution)
Cromolyn Sodium Ophthalmic Solution (Opticrom)
Crystalline Amino Acid Solution with Electrolytes (Aminosyn Electrolytes)
Cutivate
Cuvposa (Glycopyrrolate Oral Solution)
Cyanocobalamin (CaloMist Nasal Spray)
Cyclosporine Oral Solution (Gengraf Oral Solution)
Cyclogyl
Cysview (Hexaminolevulinate Hydrochloride Intravesical Solution)
DermOtic Oil (Fluocinolone Acetonide Oil Ear Drops)
Desmopressin Acetate Nasal Spray
DDAVP
Derma-Smoothe/FS
Dexamethasone Intensol
Dianeal Low Calcium
Dianeal PD
Diclofenac Potassium for Oral Solution (Cambia)
Didanosine Pediatric Powder for Oral Solution (Videx)
Differin
Dilantin 125 (Phenytoin Oral Suspension)
Ditropan
Dorzolamide Hydrochloride Ophthalmic Solution (Trusopt)
Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution (Cosopt)
Dovonex Scalp (Calcipotriene Solution)
Doxycycline Calcium Oral Suspension (Vibramycin Oral)
Efudex
Elaprase (Idursulfase Solution)
Elestat (Epinastine HCI Ophthalmic Solution)
Elocon
Epinastine HCI Ophthalmic Solution (Elestat)
Epivir HBV
Epogen (Epoetin alfa)
Erythromycin Topical Solution 1 .5% (Staticin)
Ethiodol (Ethiodized Oil)
Ethosuximide Oral Solution (Zarontin Oral Solution)
Eurax
Extraneal (lcodextrin Peritoneal Dialysis Solution)
Felbatol
Feridex I.V. (Ferumoxides Injectable Solution)
Flovent
Floxin Otic (Ofloxacin Otic Solution)
Flo-Pred (Prednisolone Acetate Oral Suspension)
Fluoroplex
Flunisolide Nasal Solution (Flunisolide Nasal Spray .025%)
Fluorometholone Ophthalmic Suspension (FML)
Flurbiprofen Sodium Ophthalmic Solution (Ocufen)
FML
Fo radii
Formoterol Fumarate Inhalation Solution (Perforomist)
Fosamax
Furadantin (Nitrofurantoin Oral Suspension)
Furoxone
Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)
Gantrisin (Acetyl Sulfisoxazole Pediatric Suspension)
Gatifloxacin Ophthalmic Solution (Zymar)
Gengraf Oral Solution (Cyclosporine Oral Solution)
Glycopyrrolate Oral Solution (Cuvposa)
Halcinonide Topical Solution (Halog Solution)
Halog Solution (Halcinonide Topical Solution)
HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution)
Heparin Lock Flush Solution (Hepflush 10)
Hexaminolevulinate Hydrochloride Intravesical Solution (Cysview)
Hydrocodone Bitartrate and Acetaminophen Oral Solution (Lortab El
Hydroquinone 3% Topical Solution (Melquin-3 Topical Solution)
IAP Antagonist
Isopto
Ipratropium Bromide Nasal Spray (Atrovent Nasal Spray)
Itraconazole Oral Solution (Sporanox Oral Solution)
Ketorolac Tromethamine Ophthalmic Solution (Acular LS)
Kaletra
Lanoxin
Lexiva
Leuprolide Acetate for Depot Suspension (Lupron Depot 1 1 .25 mg)
Levobetaxolol Hydrochloride Ophthalmic Suspension (Betaxon)
Levocarnitine Tablets, Oral Solution, Sugar-Free (Carnitor)
Levofloxacin Ophthalmic Solution 0.5% (Quixin)
Lidocaine HCI Sterile Solution (Xylocaine MPF Sterile Solution)
Lok Pak (Heparin Lock Flush Solution)
Lorazepam Intensol
Lortab Elixir (Hydrocodone Bitartrate and Acetaminophen Oral Solution)
Lotemax (Loteprednol Etabonate Ophthalmic Suspension)
Loteprednol Etabonate Ophthalmic Suspension (Alrex)
Low Calcium Peritoneal Dialysis Solutions (Dianeal Low Calcium)
Lumigan (Bimatoprost Ophthalmic Solution 0.03% for Glaucoma)
Lupron Depot 1 1 .25 mg (Leuprolide Acetate for Depot Suspension)
Megestrol Acetate Oral Suspension (Megestrol Acetate Oral Suspension)
MEK Inhibitor
Mepron
Mesnex
Mestinon
Mesalamine Rectal Suspension Enema (Rowasa)
Melquin-3 Topical Solution (Hydroquinone 3% Topical Solution)
MetMab
Methyldopate Hcl (Methyldopate Hydrochloride Injection, Solution)
Methylin Oral Solution (Methylphenidate HCI Oral Solution 5 mg/5 mL and 10 mg/5 mL)
Methylprednisolone Acetate Injectable Suspension (Depo Medrol)
Methylphenidate HCI Oral Solution 5 mg/5 mL and 10 mg/5 mL (Methylin Oral Solution)
Methylprednisolone sodium succinate (Solu Medrol)
Metipranolol Ophthalmic Solution (Optipranolol)
Migranal
Miochol-E (Acetylcholine Chloride Intraocular Solution)
Micro-K for Liquid Suspension (Potassium Chloride Extended Release Formulation for Liquid Suspension)
Minocin (Minocycline Hydrochloride Oral Suspension)
Nasacort
Neomycin and Polymyxin B Sulfates and Hydrocortisone
Nepafenac Ophthalmic Suspension (Nevanac)
Nevanac (Nepafenac Ophthalmic Suspension)
Nitrofurantoin Oral Suspension (Furadantin)
Noxafil (Posaconazole Oral Suspension)
Nystatin (oral) (Nystatin Oral Suspension)
Nystatin Oral Suspension (Nystatin (oral))
Ocufen (Flurbiprofen Sodium Ophthalmic Solution)
Ofloxacin Ophthalmic Solution (Ofloxacin Ophthalmic Solution)
Ofloxacin Otic Solution (Floxin Otic)
Olopatadine Hydrochloride Ophthalmic Solution (Pataday)
Opticrom (Cromolyn Sodium Ophthalmic Solution)
Optipranolol (Metipranolol Ophthalmic Solution)
Patanol
Pediapred
PerioGard
Phenytoin Oral Suspension (Dilantin 125)
Phisohex
Posaconazole Oral Suspension (Noxafil)
Potassium Chloride Extended Release Formulation for Liquid Suspension (Micro-K for Liquid Suspension)
Pataday (Olopatadine Hydrochloride Ophthalmic Solution)
Patanase Nasal Spray (Olopatadine Hydrochloride Nasal Spray)
PEG Electrolytes Solution (CoLyte)
Pemirolast Potassium Ophthalmic Solution (Alamast)
Penlac (Ciclopirox Topical Solution)
PENNSAID (Diclofenac Sodium Topical Solution)
Perforomist (Formoterol Fumarate Inhalation Solution)
Peritoneal Dialysis Solution
Phenylephrine Hydrochloride Ophthalmic Solution (Neo-Synephrine)
Phospholine Iodide (Echothiophate Iodide for Ophthalmic Solution)
Podofilox (Podofilox Topical Solution)
Pred Forte (Prednisolone Acetate Ophthalmic Suspension)
Pralatrexate Solution for Intravenous Injection (Folotyn)
Pred Mild
Prednisone Intensol
Prednisolone Acetate Ophthalmic Suspension (Pred Forte)
Prevacid
PrismaSol Solution (Sterile Hemofiltration Hemodiafiltration Solution)
ProAir
Proglycem
ProHance (Gadoteridol Injection Solution)
Proparacaine Hydrochloride Ophthalmic Solution (Alcaine)
Propine
Pulmicort
Pulmozyme
Quixin (Levofloxacin Ophthalmic Solution 0.5%)
QVAR
Rapamune
Rebetol
Relacon-HC
Rotarix (Rotavirus Vaccine, Live, Oral Suspension)
Rotavirus Vaccine, Live, Oral Suspension (Rotarix)
Rowasa (Mesalamine Rectal Suspension Enema)
Sabril (Vigabatrin Oral Solution)
Sacrosidase Oral Solution (Sucraid)
Sandimmune
Sepra
Serevent Diskus
Solu Cortef (Hydrocortisone Sodium Succinate)
Solu Medrol (Methylprednisolone sodium succinate)
Spiriva
Sporanox Oral Solution (Itraconazole Oral Solution)
Staticin (Erythromycin Topical Solution 1 .5%)
Stalevo
Starlix
Sterile Hemofiltration Hemodiafiltration Solution (PrismaSol Solution)
Stimate
Sucralfate (Carafate Suspension)
Sulfacetamide Sodium Ophthalmic Solution 10% (Bleph 10)
Synarel Nasal Solution (Nafarelin Acetate Nasal Solution for Endometriosis)
Taclonex Scalp (Calcipotriene and Betamethasone Dipropionate Topical Suspension)
Tamiflu
Tobi
TobraDex
Tobradex ST (Tobramycin / Dexamethasone Ophthalmic Suspension 0.3%/0.05%) Tobramycin / Dexamethasone Ophthalmic Suspension 0.3%/0.05% (Tobradex ST) Timolol
Timoptic
Travatan Z
Treprostinil Inhalation Solution (Tyvaso)
Trusopt (Dorzolamide Hydrochloride Ophthalmic Solution)
Tyvaso (Treprostinil Inhalation Solution)
Ventolin
Vfend
Vibramycin Oral (Doxycycline Calcium Oral Suspension)
Videx (Didanosine Pediatric Powder for Oral Solution)
Vigabatrin Oral Solution (Sabril)
Viokase
Viracept
Viramune
Vitamin K1 (Fluid Colloidal Solution of Vitamin K1 )
Voltaren Ophthalmic (Diclofenac Sodium Ophthalmic Solution)
Zarontin Oral Solution (Ethosuximide Oral Solution)
Ziagen
Zyvox
Zymar (Gatifloxacin Ophthalmic Solution)
Zymaxid (Gatifloxacin Ophthalmic Solution)
Drug Classes
5-alpha-reductase inhibitors
5-aminosalicylates
5HT3 receptor antagonists
adamantane antivirals
adrenal cortical steroids
adrenal corticosteroid inhibitors
adrenergic bronchodilators
agents for hypertensive emergencies agents for pulmonary hypertension aldosterone receptor antagonists alkylating agents
alpha-adrenoreceptor antagonists alpha-glucosidase inhibitors
alternative medicines
amebicides
aminoglycosides
aminopenicillins
aminosalicylates
amylin analogs
Analgesic Combinations
Analgesics
androgens and anabolic steroids angiotensin converting enzyme inhibitors angiotensin II inhibitors
anorectal preparations
anorexiants
antacids
anthelmintics
anti-angiogenic ophthalmic agents anti-CTLA-4 monoclonal antibodies anti-infectives
antiadrenergic agents, centrally acting antiadrenergic agents, peripherally acting antiandrogens
antianginal agents
antiarrhythmic agents
antiasthmatic combinations
ant biotics/antineoplastics ant cholinergic antiemetics ant cholinergic antiparkinson agents ant cholinergic bronchodilators ant cholinergic chronotropic agents ant cholinergics/antispasmodics ant coagulants
ant convulsants
ant depressants
ant diabetic agents
ant diabetic combinations ant diarrheals
ant diuretic hormones
ant dotes
ant emetic/antivertigo agents ant fungals
ant gonadotropic agents
ant gout agents
ant histamines
ant hyperlipidemic agents ant hyperlipidemic combinations ant hypertensive combinations ant hyperuricemic agents ant malarial agents
ant malarial combinations ant malarial quinolines
ant metabolites
ant migraine agents
ant neoplastic detoxifying agents ant neoplastic interferons
antineoplastic monoclonal antibodies antineoplastics
antiparkinson agents
antiplatelet agents
antipseudomonal penicillins antipsoriatics
antipsychotics
antirheumatics
antiseptic and germicides
antithyroid agents
antitoxins and antivenins
antituberculosis agents
antituberculosis combinations antitussives
antiviral agents
antiviral combinations
antiviral interferons
anxiolytics, sedatives, and hypnotics aromatase inhibitors
atypical antipsychotics
azole antifungals
bacterial vaccines
barbiturate anticonvulsants barbiturates
BCR-ABL tyrosine kinase inhibitors benzodiazepine anticonvulsants benzodiazepines
beta-adrenergic blocking agents beta-lactamase inhibitors
bile acid sequestrants
biologicals
bisphosphonates
bone resorption inhibitors
bronchodilator combinations
bronchodilators
calcitonin
calcium channel blocking agents
carbamate anticonvulsants
carbapenems
carbonic anhydrase inhibitor anticonvulsants carbonic anhydrase inhibitors
cardiac stressing agents
cardioselective beta blockers
cardiovascular agents
catecholamines
CD20 monoclonal antibodies
CD33 monoclonal antibodies
CD52 monoclonal antibodies
central nervous system agents
cephalosporins
cerumenolytics
chelating agents
chemokine receptor antagonist
chloride channel activators
cholesterol absorption inhibitors
cholinergic agonists
cholinergic muscle stimulants
cholinesterase inhibitors
CNS stimulants
coagulation modifiers
colony stimulating factors
contraceptives
corticotropin
coumarins and indandiones
cox-2 inhibitors
decongestants
dermatological agents
diagnostic radiopharmaceuticals
dibenzazepine anticonvulsants
digestive enzymes
dipeptidyl peptidase 4 inhibitors
diuretics
dopaminergic antiparkinsonism agents
drugs used in alcohol dependence
echinocandins
EGFR inhibitors
estrogen receptor antagonists
estrogens
expectorants
factor Xa inhibitors
fatty acid derivative anticonvulsants
fibric acid derivatives
first generation cephalosporins
fourth generation cephalosporins
functional bowel disorder agents
gallstone solubilizing agents
gamma-aminobutyric acid analogs
gamma-aminobutyric acid reuptake inhibitors gamma-aminobutyric acid transaminase inhibitors gastrointestinal agents
general anesthetics
genitourinary tract agents
Gl stimulants
glucocorticoids
glucose elevating agents
glycopeptide antibiotics
glycoprotein platelet inhibitors
glycylcyclines
gonadotropin releasing hormones
gonadotropin-releasing hormone antagonists gonadotropins
group I antiarrhythmics
group II antiarrhythmics
group III antiarrhythmics
group IV antiarrhythmics
group V antiarrhythmics
growth hormone receptor blockers growth hormones
H. pylori eradication agents
H2 antagonists
hematopoietic stem cell mobilizer
heparin antagonists
heparins
HER2 inhibitors
herbal products
histone deacetylase inhibitors
hormone replacement therapy
hormones
hormones/antineoplastics
hydantoin anticonvulsants
illicit (street) drugs
immune globulins
immunologic agents
immunosuppressive agents impotence agents
in vivo diagnostic biologicals incretin mimetics
inhaled anti-infectives
inhaled corticosteroids
inotropic agents
insulin
insulin-like growth factor integrase strand transfer inhibitor interferons
intravenous nutritional products iodinated contrast media ionic iodinated contrast media iron products
ketolides
laxatives
leprostatics
leukotriene modifiers
lincomycin derivatives
lipoglycopeptides
local injectable anesthetics loop diuretics
lung surfactants
lymphatic staining agents lysosomal enzymes
macrolide derivatives
macrolides
magnetic resonance imaging contrast media mast cell stabilizers
medical gas
meglitinides
metabolic agents
methylxanthines
mineralocorticoids
minerals and electrolytes
miscel laneous agents
miscel laneous analgesics
miscel laneous antibiotics
miscel laneous anticonvulsants
miscel laneous antidepressants
miscel laneous antidiabetic agents
miscel laneous antiemetics
miscel laneous antifungals
miscel laneous antihyperlipidemic agents miscel laneous antimalarials
miscel laneous antineoplastics
miscel laneous antiparkinson agents
miscel laneous antipsychotic agents
miscel laneous antituberculosis agents
miscel laneous antivirals
miscel laneous anxiolytics, sedatives and hypnotics miscel laneous biologicals
miscel laneous bone resorption inhibitors miscel laneous cardiovascular agents
miscel laneous central nervous system agents miscel laneous coagulation modifiers
miscel laneous diuretics
miscel laneous genitourinary tract agents miscel laneous Gl agents
miscel laneous hormones
miscel laneous metabolic agents miscel laneous ophthalmic agents miscel laneous otic agents
miscel laneous respiratory agents miscel laneous sex hormones
miscel laneous topical agents
miscel laneous uncategorized agents miscel laneous vaginal agents
mitotic inhibitors
monoamine oxidase inhibitors monoclonal antibodies
mouth and throat products
mTOR inhibitors
mTOR kinase inhibitors
mucolytics
multikinase inhibitors
muscle relaxants
mydriatics
narcotic analgesic combinations narcotic analgesics
nasal anti-infectives
nasal antihistamines and decongestants nasal lubricants and irrigations nasal preparations
nasal steroids
natural penicillins
neuraminidase inhibitors
neuromuscular blocking agents
next generation cephalosporins
nicotinic acid derivatives
nitrates
NNRTIs
non-cardioselective beta blockers
non-iodinated contrast media
non-ionic iodinated contrast media
non-sulfonylureas
nonsteroidal anti-inflammatory agents
norepinephrine reuptake inhibitors
norepinephrine-dopamine reuptake inhibitors nucleoside reverse transcriptase inhibitors (NRTIs) nutraceutical products
nutritional products
ophthalmic anesthetics
ophthalmic anti-infectives
ophthalmic anti-inflammatory agents
ophthalmic antihistamines and decongestants ophthalmic diagnostic agents
ophthalmic glaucoma agents
ophthalmic lubricants and irrigations
ophthalmic preparations
ophthalmic steroids
ophthalmic steroids with anti-infectives
ophthalmic surgical agents
oral nutritional supplements
otic anesthetics
otic anti-infectives
otic preparations
otic steroids
otic steroids with anti-infectives oxazolidinedione anticonvulsants parathyroid hormone and analogs penicillinase resistant penicillins penicillins
peripheral opioid receptor antagonists peripheral vasodilators
peripherally acting antiobesity agents phenothiazine antiemetics
phenothiazine antipsychotics phenylpiperazine antidepressants plasma expanders
platelet aggregation inhibitors platelet-stimulating agents
polyenes
potassium-sparing diuretics probiotics
progesterone receptor modulators progestins
prolactin inhibitors
prostaglandin D2 antagonists protease inhibitors
proton pump inhibitors
psoralens
psychotherapeutic agents
psychotherapeutic combinations purine nucleosides
pyrrolidine anticonvulsants
quinolones
radiocontrast agents
radiologic adjuncts
radiologic agents
radiologic conjugating agents
radiopharmaceuticals
RANK ligand inhibitors
recombinant human erythropoietins renin inhibitors
respiratory agents
respiratory inhalant products
rifamycin derivatives
salicylates
sclerosing agents
second generation cephalosporins selective estrogen receptor modulators selective serotonin reuptake inhibitors serotonin-norepinephrine reuptake inhibitors serotoninergic neuroenteric modulators sex hormone combinations
sex hormones
skeletal muscle relaxant combinations skeletal muscle relaxants
smoking cessation agents
somatostatin and somatostatin analogs spermicides
statins
sterile irrigating solutions
streptomyces derivatives
succinimide anticonvulsants
sulfonamides
sulfonylureas
synthetic ovulation stimulants tetracyclic antidepressants tetracyclines
therapeutic radiopharmaceuticals thiazide diuretics
thiazolidinediones
thioxanthenes
third generation cephalosporins thrombin inhibitors
thrombolytics
thyroid drugs
tocolytic agents
topica acne agents
topica agents
topica anesthetics
topica anti-infectives
topica antibiotics
topica antifungals
topica antihistamines
topica antipsoriatics
topica antivirals
topica astringents
topica debriding agents topica depigmenting agents topica emollients
topica keratolytics
topica steroids
topica steroids with anti-infectives
toxoids
triazine anticonvulsants
tricyclic antidepressants
trifunctional monoclonal antibodies tumor necrosis factor (TNF) inhibitors tyrosine kinase inhibitors
ultrasound contrast media
upper respiratory combinations urea anticonvulsants
urinary anti-infectives
urinary antispasmodics
urinary pH modifiers
uterotonic agents
vaccine
vaccine combinations
vaginal anti-infectives
vaginal preparations
vasodilators
vasopressin antagonists
vasopressors
VEGF/VEGFR inhibitors
viral vaccines
viscosupplementation agents vitamin and mineral combinations vitamins
Diagnostic Tests
17-Hydroxyprogesterone
ACE (Angiotensin I converting enzyme)
Acetaminophen
Acid phosphatase
ACTH
Activated clotting time
Activated protein C resistance
Adrenocorticotropic hormone (ACTH)
Alanine aminotransferase (ALT)
Albumin
Aldolase
Aldosterone
Alkaline phosphatase
Alkaline phosphatase (ALP)
Alphal -antitrypsin
Alpha-fetoprotein
Alpha-fetoprotien
Ammonia levels
Amylase
ANA (antinuclear antbodies)
ANA (antinuclear antibodies)
Angiotensin-converting enzyme (ACE) Anion gap
Anticardiolipin antibody
Anticardiolipin antivbodies (ACA)
Anti-centromere antibody
Antidiuretic hormone
Anti-DNA
Anti-Dnase-B
Anti-Gliadin antibody
Anti-glomerular basement membrane antibody Anti-HBc (Hepatitis B core antibodies
Anti-HBs (Hepatitis B surface antibody
Antiphospholipid antibody
Anti-RNA polymerase
Anti-Smith (Sm) antibodies Anti-Smooth Muscle antibody Antistreptolysin O (ASO)
Antithrombin III
Anti-Xa activity
Anti-Xa assay
Apolipoproteins
Arsenic
Aspartate aminotransferase (AST) B12
Basophil
Beta-2-Microglobulin
Beta-hydroxybutyrate
B-HCG
Bilirubin
Bilirubin, direct
Bilirubin, indirect
Bilirubin, total
Bleeding time
Blood gases (arterial)
Blood urea nitrogen (BUN)
BUN
BUN (blood urea nitrogen)
CA 125
CA 15-3
CA 19-9
Calcitonin
Calcium
Calcium (ionized)
Carbon monoxide (CO)
Carcinoembryonic antigen (CEA)
CBC
CEA
CEA (carcinoembryonic antigen)
Ceruloplasmin
CH50Chloride
Cholesterol
Cholesterol, HDL
Clot lysis time
Clot retraction time
CMP
CO2
Cold agglutinins
Complement C3
Copper
Corticotrophin releasing hormone (CRH) stimulation test Cortisol
Cortrosyn stimulation test
C-peptide
CPK (Total)
CPK-MB
C-reactive protein
Creatinine
Creatinine kinase (CK)
Cryoglobulins
DAT (Direct antiglobulin test)
D-Dimer
Dexamethasone suppression test
DHEA-S
Dilute Russell viper venom
Elliptocytes
Eosinophil
Erythrocyte sedimentation rate (ESR)
Estradiol
Estriol
Ethanol
Ethylene glycol
Euglobulin lysis
Factor V Leiden
Factor VIII inhibitor
Factor VIII level
Ferritin
Fibrin split products
Fibrinogen
Folate
Folate (serum
Fractional excretion of sodium (FENA) FSH (follicle stimulating factor) FTA-ABS
Gamma glutamyl transferase (GGT) Gastrin
GGTP (Gamma glutamyl transferase) Glucose
Growth hormone
Haptoglobin
HBeAg (Hepatitis Be antigen)
HBs-Ag (Hepatitis B surface antigen) Helicobacter pylori
Hematocrit
Hematocrit (HCT)
Hemoglobin
Hemoglobin A1 C
Hemoglobin electrophoresis
Hepatitis A antibodies
Hepatitis C antibodies
IAT (Indirect antiglobulin test)
Immunofixation (IFE)
Iron
Lactate dehydrogenase (LDH)
Lactic acid (lactate)
LDH
LH (Leutinizing hormone
Lipase
Lupus anticoagulant
Lymphocyte
Magnesium
MCH (mean corpuscular hemoglobin
MCHC (mean corpuscular hemoglobin concentration)
MCV (mean corpuscular volume)
Methylmalonate
Monocyte
MPV (mean platelet volume)
Myoglobin
Neutrophil
Parathyroid hormone (PTH)
Phosphorus
Platelets (pit)
Potassium
Prealbumin
Prolactin
Prostate specific antigen (PSA)
Protein C
Protein S
PSA (prostate specific antigen)
PT (Prothrombin time)
PTT (Partial thromboplastin time)
RDW (red cell distribution width)
Renin
Rennin
Reticulocyte count
reticulocytes
Rheumatoid factor (RF)
Sed Rate
Serum glutamic-pyruvic transaminase (SGPT Serum protein electrophoresis (SPEP) Sodium
T3-resin uptake (T3RU)
T4, Free
Thrombin time
Thyroid stimulating hormone (TSH)
Thyroxine (T4)
Total iron binding capacity (TIBC)
Total protein
Transferrin
Transferrin saturation
Triglyceride (TG)
Troponin
Uric acid
Vitamin B12
White blood cells (WBC)
Widal test
350. The invention of any preceding claim, wherein said fluid composition comprises an inhalation anesthetic.
351 . The invention of claim 350, wherein said inhalation anesthetic comprises a fluoroether inhalation anesthetic agent.
352. The invention of claim 350, wherein said inhalation anesthetic comprises sevoflurane, enflurane, isoflurane, methoxyflurane, desflurane, or a combination of any two or more of these.
353. The invention of any preceding claim, wherein said fluid comprisescomposition comprises a drug.
354. The invention of claim 353, wherein said drug comprises Ablavar (Gadofosveset Trisodium Injection).
355. The invention of claim 353, wherein said drug comprises Abobotulinumtoxin A Injection (Dysport).
356. The invention of claim 353, wherein said drug comprises Accretropin (Somatropin Injection).
357. The invention of claim 353, wherein said drug comprises Acetadote (Acetylcysteine Injection).
358. The invention of claim 353, wherein said drug comprises Acetazolamide Injection (Acetazolamide Injection).
359. The invention of claim 353, wherein said drug comprises Acetylcysteine Injection (Acetadote).
360. The invention of claim 353, wherein said drug comprises Actemra (Tocilizumab Injection).
361 . The invention of claim 353, wherein said drug comprises Acthrel (Corticorelin Ovine Triflutate for Injection).
362. The invention of claim 353, wherein said drug comprises Acyclovir for Injection (Zovirax Injection).
363. The invention of claim 353, wherein said drug comprises Adacel.
364. The invention of claim 353, wherein said drug comprises Adalimumab.
365. The invention of claim 353, wherein said drug comprises Adenoscan (Adenosine Injection).
366. The invention of claim 353, wherein said drug comprises Adenosine Injection (Adenoscan).
367. The invention of claim 353, wherein said drug comprises Adrenaclick.
368. The invention of claim 353, wherein said drug comprises AdreView (lobenguane I 123 Injection for Intravenous Use).
369. The invention of claim 353, wherein said drug comprises Afluria.
370. The invention of claim 353, wherein said drug comprises Ak-Fluor (Fluorescein Injection).
371 . The invention of claim 353, wherein said drug comprises Alglucerase Injection (Ceredase).
372. The invention of claim 353, wherein said drug comprises Alkeran Injection (Melphalan Hcl Injection).
373. The invention of claim 353, wherein said drug comprises Allopurinol Sodium for Injection (Aloprim).
374. The invention of claim 353, wherein said drug comprises Aloprim (Allopurinol Sodium for Injection).
375. The invention of claim 353, wherein said drug comprises Alprostadil.
376. The invention of claim 353, wherein said drug comprises Alsuma (Sumatriptan Injection).
377. The invention of claim 353, wherein said drug comprises Amino Acid Injections.
378. The invention of claim 353, wherein said drug comprises Aminosyn.
379. The invention of claim 353, wherein said drug comprises Apidra.
380. The invention of claim 353, wherein said drug comprises Apremilast.
381 . The invention of claim 353, wherein said drug comprises Alprostadil Dual Chamber System for Injection (Caverject Impulse).
382. The invention of claim 353, wherein said drug comprises AMG 108.
383. The invention of claim 353, wherein said drug comprises AMG 714.
384. The invention of claim 353, wherein said drug comprises Amiodarone HCI Injection (Amiodarone HCI Injection).
385. The invention of claim 353, wherein said drug comprises Amobarbital Sodium Injection (Amytal Sodium).
386. The invention of claim 353, wherein said drug comprises Amytal Sodium (Amobarbital Sodium Injection).
387. The invention of claim 353, wherein said drug comprises Anakinra.
388. The invention of claim 353, wherein said drug comprises Arixtra.
389. The invention of claim 353, wherein said drug comprises Amphadase (Hyaluronidase Inj).
390. The invention of claim 353, wherein said drug comprises Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection).
391 . The invention of claim 353, wherein said drug comprises Anzemet Injection (Dolasetron Mesylate Injection).
392. The invention of claim 353, wherein said drug comprises Apidra (Insulin Glulisine [rDNA origin] Inj).
393. The invention of claim 353, wherein said drug comprises Argatroban (Argatroban Injection).
394. The invention of claim 353, wherein said drug comprises Arginine Hydrochloride Injection (R-Gene 10).
395. The invention of claim 353, wherein said drug comprises Aristocort.
396. The invention of claim 353, wherein said drug comprises Aristospan.
397. The invention of claim 353, wherein said drug comprises Arsenic Trioxide Injection (Trisenox).
398. The invention of claim 353, wherein said drug comprises Articane HCI and Epinephrine Injection (Septocaine).
399. The invention of claim 353, wherein said drug comprises Arzerra (Ofatumumab Injection).
400. The invention of claim 353, wherein said drug comprises Asclera (Polidocanol Injection).
401 . The invention of claim 353, wherein said drug comprises Atenolol Inj (Tenormin I.V. Injection).
402. The invention of claim 353, wherein said drug comprises Atracurium Besylate Injection (Atracurium Besylate Injection).
403. The invention of claim 353, wherein said drug comprises Avastin.
404. The invention of claim 353, wherein said drug comprises Azactam Injection (Aztreonam Injection).
405. The invention of claim 353, wherein said drug comprises Azithromycin (Zithromax Injection).
406. The invention of claim 353, wherein said drug comprises Aztreonam Injection (Azactam Injection).
407. The invention of claim 353, wherein said drug comprises Baclofen Injection (Lioresal Intrathecal).
408. The invention of claim 353, wherein said drug comprises Bacteriostatic Water (Bacteriostatic Water for Injection).
409. The invention of claim 353, wherein said drug comprises Baclofen Injection (Lioresal Intrathecal).
410. The invention of claim 353, wherein said drug comprises Bal in Oil Ampules (Dimercarprol Injection).
41 1 . The invention of claim 353, wherein said drug comprises BayHepB.
412. The invention of claim 353, wherein said drug comprises BayTet.
413. The invention of claim 353, wherein said drug comprises Benadryl.
414. The invention of claim 353, wherein said drug comprises Bendamustine Hydrochloride Injection (Treanda).
415. The invention of claim 353, wherein said drug comprises Benztropine Mesylate Injection (Cogentin).
416. The invention of claim 353, wherein said drug comprises Betamethasone Injectable Suspension (Celestone Soluspan).
417. The invention of claim 353, wherein said drug comprises Bexxar.
418. The invention of claim 353, wherein said drug comprises Bicillin C-R 900/300 (Penicillin G Benzathine and Penicillin G Procaine Injection).
419. The invention of claim 353, wherein said drug comprises Blenoxane (Bleomycin Sulfate Injection).
420. The invention of claim 353, wherein said drug comprises Bleomycin Sulfate Injection (Blenoxane).
421 . The invention of claim 353, wherein said drug comprises Boniva Injection (Ibandronate Sodium Injection).
422. The invention of claim 353, wherein said drug comprises Botox Cosmetic (OnabotulinumtoxinA for Injection).
423. The invention of claim 353, wherein said drug comprises Bravelle (Urofollitropin Injection).
424. The invention of claim 353, wherein said drug comprises Bretylium (Bretylium Tosylate Injection ).
425. The invention of claim 353, wherein said drug comprises Brevital Sodium (Methohexital Sodium for Injection).
426. The invention of claim 353, wherein said drug comprises Brethine.
427. The invention of claim 353, wherein said drug comprises Briobacept.
428. The invention of claim 353, wherein said drug comprises BTT-1023.
429. The invention of claim 353, wherein said drug comprises Bupivacaine HCI.
430. The invention of claim 353, wherein said drug comprises Byetta.
431 . The invention of claim 353, wherein said drug comprises Ca-DTPA (Pentetate Calcium Trisodium Inj).
432. The invention of claim 353, wherein said drug comprises Cabazitaxel Injection (Jevtana).
433. The invention of claim 353, wherein said drug comprises Caffeine Alkaloid (Caffeine and Sodium Benzoate Injection).
434. The invention of claim 353, wherein said drug comprises Calcijex Injection (Calcitrol).
435. The invention of claim 353, wherein said drug comprises Calcitrol (Calcijex Injection).
436. The invention of claim 353, wherein said drug comprises Calcium Chloride (Calcium Chloride Injection 10%).
437. The invention of claim 353, wherein said drug comprises Calcium Disodium Versenate (Edetate Calcium Disodium Injection).
438. The invention of claim 353, wherein said drug comprises Camptosar Injection (Irinotecan Hydrochloride).
439. The invention of claim 353, wherein said drug comprises Canakinumab Injection (Maris).
440. The invention of claim 353, wherein said drug comprises Capastat Sulfate (Capreomycin for Injection).
441 . The invention of claim 353, wherein said drug comprises Capreomycin for Injection (Capastat Sulfate).
442. The invention of claim 353, wherein said drug comprises Cardiolite (Prep kit for Technetium Tc99 Sestamibi for Injection).
443. The invention of claim 353, wherein said drug comprises Cefazolin and Dextrose for Injection (Cefazolin Injection).
444. The invention of claim 353, wherein said drug comprises Cefepime Hydrochloride.
445. The invention of claim 353, wherein said drug comprises Cefotaxime.
446. The invention of claim 353, wherein said drug comprises Ceftriaxone.
447. The invention of claim 353, wherein said drug comprises Carnitor Injection.
448. The invention of claim 353, wherein said drug comprises Caverject.
449. The invention of claim 353, wherein said drug comprises Celestone Soluspan.
450. The invention of claim 353, wherein said drug comprises Cerebyx (Fosphenytoin Sodium Injection).
451 . The invention of claim 353, wherein said drug comprises Ceredase (Alglucerase Injection).
452. The invention of claim 353, wherein said drug comprises Ceretec (Technetium Tc99m Exametazime Injection).
453. The invention of claim 353, wherein said drug comprises Certolizumab.
454. The invention of claim 353, wherein said drug comprises CF-101 .
455. The invention of claim 353, wherein said drug comprises Chloramphenicol Sodium Succinate (Chloramphenicol Sodium Succinate Injection).
456. The invention of claim 353, wherein said drug comprises Chloramphenicol Sodium Succinate Injection (Chloramphenicol Sodium Succinate).
457. The invention of claim 353, wherein said drug comprises Choriogonadotropin Alfa Injection (Ovidrel).
458. The invention of claim 353, wherein said drug comprises Cimzia.
459. The invention of claim 353, wherein said drug comprises Cisplatin (Cisplatin Injection).
460. The invention of claim 353, wherein said drug comprises Clomiphine Citrate.
461 . The invention of claim 353, wherein said drug comprises Clonidine Injection (Duraclon).
462. The invention of claim 353, wherein said drug comprises Cogentin (Benztropine Mesylate Injection).
463. The invention of claim 353, wherein said drug comprises Colistimethate Injection (Coly-Mycin M).
464. The invention of claim 353, wherein said drug comprises Coly-Mycin M (Colistimethate Injection).
465. The invention of claim 353, wherein said drug comprises Compath.
466. The invention of claim 353, wherein said drug comprises Conivaptan Hcl Injection (Vaprisol).
467. The invention of claim 353, wherein said drug comprises Conjugated Estrogens for Injection (Premarin Injection).
468. The invention of claim 353, wherein said drug comprises Copaxone.
469. The invention of claim 353, wherein said drug comprises Corticorelin Ovine Triflutate for Injection (Acthrel).
470. The invention of claim 353, wherein said drug comprises Corvert (Ibutilide Fumarate Injection).
471 . The invention of claim 353, wherein said drug comprises Cubicin (Daptomycin Injection).
472. The invention of claim 353, wherein said drug comprises CF-101 .
473. The invention of claim 353, wherein said drug comprises Cyanokit (Hydroxocobalamin for Injection).
474. The invention of claim 353, wherein said drug comprises Cytarabine Liposome Injection (DepoCyt).
475. The invention of claim 353, wherein said drug comprises Cyanocobalamin.
476. The invention of claim 353, wherein said drug comprises D.H.E. 45.
477. The invention of claim 353, wherein said drug comprises Dacogen (Decitabine Injection).
478. The invention of claim 353, wherein said drug comprises Dalteparin.
479. The invention of claim 353, wherein said drug comprises Dantrium IV (Dantrolene Sodium for Injection).
480. The invention of claim 353, wherein said drug comprises Dantrolene Sodium for Injection (Dantrium IV).
481 . The invention of claim 353, wherein said drug comprises Daptomycin Injection (Cubicin).
482. The invention of claim 353, wherein said drug comprises Darbepoietin
Alfa.
483. The invention of claim 353, wherein said drug comprises DDAVP Injection (Desmopressin Acetate Injection).
484. The invention of claim 353, wherein said drug comprises Decavax.
485. The invention of claim 353, wherein said drug comprises Decitabine Injection (Dacogen).
486. The invention of claim 353, wherein said drug comprises Dehydrated Alcohol (Dehydrated Alcohol Injection).
486. The invention of claim 353, wherein said drug comprises Denosumab Injection (Prolia).
487. The invention of claim 353, wherein said drug comprises Delatestryl.
488. The invention of claim 353, wherein said drug comprises Delestrogen.
489. The invention of claim 353, wherein said drug comprises Delteparin Sodium.
490. The invention of claim 353, wherein said drug comprises Depacon (Valproate Sodium Injection).
491 . The invention of claim 353, wherein said drug comprises Depo Medrol (Methylprednisolone Acetate Injectable Suspension).
492. The invention of claim 353, wherein said drug comprises DepoCyt (Cytarabine Liposome Injection).
493. The invention of claim 353, wherein said drug comprises DepoDur (Morphine Sulfate XR Liposome Injection).
494. The invention of claim 353, wherein said drug comprises Desmopressin Acetate Injection (DDAVP Injection).
495. The invention of claim 353, wherein said drug comprises Depo-Estradiol.
496. The invention of claim 353, wherein said drug comprises Depo-Provera 104mg/ml.
497. The invention of claim 353, wherein said drug comprises Depo-Provera 150mg/ml.
498. The invention of claim 353, wherein said drug comprises Depo- Testosterone.
499. The invention of claim 353, wherein said drug comprises Dexrazoxane for Injection, Intravenous Infusion Only (Totect).
500. The invention of claim 353, wherein said drug comprises Dextrose / Electrolytes.
501 . The invention of claim 353, wherein said drug comprises Dextrose and Sodium Chloride Inj (Dextrose 5% in 0.9% Sodium Chloride).
502. The invention of claim 353, wherein said drug comprises Dextrose.
503. The invention of claim 353, wherein said drug comprises Diazepam Injection (Diazepam Injection).
504. The invention of claim 353, wherein said drug comprises Digoxin Injection (Lanoxin Injection).
505. The invention of claim 353, wherein said drug comprises Dilaudid-HP (Hydromorphone Hydrochloride Injection).
506. The invention of claim 353, wherein said drug comprises Dimercarprol Injection (Bal in Oil Ampules).
507. The invention of claim 353, wherein said drug comprises Diphenhydramine Injection (Benadryl Injection).
508. The invention of claim 353, wherein said drug comprises Dipyridamole Injection (Dipyridamole Injection).
509. The invention of claim 353, wherein said drug comprises Docetaxel for Injection (Taxotere).
510. The invention of claim 353, wherein said drug comprises Dolasetron Mesylate Injection (Anzemet Injection).
51 1 . The invention of claim 353, wherein said drug comprises Doribax (Doripenem for Injection).
512. The invention of claim 353, wherein said drug comprises Doripenem for Injection (Doribax).
513. The invention of claim 353, wherein said drug comprises Doxercalciferol Injection (Hectorol Injection).
514. The invention of claim 353, wherein said drug comprises Doxil (Doxorubicin Hcl Liposome Injection).
515. The invention of claim 353, wherein said drug comprises Doxorubicin Hcl Liposome Injection (Doxil).
516. The invention of claim 353, wherein said drug comprises Duraclon (Clonidine Injection).
517. The invention of claim 353, wherein said drug comprises Duramorph (Morphine Injection).
518. The invention of claim 353, wherein said drug comprises Dysport (Abobotulinumtoxin A Injection).
519. The invention of claim 353, wherein said drug comprises Ecallantide Injection (Kalbitor).
520. The invention of claim 353, wherein said drug comprises Edetate Calcium Disodium Injection (Calcium Disodium Versenate).
521 . The invention of claim 353, wherein said drug comprises Edex (Alprostadil for Injection).
522. The invention of claim 353, wherein said drug comprises Engerix.
523. The invention of claim 353, wherein said drug comprises Edrophonium Injection (Enlon).
524. The invention of claim 353, wherein said drug comprises Eloxatin (Oxaliplatin Injection).
525. The invention of claim 353, wherein said drug comprises Emend Injection (Fosaprepitant Dimeglumine Injection).
526. The invention of claim 353, wherein said drug comprises Enalaprilat Injection (Enalaprilat Injection).
527. The invention of claim 353, wherein said drug comprises Enlon (Edrophonium Injection).
528. The invention of claim 353, wherein said drug comprises Enoxaparin Sodium Injection (Lovenox).
529. The invention of claim 353, wherein said drug comprises Eovist (Gadoxetate Disodium Injection).
530. The invention of claim 353, wherein said drug comprises Enbrel.
531 . The invention of claim 353, wherein said drug comprises Enoxaparin.
532. The invention of claim 353, wherein said drug comprises Epinepherine.
533. The invention of claim 353, wherein said drug comprises Epipen.
534. The invention of claim 353, wherein said drug comprises Epipen Jr.
535. The invention of claim 353, wherein said drug comprises Erbitux.
536. The invention of claim 353, wherein said drug comprises Ertapenem Injection (Invanz).
537. The invention of claim 353, wherein said drug comprises Erythropoieten.
538. The invention of claim 353, wherein said drug comprises Essential Amino Acid Injection (Nephramine).
539. The invention of claim 353, wherein said drug comprises Estradiol Cypionate.
540. The invention of claim 353, wherein said drug comprises Estradiol Valerate.
541 . The invention of claim 353, wherein said drug comprises Etanercept.
542. The invention of claim 353, wherein said drug comprises Exenatide Injection (Byetta).
543. The invention of claim 353, wherein said drug comprises Famotidine Injection.
544. The invention of claim 353, wherein said drug comprises FDG (Fludeoxyglucose F 18 Injection).
545. The invention of claim 353, wherein said drug comprises Feraheme (Ferumoxytol Injection).
546. The invention of claim 353, wherein said drug comprises Feridex I.V. (Ferumoxides Injectable Solution).
547. The invention of claim 353, wherein said drug comprises Fertinex.
548. The invention of claim 353, wherein said drug comprises Ferumoxides Injectable Solution (Feridex I.V.).
549. The invention of claim 353, wherein said drug comprises Ferumoxytol Injection (Feraheme).
550. The invention of claim 353, wherein said drug comprises Flagyl Injection (Metronidazole Injection).
551 . The invention of claim 353, wherein said drug comprises Fluarix.
552. The invention of claim 353, wherein said drug comprises Fludeoxyglucose F 18 Injection (FDG).
553. The invention of claim 353, wherein said drug comprises Fluorescein Injection (Ak-Fluor).
554. The invention of claim 353, wherein said drug comprises Follistim AQ Cartridge (Follitropin Beta Injection).
555. The invention of claim 353, wherein said drug comprises Follitropin Alfa Injection (Gonal-f RFF).
556. The invention of claim 353, wherein said drug comprises Follitropin Beta Injection (Follistim AQ Cartridge).
557. The invention of claim 353, wherein said drug comprises Folotyn (Pralatrexate Solution for Intravenous Injection).
558. The invention of claim 353, wherein said drug comprises Fondaparinux.
559. The invention of claim 353, wherein said drug comprises Forteo (Teriparatide (rDNA origin) Injection).
560. The invention of claim 353, wherein said drug comprises Fostamatinib.
561 . The invention of claim 353, wherein said drug comprises Fosaprepitant Dimeglumine Injection (Emend Injection).
562. The invention of claim 353, wherein said drug comprises Foscarnet Sodium Injection (Foscavir).
563. The invention of claim 353, wherein said drug comprises Foscavir (Foscarnet Sodium Injection).
564. The invention of claim 353, wherein said drug comprises Fosphenytoin Sodium Injection (Cerebyx).
565. The invention of claim 353, wherein said drug comprises Fospropofol Disodium Injection (Lusedra).
566. The invention of claim 353, wherein said drug comprises Fragmin.
567. The invention of claim 353, wherein said drug comprises Gadobenate Dimeglumine Injection (Multihance).
568. The invention of claim 353, wherein said drug comprises Gadofosveset Trisodium Injection (Ablavar).
569. The invention of claim 353, wherein said drug comprises Gadoteridol Injection Solution (ProHance).
570. The invention of claim 353, wherein said drug comprises Gadoversetamide Injection (OptiMARK).
571 . The invention of claim 353, wherein said drug comprises Gadoxetate Disodium Injection (Eovist).
572. The invention of claim 353, wherein said drug comprises Ganirelix (Ganirelix Acetate Injection).
573. The invention of claim 353, wherein said drug comprises Gardasil.
574. The invention of claim 353, wherein said drug comprises Gemtuzumab Ozogamicin for Injection (Mylotarg).
575. The invention of claim 353, wherein said drug comprises Genotropin.
576. The invention of claim 353, wherein said drug comprises Gentamicin Injection.
577. The invention of claim 353, wherein said drug comprises Golimumab Injection (Simponi Injection).
578. The invention of claim 353, wherein said drug comprises Gonal-f RFF (Follitropin Alfa Injection).
579. The invention of claim 353, wherein said drug comprises Granisetron Hydrochloride (Kytril Injection).
580. The invention of claim 353, wherein said drug comprises Gentamicin Sulfate.
581 . The invention of claim 353, wherein said drug comprises Glatiramer Acetate.
582. The invention of claim 353, wherein said drug comprises Glucagen.
583. The invention of claim 353, wherein said drug comprises Glucagon.
584. The invention of claim 353, wherein said drug comprises Haldol (Haloperidol Injection).
585. The invention of claim 353, wherein said drug comprises Havrix.
586. The invention of claim 353, wherein said drug comprises Hectorol InjectiZn (Doxercalciferol Injection).
587. The invention of claim 353, wherein said drug comprises Heparin.
588. The invention of claim 353, wherein said drug comprises Herceptin.
589. The invention of claim 353, wherein said drug comprises hG-CSF.
590. The invention of claim 353, wherein said drug comprises Humalog.
591 . The invention of claim 353, wherein said drug comprises Human Growth Hormone.
592. The invention of claim 353, wherein said drug comprises Humatrope.
593. The invention of claim 353, wherein said drug comprises HuMax.
594. The invention of claim 353, wherein said drug comprises Humegon.
595. The invention of claim 353, wherein said drug comprises Humira.
596. The invention of claim 353, wherein said drug comprises Humulin.
597. The invention of claim 353, wherein said drug comprises Ibandr8nate Sodium Injection (Boniva Injection).
598. The invention of claim 353, wherein said drug comprises Ibuprofen Lysine Injection (NeoProfen).
599. The invention of claim 353, wherein said drug comprises Ibutilide Fumarate Injection (Corvert).
600. The invention of claim 353, wherein said drug comprises Idamycin PFS (Idarubicin Hydrochloride Injection).
601 . The invention of claim 353, wherein said drug comprises Idarubicin Hydrochloride Injection (Idamycin PFS).
602. The invention of claim 353, wherein said drug comprises Maris (Canakinumab Injection).
603. The invention of claim 353, wherein said drug comprises Imipenem and Cilastatin for Injection (Primaxin I.V.).
604. The invention of claim 353, wherein said drug comprises Imitrex.
605. The invention of claim 353, wherein said drug comprises Incobotulinumtoxin A for Injection (Xeomin).
606. The invention of claim 353, wherein said drug comprises Increlex (Mecasermin [rDNA origin] Injection).
607. The invention of claim 353, wherein said drug comprises Indocin IV (Indomethacin Inj).
608. The invention of claim 353, wherein said drug comprises Indomethacin Inj (Indocin IV).
609. The invention of claim 353, wherein said drug comprises Infanrix.
610. The invention of claim 353, wherein said drug comprises Innohep.
61 1 . The invention of claim 353, wherein said drug comprises Insulin/
612. The invention of claim 353, wherein said drug comprises Insulin Aspart [rDNA origin] Inj (NovoLog).
613. The invention of claim 353, wherein said drug comprises Insulin Glargine [rDNA origin] Injection (Lantus).
614. The invention of claim 353, wherein said drug comprises Insulin Glulisine [rDNA origin] Inj (Apidra).
615. The invention of claim 353, wherein said drug comprises Interferon alfa- 2b, Recombinant for Injection (Intron A).
616. The invention of claim 353, wherein said drug comprises Intron A (Interferon alfa-2b, Recombinant for Injection).
617. The invention of claim 353, wherein said drug comprises Invanz (Ertapenem Injection).
618. The invention of claim 353, wherein said drug comprises Invega Sustenna (Paliperidone Palmitate Extended- Release Injectable Suspension).
619. The invention of claim 353, wherein said drug comprises lobenguane I 123 Injection for Intravenous Use (AdreView).
620. The invention of claim 353, wherein said drug comprises lopromide Injection (Ultravist).
621 . The invention of claim 353, wherein said drug comprises loversol Injection (Optiray Injection).
622. The invention of claim 353, wherein said drug comprises Iplex (Mecasermin Rinfabate [rDNA origin] Injection).
623. The invention of claim 353, wherein said drug comprises Iprivask.
624. The invention of claim 353, wherein said drug comprises Irinotecan Hydrochloride (Camptosar Injection).
625. The invention of claim 353, wherein said drug comprises Iron Sucrose Injection (Venofer).
626. The invention of claim 353, wherein said drug comprises Istodax (Romidepsin for Injection).
627. The invention of claim 353, wherein said drug comprises Itraconazole Injection (Sporanox Injection).
628. The invention of claim 353, wherein said drug comprises Jevtana (Cabazitaxel Injection).
629. The invention of claim 353, wherein said drug comprises Kalbitor (Ecallantide Injection).
630. The invention of claim 353, wherein said drug comprises KCL in D5NS (Potassium Chloride in 5% Dextrose and Sodium Chloride Injection).
631 . The invention of claim 353, wherein said drug comprises KCL in D5W.
632. The invention of claim 353, wherein said drug comprises KCL in NS.
633. The invention of claim 353, wherein said drug comprises Kenalog 10 Injection (Triamcinolone Acetonide Injectable Suspension).
634. The invention of claim 353, wherein said drug comprises Keppra Injection (Levetiracetam).
635. The invention of claim 353, wherein said drug comprises Kineret.
636. The invention of claim 353, wherein said drug comprises Kinlytic (Urokinase Injection).
637. The invention of claim 353, wherein said drug comprises Kinrix.
638. The invention of claim 353, wherein said drug comprises Kytril Injection (Granisetron Hydrochloride).
639. The invention of claim 353, wherein said drug comprises lacosamide Tablet and Injection (Vimpat).
640. The invention of claim 353, wherein said drug comprises Lactated Ringer's.
641 . The invention of claim 353, wherein said drug comprises Lanoxin Injection (Digoxin Injection).
642. The invention of claim 353, wherein said drug comprises Lansoprazole for Injection (Prevacid I.V.).
643. The invention of claim 353, wherein said drug comprises Lantus.
644. The invention of claim 353, wherein said drug comprises Leucovorin Calcium (Leucovorin Calcium Injection).
645. The invention of claim 353, wherein said drug comprises Lente (L).
646. The invention of claim 353, wherein said drug comprises Levemir.
647. The invention of claim 353, wherein said drug comprises Leuproide Acetate.
648. The invention of claim 353, wherein said drug comprises Levothyroxine.
649. The invention of claim 353, wherein said drug comprises Levetiracetam (Keppra Injection).
650. The invention of claim 353, wherein said drug comprises Lovenox.
651 . The invention of claim 353, wherein said drug comprises Levocarnitine Injection (Carnitor Injection).
652. The invention of claim 353, wherein said drug comprises Lexiscan (Regadenoson Injection).
653. The invention of claim 353, wherein said drug comprises Lioresal Intrathecal (Baclofen Injection).
654. The invention of claim 353, wherein said drug comprises Liraglutide [rDNA] Injection (Victoza).
655. The invention of claim 353, wherein said drug comprises Lovenox (Enoxaparin Sodium Injection).
656. The invention of claim 353, wherein said drug comprises Lucentis (Ranibizumab Injection).
657. The invention of claim 353, wherein said drug comprises Lupron (Leuprolide Acetate Injection).
658. The invention of claim 353, wherein said drug comprises Lusedra (Fospropofol Disodium Injection).
659. The invention of claim 353, wherein said drug comprises Magnesium Sulfate (Magnesium Sulfate Injection).
660. The invention of claim 353, wherein said drug comprises Mannitol Injection (Mannitol IV).
661 . The invention of claim 353, wherein said drug comprises Marcaine (Bupivacaine Hydrochloride and Epinephrine Injection).
662. The invention of claim 353, wherein said drug comprises Maxipime (Cefepime Hydrochloride for Injection).
663. The invention of claim 353, wherein said drug comprises MDP Multidose Kit of Technetium Injection (Technetium Tc99m Medronate Injection).
664. The invention of claim 353, wherein said drug comprises Mecasermin [rDNA origin] Injection (Increlex).
665. The invention of claim 353, wherein said drug comprises Mecasermin Rinfabate [rDNA origin] Injection (Iplex).
666. The invention of claim 353, wherein said drug comprises Melphalan Hcl Injection (Alkeran Injection).
667. The invention of claim 353, wherein said drug comprises Methotrexate.
668. The invention of claim 353, wherein said drug comprises Menactra.
669. The invention of claim 353, wherein said drug comprises Menopur (Menotropins Injection).
670. The invention of claim 353, wherein said drug comprises Menotropins for Injection (Repronex).
671 . The invention of claim 353, wherein said drug comprises Methohexital Sodium for Injection (Brevital Sodium).
672. The invention of claim 353, wherein said drug comprises Methyldopate Hydrochloride Injection, Solution (Methyldopate Hcl).
673. The invention of claim 353, wherein said drug comprises Methylene Blue (Methylene Blue Injection).
674. The invention of claim 353, wherein said drug comprises Methylprednisolone Acetate Injectable Suspension (Depo Medrol).
675. The invention of claim 353, wherein said drug comprises Metoclopramide Injection (Reglan Injection).
676. The invention of claim 353, wherein said drug comprises Metrodin (Urofollitropin for Injection).
677. The invention of claim 353, wherein said drug comprises Metronidazole Injection (Flagyl Injection).
678. The invention of claim 353, wherein said drug comprises Miacalcin.
679. The invention of claim 353, wherein said drug comprises Midazolam (Midazolam Injection).
680. The invention of claim 353, wherein said drug comprises Minocin Injection (Minocycline Inj).
681 . The invention of claim 353, wherein said drug comprises Minocycline Inj (Minocin Injection).
682. The invention of claim 353, wherein said drug comprises Mitoxantrone for Injection Concentrate (Novantrone).
683. The invention of claim 353, wherein said drug comprises Morphine Injection (Duramorph).
684. The invention of claim 353, wherein said drug comprises Morphine Sulfate XR Liposome Injection (DepoDur).
685. The invention of claim 353, wherein said drug comprises Morrhuate Sodium (Morrhuate Sodium Injection).
686. The invention of claim 353, wherein said drug comprises Mozobil (Plerixafor Injection).
687. The invention of claim 353, wherein said drug comprises Multihance (Gadobenate Dimeglumine Injection).
688. The invention of claim 353, wherein said drug comprises Multiple Electrolytes and Dextrose Injection.
689. The invention of claim 353, wherein said drug comprises Multiple Electrolytes Injection .
690. The invention of claim 353, wherein said drug comprises Mylotarg (Gemtuzumab Ozogamicin for Injection).
691 . The invention of claim 353, wherein said drug comprises Nafcillin Injection (Nafcillin Sodium).
692. The invention of claim 353, wherein said drug comprises Nafcillin Sodium (Nafcillin Injection).
693. The invention of claim 353, wherein said drug comprises Naltrexone XR Inj (Vivitrol).
694. The invention of claim 353, wherein said drug comprises NeoProfen (Ibuprofen Lysine Injection).
695. The invention of claim 353, wherein said drug comprises Nandrol Decanoate.
696. The invention of claim 353, wherein said drug comprises Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection).
697. The invention of claim 353, wherein said drug comprises NeoTect (Technetium Tc 99m Depreotide Injection).
398. The invention of claim 353, wherein said drug comprises Nephramine (Essential Amino Acid Injection).
699. The invention of claim 353, wherein said drug comprises Neulasta.
700. The invention of claim 353, wherein said drug comprises Neupogen.
701 . The invention of claim 353, wherein said drug comprises Novolin.
702. The invention of claim 353, wherein said drug comprises Novolog.
703. The invention of claim 353, wherein said drug comprises NeoRecormon.
704. The invention of claim 353, wherein said drug comprises Neutrexin (Trimetrexate Glucuronate Inj).
705. The invention of claim 353, wherein said drug comprises NPH (N).
706. The invention of claim 353, wherein said drug comprises Nexterone (Amiodarone HCI Injection).
707. The invention of claim 353, wherein said drug comprises Norditropin (Somatropin Injection).
708. The invention of claim 353, wherein said drug comprises Normal Saline (Sodium Chloride Injection).
709. The invention of claim 353, wherein said drug comprises Novantrone (Mitoxantrone for Injection Concentrate).
710. The invention of claim 353, wherein said drug comprises Novolin 70/30 Innolet (70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin Injection).
71 1 . The invention of claim 353, wherein said drug comprises NovoLog (Insulin Aspart [rDNA origin] Inj).
712. The invention of claim 353, wherein said drug comprises Nutropin (Somatropin (rDNA origin) for Inj).
713. The invention of claim 353, wherein said drug comprises Nutropin Depot (Somatropin (rDNA origin) for Inj).
714. The invention of claim 353, wherein said drug comprises Octreotide Acetate Injection (Sandostatin LAR).
715. The invention of claim 353, wherein said drug comprises Ocrelizumab.
716. The invention of claim 353, wherein said drug comprises Ofatumumab Injection (Arzerra).
717. The invention of claim 353, wherein said drug comprises Olanzapine Extended Release Injectable Suspension (Zyprexa Relprevv).
718. The invention of claim 353, wherein said drug comprises Omnitrope (Somatropin [ rDNA origin] Injection).
719. The invention of claim 353, wherein said drug comprises Ondansetron Hydrochloride Injection (Zofran Injection).
720. The invention of claim 353, wherein said drug comprises OptiMARK (Gadoversetamide Injection).
721 . The invention of claim 353, wherein said drug comprises Optiray Injection (loversol Injection).
722. The invention of claim 353, wherein said drug comprises Orencia.
723. The invention of claim 353, wherein said drug comprises Osmitrol Injection in Aviva (Mannitol Injection in Aviva Plastic Vessel).
724. The invention of claim 353, wherein said drug comprises Osmitrol Injection in Viaflex (Mannitol Injection in Viaflex Plastic Vessel).
725. The invention of claim 353, wherein said drug comprises Ovidrel (Choriogonadotropin Alfa Injection).
726. The invention of claim 353, wherein said drug comprises Oxacillin (Oxacillin for Injection).
727. The invention of claim 353, wherein said drug comprises Oxaliplatin Injection (Eloxatin).
728. The invention of claim 353, wherein said drug comprises Oxytocin Injection (Pitocin).
729. The invention of claim 353, wherein said drug comprises Paliperidone Palmitate Extended-Release Injectable Suspension (Invega Sustenna).
730. The invention of claim 353, wherein said drug comprises Pamidronate Disodium Injection (Pamidronate Disodium Injection).
731 . The invention of claim 353, wherein said drug comprises Panitumumab Injection for Intravenous Use (Vectibix).
732. The invention of claim 353, wherein said drug comprises Papaverine Hydrochloride Injection (Papaverine Injection).
733. The invention of claim 353, wherein said drug comprises Papaverine Injection (Papaverine Hydrochloride Injection).
734. The invention of claim 353, wherein said drug comprises Parathyroid Hormone.
735. The invention of claim 353, wherein said drug comprises Paricalcitol Injection Fliptop Vial (Zemplar Injection).
736. The invention of claim 353, wherein said drug comprises Pediarix.
737. The invention of claim 353, wherein said drug comprises PEGIntron.
738. The invention of claim 353, wherein said drug comprises Peginterferon.
739. The invention of claim 353, wherein said drug comprises Pegf.
740. The invention of claim 353, wherein said drug comprises Penicillin G Benzathine and Penicillin G Procaine.
741 . The invention of claim 353, wherein said drug comprises Pentetate Calcium Trisodium Inj (Ca-DTPA).
742. The invention of claim 353, wherein said drug comprises Pentetate Zinc Trisodium Injection (Zn-DTPA).
743. The invention of claim 353, wherein said drug comprises Pepcid Injection (Famotidine Injection).
744. The invention of claim 353, wherein said drug comprises Pergonal.
745. The invention of claim 353, wherein said drug comprises Phentolamine Mesylate (Phentolamine Mesylate for Injection).
746. The invention of claim 353, wherein said drug comprises Physostigmine Salicylate (Physostigmine Salicylate (injection)).
747. The invention of claim 353, wherein said drug comprises Physostigmine Salicylate (injection) (Physostigmine Salicylate).
748. The invention of claim 353, wherein said drug comprises Piperacillin and Tazobactam Injection (Zosyn).
749. The invention of claim 353, wherein said drug comprises Pitocin (Oxytocin Injection).
750. The invention of claim 353, wherein said drug comprises Plasma-Lyte 148 (Multiple Electrolytes Inj).
751 . The invention of claim 353, wherein said drug comprises Plasma-Lyte 56 and Dextrose (Multiple Electrolytes and Dextrose Injection in Viaflex Plastic Vessel).
752. The invention of claim 353, wherein said drug comprises PlasmaLyte.
753. The invention of claim 353, wherein said drug comprises Plerixafor Injection (Mozobil).
754. The invention of claim 353, wherein said drug comprises Polidocanol Injection (Asclera).
755. The invention of claim 353, wherein said drug comprises Potassium Chloride.
756. The invention of claim 353, wherein said drug comprises Pralatrexate Solution for Intravenous Injection (Folotyn).
757. The invention of claim 353, wherein said drug comprises Pramlintide Acetate Injection (Symlin).
758. The invention of claim 353, wherein said drug comprises Premarin Injection (Conjugated Estrogens for Injection).
759. The invention of claim 353, wherein said drug comprises Prep kit for Technetium Tc99 Sestamibi for Injection (Cardiolite).
760. The invention of claim 353, wherein said drug comprises Prevacid I.V. (Lansoprazole for Injection).
761 . The invention of claim 353, wherein said drug comprises Primaxin I.V. (Imipenem and Cilastatin for Injection).
762. The invention of claim 353, wherein said drug comprises Progesterone.
763. The invention of claim 353, wherein said drug comprises ProHance (Gadoteridol Injection Solution).
764. The invention of claim 353, wherein said drug comprises Prolia (Denosumab Injection).
765. The invention of claim 353, wherein said drug comprises Promethazine HCI Injection (Promethazine Hydrochloride Injection).
766. The invention of claim 353, wherein said drug comprises Propranolol Hydrochloride Injection (Propranolol Hydrochloride Injection).
767. The invention of claim 353, wherein said drug comprises Quinidine Gluconate Injection (Quinidine Injection).
768. The invention of claim 353, wherein said drug comprises Quinidine Injection (Quinidine Gluconate Injection).
769. The invention of claim 353, wherein said drug comprises R-Gene 10 (396Arginine Hydrochloride Injection).
770. The invention of claim 353, wherein said drug comprises Ranibizumab Injection (Lucentis).
771 . The invention of claim 353, wherein said drug comprises Ranitidine Hydrochloride Injection (Zantac Injection).
772. The invention of claim 353, wherein said drug comprises Reclast (Zoledronic Acid Injection).
773. The invention of claim 353, wherein said drug comprises Recombivarix
HB.
774. The invention of claim 353, wherein said drug comprises Regadenoson Injection (Lexiscan).
775. The invention of claim 353, wherein said drug comprises Reglan Injection (Metoclopramide Injection).
776. The invention of claim 353, wherein said drug comprises Remicade.
777. The invention of claim 353, wherein said drug comprises Repronex (Menotropins for Injection).
778. The invention of claim 353, wherein said drug comprises Retrovir IV (Zidovudine Injection).
779. The invention of claim 353, wherein said drug comprises Ringer's and 5% Dextrose Injection (Ringers in Dextrose).
780. The invention of claim 353, wherein said drug comprises Ringer's Injection (Ringers Injection).
781 . The invention of claim 353, wherein said drug comprises Rituxan.
782. The invention of claim 353, wherein said drug comprises Rituximab.
783. The invention of claim 353, wherein said drug comprises Rocuronium Bromide Injection (Zemuron).
784. The invention of claim 353, wherein said drug comprises Romidepsin for Injection (Istodax).
785. The invention of claim 353, wherein said drug comprises Saizen (Somatropin Injection).
786. The invention of claim 353, wherein said drug comprises Sandostatin LAR (Octreotide Acetate Injection).
787. The invention of claim 353, wherein said drug comprises Sensorcaine (Bupivacaine HCI Injections).
788. The invention of claim 353, wherein said drug comprises Septocaine (Articane HCI and Epinephrine Injection).
789. The invention of claim 353, wherein said drug comprises Serostim LQ (Somatropin (rDNA origin) Injection).
790. The invention of claim 353, wherein said drug comprises Simponi Injection (Golimumab Injection).
791 . The invention of claim 353, wherein said drug comprises Sodium Acetate (Sodium Acetate Injection).
792. The invention of claim 353, wherein said drug comprises Sodium Bicarbonate (Sodium Bicarbonate 5% Injection).
793. The invention of claim 353, wherein said drug comprises Sodium Lactate (Sodium Lactate Injection in AVIVA).
794. The invention of claim 353, wherein said drug comprises Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul).
795. The invention of claim 353, wherein said drug comprises Somatropin (rDNA origin) for Inj (Nutropin).
796. The invention of claim 353, wherein said drug comprises Sporanox Injection (Itraconazole Injection).
797. The invention of claim 353, wherein said drug comprises Stelara Injection (Ustekinumab).
798. The invention of claim 353, wherein said drug comprises Sufenta (Sufentanil Citrate Injection).
799. The invention of claim 353, wherein said drug comprises Sufentanil Citrate Injection (Sufenta ).
800. The invention of claim 353, wherein said drug comprises Sumavel.
801 . The invention of claim 353, wherein said drug comprises Sumatriptan Injection (Alsuma).
802. The invention of claim 353, wherein said drug comprises Symlin.
803. The invention of claim 353, wherein said drug comprises Symlin Pen.
804. The invention of claim 353, wherein said drug comprises Synvisc-One (Hylan G-F 20 Single Intra-articular Injection).
805. The invention of claim 353, wherein said drug comprises Taxotere (Docetaxel for Injection).
806. The invention of claim 353, wherein said drug comprises vvTechnetium Tc
99m.
807. The invention of claim 353, wherein said drug comprises Telavancin for Injection (Vibativ).
808. The invention of claim 353, wherein said drug comprises Temsirolimus Injection (Torisel).
809. The invention of claim 353, wherein said drug comprises Tenormin I.V. Injection (Atenolol Inj).
810. The invention of claim 353, wherein said drug comprises Teriparatide (rDNA origin) Injection (Forteo).
81 1 . The invention of claim 353, wherein said drug comprises Testosterone Cypionate.
812. The invention of claim 353, wherein said drug comprises Testosterone Enanthate.
813. The invention of claim 353, wherein said drug comprises Testosterone Propionate.
814. The invention of claim 353, wherein said drug comprises Tev-Tropin (Somatropin, rDNA Origin, for Injection).
815. The invention of claim 353, wherein said drug comprises tgAAC94.
816. The invention of claim 353, wherein said drug comprises Thallous Chloride.
817. The invention of claim 353, wherein said drug comprises Theophylline.
818. The invention of claim 353, wherein said drug comprises Thiotepa (Thiotepa Injection).
819. The invention of claim 353, wherein said drug comprises Thyrogen (Thyrotropin Alfa for Injection).
820. The invention of claim 353, wherein said drug comprises Ticarcillin Disodium and Clavulanate Potassium Galaxy (Timentin Injection).
821 . The invention of claim 353, wherein said drug comprises Tigan Injection (Trimethobenzamide Hydrochloride Injectable).
822. The invention of claim 353, wherein said drug comprises Timentin Injection (Ticarcillin Disodium and Clavulanate Potassium Galaxy).
823. The invention of claim 353, wherein said drug comprises Tobramycin Injection (Tobramycin Injection).
824. The invention of claim 353, wherein said drug comprises Tocilizumab Injection (Actemra).
825. The invention of claim 353, wherein said drug comprises Torisel (Temsirolimus Injection).
826. The invention of claim 353, wherein said drug comprises Totect (Dexrazoxane for Injection, Intravenous Infusion Only ).
827. The invention of claim 353, wherein said drug comprises Travasol (Amino Acids (Injection)).
828. The invention of claim 353, wherein said drug comprises Treanda (Bendamustine Hydrochloride Injection).
829. The invention of claim 353, wherein said drug comprises Trelstar (Triptorelin Pamoate for Injectable Suspension).
830. The invention of claim 353, wherein said drug comprises Triamcinolone Acetonide.
831 . The invention of claim 353, wherein said drug comprises Triamcinolone Di acetate.
832. The invention of claim 353, wherein said drug comprises Triamcinolone Hexacetonide Injectable Suspension (Aristospan Injection 20 mg).
833. The invention of claim 353, wherein said drug comprises Triesence (Triamcinolone Acetonide Injectable Suspension).
834. The invention of claim 353, wherein said drug comprises Trimethobenzamide Hydrochloride Injectable (Tigan Injection).
835. The invention of claim 353, wherein said drug comprises Trimetrexate Glucuronate Inj (Neutrexin).
836. The invention of claim 353, wherein said drug comprises Triptorelin Pamoate for Injectable Suspension (Trelstar).
837. The invention of claim 353, wherein said drug comprises Twinject.
838. The invention of claim 353, wherein said drug comprises Trivaris (Triamcinolone Acetonide Injectable Suspension).
839. The invention of claim 353, wherein said drug comprises Trisenox (Arsenic Trioxide Injection).
840. The invention of claim 353, wherein said drug comprises Twinrix.
841 . The invention of claim 353, wherein said drug comprises Typhoid Vi.
842. The invention of claim 353, wherein said drug comprises Ultravist (lopromide Injection).
843. The invention of claim 353, wherein said drug comprises Urofollitropin for Injection (Metrodin).
844. The invention of claim 353, wherein said drug comprises Urokinase Injection (Kinlytic).
845. The invention of claim 353, wherein said drug comprises Ustekinumab (Stelara Injection).
846. The invention of claim 353, wherein said drug comprises Ultralente (U).
847. The invention of claim 353, wherein said drug comprises Valproate Sodium Injection (Depacon).
848. The invention of claim 353, wherein said drug comprises Valtropin (Somatropin Injection).
849. The invention of claim 353, wherein said drug comprises Vancomycin Hydrochloride (Vancomycin Hydrochloride Injection).
850. The invention of claim 353, wherein said drug comprises Vancomycin Hydrochloride Injection (Vancomycin Hydrochloride).
851 . The invention of claim 353, wherein said drug comprises Vaprisol (Conivaptan Hcl Injection).
852. The invention of claim 353, wherein said drug comprises VAQTA.
853. The invention of claim 353, wherein said drug comprises Vasovist (Gadofosveset Trisodium Injection for Intravenous Use).
854. The invention of claim 353, wherein said drug comprises Vectibix (Panitumumab Injection for Intravenous Use).
855. The invention of claim 353, wherein said drug comprises Venofer (Iron Sucrose Injection).
856. The invention of claim 353, wherein said drug comprises Verteporfin Inj (Visudyne).
857. The invention of claim 353, wherein said drug comprises Vibativ (Telavancin for Injection).
858. The invention of claim 353, wherein said drug comprises Victoza (Liraglutide [rDNA] Injection).
859. The invention of claim 353, wherein said drug comprises Vimpat (lacosamide Tablet and Injection).
860. The invention of claim 353, wherein said drug comprises Vinblastine Sulfate (Vinblastine Sulfate Injection).
861 . The invention of claim 353, wherein said drug comprises Vincasar PFS (Vincristine Sulfate Injection).
862. The invention of claim 353, wherein said drug comprises Victoza.
863. The invention of claim 353, wherein said drug comprises Vincristine Sulfate (Vincristine Sulfate Injection).
864. The invention of claim 353, wherein said drug comprises Visudyne (Verteporfin Inj).
865. The invention of claim 353, wherein said drug comprises Vitamin B-12.
866. The invention of claim 353, wherein said drug comprises Vivitrol (Naltrexone XR Inj).
867. The invention of claim 353, wherein said drug comprises Voluven (Hydroxyethyl Starch in Sodium Chloride Injection).
868. The invention of claim 353, wherein said drug comprises Xeomin (Incobotulinumtoxin A for Injection).
869. The invention of claim 353, wherein said drug comprises Zantac Injection (Ranitidine Hydrochloride Injection).
870. The invention of claim 353, wherein said drug comprises Zemplar Injection (Paricalcitol Injection Fliptop Vial).
871 . The invention of claim 353, wherein said drug comprises Zemuron (Rocuronium Bromide Injection).
872. The invention of claim 353, wherein said drug comprises Zevalin.
873. The invention of claim 353, wherein said drug comprises Zidovudine Injection (Retrovir IV).
874. The invention of claim 353, wherein said drug comprises Zithromax Injection (Azithromycin).
875. The invention of claim 353, wherein said drug comprises Zn-DTPA (Pentetate Zinc Trisodium Injection).
876. The invention of claim 353, wherein said drug comprises Zofran Injection (Ondansetron Hydrochloride Injection).
877. The invention of claim 353, wherein said drug comprises Zingo.
878. The invention of claim 353, wherein said drug comprises Zoledronic Acid for Inj (Zometa).
879. The invention of claim 353, wherein said drug comprises Zoledronic Acid Injection (Reclast).
880. The invention of claim 353, wherein said drug comprises Zometa (Zoledronic Acid for Inj).
881 . The invention of claim 353, wherein said drug comprises Zosyn (Piperacillin and Tazobactam Injection).
882. The invention of claim 353, wherein said drug comprises Zyprexa Relprevv (Olanzapine Extended Release Injectable Suspension).
883. The invention of claim 353, wherein said drug comprises Ability.
884. The invention of claim 353, wherein said drug comprises AccuNeb (Albuterol Sulfate Inhalation Solution).
885. The invention of claim 353, wherein said drug comprises Actidose Aqua (Activated Charcoal Suspension).
886. The invention of claim 353, wherein said drug comprises Activated Charcoal Suspension (Actidose Aqua).
887. The invention of claim 353, wherein said drug comprises Advair.
888. The invention of claim 353, wherein said drug comprises Agenerase Oral Solution (Amprenavir Oral Solution).
889. The invention of claim 353, wherein said drug comprises Akten (Lidocaine Hydrochloride Ophthalmic Gel).
890. The invention of claim 353, wherein said drug comprises Alamast (Pemirolast Potassium Ophthalmic Solution).
891 . The invention of claim 353, wherein said drug comprises Albumin (Human) 5% Solution (Buminate 5%).
892. The invention of claim 353, wherein said drug comprises Albuterol Sulfate Inhalation Solution.
893. The invention of claim 353, wherein said drug comprises Alinia.
894. The invention of claim 353, wherein said drug comprises Alocril.
895. The invention of claim 353, wherein said drug comprises Alphagan.
896. The invention of claim 353, wherein said drug comprises Alrex.
897. The invention of claim 353, wherein said drug comprises Alvesco.
898. The invention of claim 353, wherein said drug comprises Amprenavir Oral Solution.
899. The invention of claim 353, wherein said drug comprises Analpram-HC.
900. The invention of claim 353, wherein said drug comprises Arformoterol Tartrate Inhalation Solution (Brovana).
901 . The invention of claim 353, wherein said drug comprises Aristospan Injection 20 mg (Triamcinolone Hexacetonide Injectable Suspension).
902. The invention of claim 353, wherein said drug comprises Asacol.
903. The invention of claim 353, wherein said drug comprises Asmanex Astepro.
904. The invention of claim 353, wherein said drug comprises Astepro (Azelastine Hydrochloride Nasal Spray).
905. The invention of claim 353, wherein said drug comprises Atrovent Nasal Spray (Ipratropium Bromide Nasal Spray).
906. The invention of claim 353, wherein said drug comprises Atrovent Nasal Spray .06.
907. The invention of claim 353, wherein said drug comprises Augmentin ES-
600.
908. The invention of claim 353, wherein said drug comprises Azasite (Azithromycin Ophthalmic Solution).
909. The invention of claim 353, wherein said drug comprises Azelaic Acid (Finacea Gel).
910. The invention of claim 353, wherein said drug comprises Azelastine Hydrochloride Nasal Spray (Astepro).
91 1 . The invention of claim 353, wherein said drug comprises Azelex (Azelaic Acid Cream).
912. The invention of claim 353, wherein said drug comprises Azopt (Brinzolamide Ophthalmic Suspension).
913. The invention of claim 353, wherein said drug comprises Bacteriostatic
Saline.
914. The invention of claim 353, wherein said drug comprises Balanced Salt.
915. The invention of claim 353, wherein said drug comprises Bepotastine.
916. The invention of claim 353, wherein said drug comprises Bactroban Nasal.
917. The invention of claim 353, wherein said drug comprises Bactroban.
918. The invention of claim 353, wherein said drug comprises Beclovent.
919. The invention of claim 353, wherein said drug comprises Benzac W.
920. The invention of claim 353, wherein said drug comprises Betimol.
921 . The invention of claim 353, wherein said drug comprises Betoptic S.
922. The invention of claim 353, wherein said drug comprises Bepreve.
923 The invention of claim 353, wherein said drug comprises Bimatoprost Ophthalmic Solution.
924. The invention of claim 353, wherein said drug comprises Bleph 10 (Sulfacetamide .Sodium Ophthalmic Solution 10%).
925. The invention of claim 353, wherein said drug comprises Brinzolamide Ophthalmic Suspension (Azopt).
926. The invention of claim 353, wherein said drug comprises Bromfenac Ophthalmic Solution (Xibrom).
927. The invention of claim 353, wherein said drug comprises Bromhist.
928. The invention of claim 353, wherein said drug comprises Brovana (Arformoterol Tartrate Inhalation Solution).
929. The invention of claim 353, wherein said drug comprises Budesonide Inhalation Suspension (Pulmicort Respules).
930. The invention of claim 353, wherein said drug comprises Cambia (Diclofenac Potassium for Oral Solution).
931 . The invention of claim 353, wherein said drug comprises Capex.
932. The invention of claim 353, wherein said drug comprises Carac.
933. The invention of claim 353, wherein said drug comprises Carboxine-PSE.
934. The invention of claim 353, wherein said drug comprises Carnitor.
935. The invention of claim 353, wherein said drug comprises Cayston (Aztreonam for Inhalation Solution).
936. The invention of claim 353, wherein said drug comprises Cellcept.
937. The invention of claim 353, wherein said drug comprises Centany .
938. The invention of claim 353, wherein said drug comprises Cerumenex.
939. The invention of claim 353, wherein said drug comprises Ciloxan Ophthalmic Solution (Ciprofloxacin HCL Ophthalmic Solution).
940. The invention of claim 353, wherein said drug comprises Ciprodex.
941 . The invention of claim 353, wherein said drug comprises Ciprofloxacin HCL Ophthalmic Solution (Ciloxan Ophthalmic Solution).
942. The invention of claim 353, wherein said drug comprises Clemastine Fumarate Syrup (Clemastine Fumarate Syrup).
943. The invention of claim 353, wherein said drug comprises CoLyte (PEG Electrolytes Solution).
944. The invention of claim 353, wherein said drug comprises Combiven.
945. The invention of claim 353, wherein said drug comprises Comtan.
946. The invention of claim 353, wherein said drug comprises Condylox.
947. The invention of claim 353, wherein said drug comprises Cordran.
948. The invention of claim 353, wherein said drug comprises Cortisporin Ophthalmic Suspension.
949. The invention of claim 353, wherein said drug comprises Cortisporin Otic Suspension.
950. The invention of claim 353, wherein said drug comprises Cromolyn Sodium Inhalation Solution (Intal Nebulizer Solution).
951 . The invention of claim 353, wherein said drug comprises Cromolyn Sodium Ophthalmic Solution (Opticrom).
952. The invention of claim 353, wherein said drug comprises Crystalline Amino Acid Solution with Electrolytes (Aminosyn Electrolytes).
953. The invention of claim 353, wherein said drug comprises Cutivate.
954. The invention of claim 353, wherein said drug comprises Cuvposa (Glycopyrrolate Oral Solution).
955. The invention of claim 353, wherein said drug comprises Cyanocobalamin (CaloMist Nasal Spray).
956. The invention of claim 353, wherein said drug comprises Cyclosporine Oral Solution (Gengraf Oral Solution).
957. The invention of claim 353, wherein said drug comprises Cyclogyl.
958. The invention of claim 353, wherein said drug comprises Cysview (Hexaminolevulinate Hydrochloride Intravesical Solution).
959. The invention of claim 353, wherein said drug comprises DermOtic Oil (Fluocinolone Acetonide Oil Ear Drops).
960. The invention of claim 353, wherein said drug comprises Desmopressin Acetate Nasal Spray.
961 . The invention of claim 353, wherein said drug comprises DDAVP.
962. The invention of claim 353, wherein said drug comprises Derma- Smoothe/FS.
963. The invention of claim 353, wherein said drug comprises Dexamethasone Intensol.
964. The invention of claim 353, wherein said drug comprises Dianeal Low Calcium.
965. The invention of claim 353, wherein said drug comprises Dianeal PD.
966. The invention of claim 353, wherein said drug comprises Diclofenac Potassium for Oral Solution (Cambia).
967. The invention of claim 353, wherein said drug comprises Didanosine Pediatric Powder for Oral Solution (Videx).
968. The invention of claim 353, wherein said drug comprises Differin.
969. The invention of claim 353, wherein said drug comprises Dilantin 125 (Phenytoin Oral Suspension).
970. The invention of claim 353, wherein said drug comprises Ditropan.
971 . The invention of claim 353, wherein said drug comprises Dorzolamide Hydrochloride Ophthalmic Solution (Trusopt).
972. The invention of claim 353, wherein said drug comprises Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution (Cosopt).
973. The invention of claim 353, wherein said drug comprises Dovonex Scalp (Calcipotriene Solution).
974. The invention of claim 353, wherein said drug comprises Doxycycline Calcium Oral Suspension (Vibramycin Oral).
975. The invention of claim 353, wherein said drug comprises Efudex.
976. The invention of claim 353, wherein said drug comprises Elaprase (Idursulfase Solution).
977. The invention of claim 353, wherein said drug comprises Elestat (Epinastine HCI Ophthalmic Solution).
978. The invention of claim 353, wherein said drug comprises Elocon.
979. The invention of claim 353, wherein said drug comprises Epinastine HCI Ophthalmic Solution (Elestat).
980. The invention of claim 353, wherein said drug comprises Epivir HBV.
981 . The invention of claim 353, wherein said drug comprises Epogen.
982. The invention of claim 353, wherein said drug comprises Erythromycin Topical Solution 1 .5% (Staticin).
983. The invention of claim 353, wherein said drug comprises Ethiodol (Ethiodized Oil).
984. The invention of claim 353, wherein said drug comprises Ethosuximide Oral Solution (Zarontin Oral Solution).
985. The invention of claim 353, wherein said drug comprises Eurax.
986. The invention of claim 353, wherein said drug comprises Extraneal (lcodextrin Peritoneal Dialysis Solution).
987. The invention of claim 353, wherein said drug comprises Felbatol.
988. The invention of claim 353, wherein said drug comprises Feridex I.V. (Ferumoxides Injectable Solution).
989. The invention of claim 353, wherein said drug comprises Flovent.
990. The invention of claim 353, wherein said drug comprises Floxin Otic (Ofloxacin Otic Solution).
991 . The invention of claim 353, wherein said drug comprises Flo-Pred (Prednisolone Acetate Oral Suspension).
992. The invention of claim 353, wherein said drug comprises Fluoroplex.
993. The invention of claim 353, wherein said drug comprises Flunisolide Nasal Solution (Flunisolide Nasal Spray .025%).
994. The invention of claim 353, wherein said drug comprises Fluorometholone Ophthalmic Suspension (FML).
995. The invention of claim 353, wherein said drug comprises Flurbiprofen Sodium Ophthalmic Solution (Ocufen).
996. The invention of claim 353, wherein said drug comprises FML.
997. The invention of claim 353, wherein said drug comprises Foradil.
998. The invention of claim 353, wherein said drug comprises Formoterol Fumarate Inhalation Solution (Perforomist).
999. The invention of claim 353, wherein said drug comprises Fosamax.
1000. The invention of claim 353, wherein said drug comprises Furadantin (Nitrofurantoin Oral Suspension).
1001 . The invention of claim 353, wherein said drug comprises Furoxone.
1002. The invention of claim 353, wherein said drug comprises Gammagard Liquid (Immune Globulin Intravenous (Human) 10%).
1003. The invention of claim 353, wherein said drug comprises Gantrisin (Acetyl Sulfisoxazole Pediatric Suspension).
1004. The invention of claim 353, wherein said drug comprises Gatifloxacin Ophthalmic Solution (Zymar).
1005. The invention of claim 353, wherein said drug comprises Gengraf Oral Solution (Cyclosporine Oral Solution).
1006. The invention of claim 353, wherein said drug comprises Glycopyrrolate Oral Solution (Cuvposa).
1007. The invention of claim 353, wherein said drug comprises Halcinonide Topical Solution (Halog Solution).
1008. The invention of claim 353, wherein said drug comprises Halog Solution (Halcinonide Topical Solution).
1009. The invention of claim 353, wherein said drug comprises HEP-LOCK U/P (Preservative- Free Heparin Lock Flush Solution).
1010. The invention of claim 353, wherein said drug comprises Heparin Lock Flush Solution (Hepflush 10).
101 1 . The invention of claim 353, wherein said drug comprises Hexaminolevulinate Hydrochloride Intravesical Solution (Cysview).
1012. The invention of claim 353, wherein said drug comprises Hydrocodone Bitartrate and Acetaminophen Oral Solution (Lortab Elixir).
1013. The invention of claim 353, wherein said drug comprises Hydroquinone 3% Topical Solution (Melquin-3 Topical Solution).
1014. The invention of claim 353, wherein said drug comprises Isopto.
1015. The invention of claim 353, wherein said drug comprises Ipratropium Bromide Nasal Spray (Atrovent Nasal Spray).
1016. The invention of claim 353, wherein said drug comprises Itraconazole Oral Solution (Sporanox Oral Solution).
1017. The invention of claim 353, wherein said drug comprises Ketorolac Tromethamine Ophthalmic Solution (Acular LS).
1018. The invention of claim 353, wherein said drug comprises Kaletra .
1019. The invention of claim 353, wherein said drug comprises Lanoxin .
1020. The invention of claim 353, wherein said drug comprises Lexiva.
1021 . The invention of claim 353, wherein said drug comprises Leuprolide Acetate for Depot Suspension (Lupron Depot 1 1 .25 mg).
1022. The invention of claim 353, wherein said drug comprises Levobetaxolol Hydrochloride Ophthalmic Suspension (Betaxon).
1023. The invention of claim 353, wherein said drug comprises Levocarnitine Tablets, Oral Solution, Sugar-Free (Carnitor).
1024. The invention of claim 353, wherein said drug comprises Levofloxacin Ophthalmic Solution 0.5% (Quixin).
1025. The invention of claim 353, wherein said drug comprises Lidocaine HCI Sterile Solution (Xylocaine MPF Sterile Solution).
1026. The invention of claim 353, wherein said drug comprises Lok Pak (Heparin Lock Flush Solution).
1027. The invention of claim 353, wherein said drug comprises Lorazepam Intensol.
1028. The invention of claim 353, wherein said drug comprises Lortab Elixir (Hydrocodone Bitartrate and Acetaminophen Oral Solution).
1029. The invention of claim 353, wherein said drug comprises Lotemax (Loteprednol Etabonate Ophthalmic Suspension).
1030. The invention of claim 353, wherein said drug comprises Loteprednol Etabonate Ophthalmic Suspension (Alrex).
1031 . The invention of claim 353, wherein said drug comprises Low Calcium Peritoneal Dialysis Solutions (Dianeal Low Calcium).
1032. The invention of claim 353, wherein said drug comprises Lumigan (Bimatoprost Ophthalmic Solution 0.03% for Glaucoma).
1033. The invention of claim 353, wherein said drug comprises Lupron Depot 1 1 .25 mg (Leuprolide Acetate for Depot Suspension).
1034. The invention of claim 353, wherein said drug comprises Megestrol Acetate Oral Suspension (Megestrol Acetate Oral Suspension).
1035. The invention of claim 353, wherein said drug comprises Mepron.
1036. The invention of claim 353, wherein said drug comprises Mesnex.
1037. The invention of claim 353, wherein said drug comprises Mestinon.
1038. The invention of claim 353, wherein said drug comprises Mesalamine Rectal Suspension Enema (Rowasa).
1039. The invention of claim 353, wherein said drug comprises Melquin-3 Topical Solution (Hydroquinone 3% Topical Solution).
1040. The invention of claim 353, wherein said drug comprises Methyldopate Hcl (Methyldopate Hydrochloride Injection, Solution).
1041 . The invention of claim 353, wherein said drug comprises Methylin Oral Solution (Methylphenidate HCI Oral Solution 5 mg/5 ml_ and 10 mg/5 ml_).
1042. The invention of claim 353, wherein said drug comprises Methylprednisolone Acetate Injectable Suspension (Depo Medrol).
1043. The invention of claim 353, wherein said drug comprises Methylphenidate HCI Oral Solution 5 mg/5 ml_ and 10 mg/5 ml_ (Methylin Oral Solution).
1044. The invention of claim 353, wherein said drug comprises Methylprednisolone sodium succinate (Solu Medrol).
1045. The invention of claim 353, wherein said drug comprises Metipranolol Ophthalmic Solution (Optipranolol).
1046. The invention of claim 353, wherein said drug comprises Migranal.
1047. The invention of claim 353, wherein said drug comprises Miochol-E (Acetylcholine Chloride Intraocular Solution).
1048. The invention of claim 353, wherein said drug comprises Micro-K for Liquid Suspension (Potassium Chloride Extended Release Formulation for Liquid Suspension).
1049. The invention of claim 353, wherein said drug comprises Minocin (Minocycline Hydrochloride Oral Suspension).
1050. The invention of claim 353, wherein said drug comprises Nasacort.
1051 . The invention of claim 353, wherein said drug comprises Neomycin and Polymyxin B Sulfates and Hydrocortisone.
1052. The invention of claim 353, wherein said drug comprises Nepafenac Ophthalmic Suspension (Nevanac).
1053. The invention of claim 353, wherein said drug comprises Nevanac (Nepafenac Ophthalmic Suspension).
1054. The invention of claim 353, wherein said drug comprises Nitrofurantoin Oral Suspension (Furadantin).
1055. The invention of claim 353, wherein said drug comprises Noxafil (Posaconazole Oral Suspension).
1056. The invention of claim 353, wherein said drug comprises Nystatin (oral) (Nystatin Oral Suspension).
1057. The invention of claim 353, wherein said drug comprises Nystatin Oral Suspension (Nystatin (oral)).
1058. The invention of claim 353, wherein said drug comprises Ocufen (Flurbiprofen Sodium Ophthalmic Solution).
1059. The invention of claim 353, wherein said drug comprises Ofloxacin Ophthalmic Solution (Ofloxacin Ophthalmic Solution).
1060. The invention of claim 353, wherein said drug comprises Ofloxacin Otic Solution (Floxin Otic).
1061 . The invention of claim 353, wherein said drug comprises Olopatadine Hydrochloride Ophthalmic Solution (Pataday).
1062. The invention of claim 353, wherein said drug comprises Opticrom (Cromolyn Sodium Ophthalmic Solution).
1063. The invention of claim 353, wherein said drug comprises Optipranolol (Metipranolol Ophthalmic Solution).
1064. The invention of claim 353, wherein said drug comprises Patanol .
1065. The invention of claim 353, wherein said drug comprises Pediapred.
1066. The invention of claim 353, wherein said drug comprises PerioGard.
1067. The invention of claim 353, wherein said drug comprises Phenytoin Oral Suspension (Dilantin 125).
1068. The invention of claim 353, wherein said drug comprises Phisohex.
1069. The invention of claim 353, wherein said drug comprises Posaconazole Oral Suspension (Noxafil).
1070. The invention of claim 353, wherein said drug comprises Potassium Chloride Extended Release Formulation for Liquid Suspension (Micro-K for Liquid Suspension).
1071 . The invention of claim 353, wherein said drug comprises Pataday (Olopatadine Hydrochloride Ophthalmic Solution).
1072. The invention of claim 353, wherein said drug comprises Patanase Nasal Spray (Olopatadine Hydrochloride Nasal Spray).
1073. The invention of claim 353, wherein said drug comprises PEG Electrolytes Solution (CoLyte).
1074. The invention of claim 353, wherein said drug comprises Pemirolast Potassium Ophthalmic Solution (Alamast).
1075. The invention of claim 353, wherein said drug comprises Penlac (Ciclopirox Topical Solution).
1076. The invention of claim 353, wherein said drug comprises PENNSAID (Diclofenac Sodium Topical Solution).
1077. The invention of claim 353, wherein said drug comprises Perforomist (Formoterol Fumarate Inhalation Solution).
1078. The invention of claim 353, wherein said drug comprises Peritoneal Dialysis Solution.
1079. The invention of claim 353, wherein said drug comprises Phenylephrine Hydrochloride Ophthalmic Solution (Neo-Synephrine).
1080. The invention of claim 353, wherein said drug comprises Phospholine Iodide (Echothiophate Iodide for Ophthalmic Solution).
1081 . The invention of claim 353, wherein said drug comprises Podofilox (Podofilox Topical Solution).
1082. The invention of claim 353, wherein said drug comprises Pred Forte (Prednisolone Acetate Ophthalmic Suspension).
1083. The invention of claim 353, wherein said drug comprises Pralatrexate Solution for Intravenous Injection (Folotyn).
1084. The invention of claim 353, wherein said drug comprises Pred Mild.
1085. The invention of claim 353, wherein said drug comprises Prednisone Intensol.
1086. The invention of claim 353, wherein said drug comprises Prednisolone Acetate Ophthalmic Suspension (Pred Forte).
1087. The invention of claim 353, wherein said drug comprises Prevacid.
1088. The invention of claim 353, wherein said drug comprises PrismaSol Solution (Sterile Hemofiltration Hemodiafiltration Solution).
1089. The invention of claim 353, wherein said drug comprises ProAir.
1090. The invention of claim 353, wherein said drug comprises Proglycem.
1091 . The invention of claim 353, wherein said drug comprises ProHance (Gadoteridol Injection Solution).
1092. The invention of claim 353, wherein said drug comprises Proparacaine Hydrochloride Ophthalmic Solution (Alcaine).
1093. The invention of claim 353, wherein said drug comprises Propine.
1094. The invention of claim 353, wherein said drug comprises Pulmicort.
1095. The invention of claim 353, wherein said drug comprises Pulmozyme.
1096. The invention of claim 353, wherein said drug comprises Quixin (Levofloxacin Ophthalmic Solution 0.5%).
1097. The invention of claim 353, wherein said drug comprises QVAR.
1098. The invention of claim 353, wherein said drug comprises Rapamune.
1099. The invention of claim 353, wherein said drug comprises Rebetol.
1 100. The invention of claim 353, wherein said drug comprises Relacon-HC.
1 101 . The invention of claim 353, wherein said drug comprises Rotarix (Rotavirus Vaccine, Live, Oral Suspension).
1 102. The invention of claim 353, wherein said drug comprises Rotavirus Vaccine, Live, Oral Suspension (Rotarix).
1 103. The invention of claim 353, wherein said drug comprises Rowasa (Mesalamine Rectal Suspension Enema).
1 104. The invention of claim 353, wherein said drug comprises Sabril (Vigabatrin Oral Solution).
1 105. The invention of claim 353, wherein said drug comprises Sacrosidase Oral Solution (Sucraid).
1 106. The invention of claim 353, wherein said drug comprises Sandimmune.
1 107. The invention of claim 353, wherein said drug comprises Serevent Diskus.
1 108. The invention of claim 353, wherein said drug comprises Solu Cortef (Hydrocortisone Sodium Succinate).
1 109. The invention of claim 353, wherein said drug comprises Solu Medrol (Methylprednisolone sodium succinate).
1 1 10. The invention of claim 353, wherein said drug comprises Spiriva.
1 1 1 1 . The invention of claim 353, wherein said drug comprises Sporanox Oral Solution (Itraconazole Oral Solution).
1 1 12. The invention of claim 353, wherein said drug comprises Staticin (Erythromycin Topical Solution 1 .5%).
1 1 13. The invention of claim 353, wherein said drug comprises Stalevo.
1 1 14. The invention of claim 353, wherein said drug comprises Starlix.
1 1 15. The invention of claim 353, wherein said drug comprises Sterile Hemofiltration Hemodiafiltration Solution (PrismaSol Solution).
1 1 16. The invention of claim 353, wherein said drug comprises Stimate.
1 1 17. The invention of claim 353, wherein said drug comprises Sucralfate (Carafate Suspension).
1 1 18. The invention of claim 353, wherein said drug comprises Sulfacetamide Sodium Ophthalmic Solution 10% (Bleph 10).
1 1 19. The invention of claim 353, wherein said drug comprises Synarel Nasal Solution (Nafarelin Acetate Nasal Solution for Endometriosis).
1 120. The invention of claim 353, wherein said drug comprises Taclonex Scalp (Calcipotriene and Betamethasone Dipropionate Topical Suspension).
1 121 . The invention of claim 353, wherein said drug comprises Tamiflu.
1 122. The invention of claim 353, wherein said drug comprises Tobi.
1 123. The invention of claim 353, wherein said drug comprises TobraDex.
1 124. The invention of claim 353, wherein said drug comprises Tobradex ST (Tobramycin / Dexamethasone Ophthalmic Suspension 0.3%/0.05%).
1 125. The invention of claim 353, wherein said drug comprises Tobramycin / Dexamethasone Ophthalmic Suspension 0.3%/0.05% (Tobradex ST).
1 126. The invention of claim 353, wherein said drug comprises Timolol.
1 127. The invention of claim 353, wherein said drug comprises Timoptic.
1 128. The invention of claim 353, wherein said drug comprises Travatan Z.
1 129. The invention of claim 353, wherein said drug comprises Treprostinil Inhalation Solution (Tyvaso).
1 130. The invention of claim 353, wherein said drug comprises Trusopt (Dorzolamide Hydrochloride Ophthalmic Solution).
1 131 . The invention of claim 353, wherein said drug comprises Tyvaso (Treprostinil Inhalation Solution).
1 132. The invention of claim 353, wherein said drug comprises Ventolin.
1 133. The invention of claim 353, wherein said drug comprises Vfend.
1 134. The invention of claim 353, wherein said drug comprises Vibramycin Oral (Doxycycline Calcium Oral Suspension).
1 135. The invention of claim 353, wherein said drug comprises Videx (Didanosine Pediatric Powder for Oral Solution).
1 136. The invention of claim 353, wherein said drug comprises Vigabatrin Oral Solution (Sabril).
1 137. The invention of claim 353, wherein said drug comprises Viokase.
1 138. The invention of claim 353, wherein said drug comprises Viracept.
1 139. The invention of claim 353, wherein said drug comprises Viramune.
1 140. The invention of claim 353, wherein said drug comprises Vitamin K1 (Aqueous Colloidal Solution of Vitamin K1 ).
1 141 . The invention of claim 353, wherein said drug comprises Voltaren Ophthalmic (Diclofenac Sodium Ophthalmic Solution).
1 142. The invention of claim 353, wherein said drug comprises Zarontin Oral Solution (Ethosuximide Oral Solution).
1 143. The invention of claim 353, wherein said drug comprises Ziagen.
1 144. The invention of claim 353, wherein said drug comprises Zyvox.
1 145. The invention of claim 353, wherein said drug comprises Zymar (Gatifloxacin Ophthalmic Solution).
1 146. The invention of claim 353, wherein said drug comprises Zymaxid (Gatifloxacin Ophthalmic Solution)
1 147 The invention of any preceding claim, wherein said fluid comprisescomposition comprises a diagnostic test material.
1 148. The invention of claim 1 147, wherein said diagnostic test material comprisescomprises17-Hydroxyprogesterone.
1 149. The invention of claim 1 147, wherein said diagnostic test material comprises ACE (Angiotensin I converting enzyme)
1 150. The invention of claim 1 147, wherein said diagnostic test material comprises Acetaminophen.
1 151 . The invention of claim 1 147, wherein said diagnostic test material comprises Acid phosphatase.
1 152. The invention of claim 1 147, wherein said diagnostic test material comprises ACTH.
1 153. The invention of claim 1 147, wherein said diagnostic test material comprises Activated clotting time.
1 154. The invention of claim 1 147, wherein said diagnostic test material comprises Activated protein C resistance.
1 155. The invention of claim 1 147, wherein said diagnostic test material comprises Adrenocorticotropic hormone (ACTH).
1 156. The invention of claim 1 147, wherein said diagnostic test material comprises Alanine aminotransferase (ALT).
1 157. The invention of claim 1 147, wherein said diagnostic test material comprises Albumin.
1 158. The invention of claim 1 147, wherein said diagnostic test material comprises Aldolase.
1 159. The invention of claim 1 147, wherein said diagnostic test material comprises Aldosterone.
1 160. The invention of claim 1 147, wherein said diagnostic test material comprises Alkaline phosphatase.
1 161 . The invention of claim 1 147, wherein said diagnostic test material comprises Alkaline phosphatase (ALP).
1 162. The invention of claim 1 147, wherein said diagnostic test material comprises Alphal -antitrypsin.
1 163. The invention of claim 1 147, wherein said diagnostic test material comprises Alpha-fetoprotein.
1 164. The invention of claim 1 147, wherein said diagnostic test material comprises Alpha-fetoprotien .
1 165. The invention of claim 1 147, wherein said diagnostic test material comprises Ammonia levels.
1 166. The invention of claim 1 147, wherein said diagnostic test material comprises Amylase.
1 167. The invention of claim 1 147, wherein said diagnostic test material comprises ANA (antinuclear antbodies).
1 168. The invention of claim 1 147, wherein said diagnostic test material comprises ANA (antinuclear antibodies).
1 169. The invention of claim 1 147, wherein said diagnostic test material comprises Angiotensin-converting enzyme (ACE).
1 170. The invention of claim 1 147, wherein said diagnostic test material comprises Anion gap.
1 171 . The invention of claim 1 147, wherein said diagnostic test material comprises Anticardiolipin antibody.
1 172. The invention of claim 1 147, wherein said diagnostic test material comprises Anticardiolipin antivbodies (ACA).
1 173. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-centromere antibody.
1 174. The invention of claim 1 147, wherein said diagnostic test material comprises Antidiuretic hormone.
1 175. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-DNA.
1 176. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-Dnase-B.
1 177. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-Gliadin antibody.
1 178. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-glomerular basement membrane antibody.
1 179. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-HBc (Hepatitis B core antibodies.
1 180. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-HBs (Hepatitis B surface antibody.
1 181 . The invention of claim 1 147, wherein said diagnostic test material comprises Antiphospholipid antibody.
1 182. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-RNA polymerase.
1 183. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-Smith (Sm) antibodies.
1 184. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-Smooth Muscle antibody.
1 185. The invention of claim 1 147, wherein said diagnostic test material comprises Antistreptolysin O (ASO).
1 186. The invention of claim 1 147, wherein said diagnostic test material comprises Antithrombin III.
1 187. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-Xa activity.
1 188. The invention of claim 1 147, wherein said diagnostic test material comprises Anti-Xa assay.
1 189. The invention of claim 1 147, wherein said diagnostic test material comprises Apolipoproteins.
1 190. The invention of claim 1 147, wherein said diagnostic test material comprises Arsenic.
1 191 . The invention of claim 1 147, wherein said diagnostic test material comprises Aspartate aminotransferase (AST).
1 192. The invention of claim 1 147, wherein said diagnostic test material comprises B12.
1 193. The invention of claim 1 147, wherein said diagnostic test material comprises Basophil.
1 194. The invention of claim 1 147, wherein said diagnostic test material comprises Beta-2-. Microglobulin
1 195. The invention of claim 1 147, wherein said diagnostic test material comprises Beta-hydroxybutyrate.
1 196. The invention of claim 1 147, wherein said diagnostic test material comprises B-HCG.
1 197. The invention of claim 1 147, wherein said diagnostic test material comprises Bilirubin.
1 198. The invention of claim 1 147, wherein said diagnostic test material comprises Bilirubin, direct.
1 199. The invention of claim 1 147, wherein said diagnostic test material comprises Bilirubin, indirect.
1200. The invention of claim 1 147, wherein said diagnostic test material comprises Bilirubin, total.
1201 . The invention of claim 1 147, wherein said diagnostic test material comprises Bleeding time.
1202. The invention of claim 1 147, wherein said diagnostic test material comprises Blood gases (arterial).
1203. The invention of claim 1 147, wherein said diagnostic test material comprises Blood urea nitrogen (BUN).
1204. The invention of claim 1 147, wherein said diagnostic test material comprises BUN.
1205. The invention of claim 1 147, wherein said diagnostic test material comprises BUN (blood urea nitrogen).
1206. The invention of claim 1 147, wherein said diagnostic test material comprises CA 125.
1207. The invention of claim 1 147, wherein said diagnostic test material comprises CA 15-3.
1208. The invention of claim 1 147, wherein said diagnostic test material comprises CA 19-9.
1209. The invention of claim 1 147, wherein said diagnostic test material comprises Calcitonin.
1210. The invention of claim 1 147, wherein said diagnostic test material comprises Calcium.
121 1 . The invention of claim 1 147, wherein said diagnostic test material comprises Calcium .(ionized)
1212. The invention of claim 1 147, wherein said diagnostic test material comprises Carbon monoxide (CO).
1213. The invention of claim 1 147, wherein said diagnostic test material comprises Carcinoembryonic antigen (CEA).
1314. The invention of claim 1 147, wherein said diagnostic test material comprises CBC.
1215. The invention of claim 1 147, wherein said diagnostic test material comprises CEA.
1216. The invention of claim 1 147, wherein said diagnostic test material comprises CEA (carcinoembryonic antigen).
1217. The invention of claim 1 147, wherein said diagnostic test material comprises Ceruloplasmin.
1218. The invention of claim 1 147, wherein said diagnostic test material comprises CH50Chloride.
1219. The invention of claim 1 147, wherein said diagnostic test material comprises Cholesterol.
1220. The invention of claim 1 147, wherein said diagnostic test material comprises Cholesterol, HDL.
1221 . The invention of claim 1 147, wherein said diagnostic test material comprises Clot lysis time.
1222. Clot The invention of claim 1 147, wherein said diagnostic test material comprises retraction time.
1223. The invention of claim 1 147, wherein said diagnostic test material comprises CMP.
1224. The invention of claim 1 147, wherein said diagnostic test material comprises C02.
1225. The invention of claim 1 147, wherein said diagnostic test material comprises Cold agglutinins.
1226. The invention of claim 1 147, wherein said diagnostic test material comprises Complement C3.
1227. The invention of claim 1 147, wherein said diagnostic test material comprises Copper.
1228. The invention of claim 1 147, wherein said diagnostic test material comprises Corticotrophin releasing hormone (CRH) stimulation test.
1229. The invention of claim 1 147, wherein said diagnostic test material comprises Cortisol.
1230. The invention of claim 1 147, wherein said diagnostic test material comprises Cortrosyn stimulation test.
1231 . The invention of claim 1 147, wherein said diagnostic test material comprises C-peptide.
1232. The invention of claim 1 147, wherein said diagnostic test material comprises CPK (Total).
1233. The invention of claim 1 147, wherein said diagnostic test material comprises CPK-MB.
1234. The invention of claim 1 147, wherein said diagnostic test material comprises C-reactive protein.
1235. The invention of claim 1 147, wherein said diagnostic test material comprises Creatinine.
1236. The invention of claim 1 147, wherein said diagnostic test material comprises Creatinine kinase (CK).
1237. The invention of claim 1 147, wherein said diagnostic test material comprises Cryoglobulins.
1238. The invention of claim 1 147, wherein said diagnostic test material comprises DAT (Direct antiglobulin test).
1239. The invention of claim 1 147, wherein said diagnostic test material comprises D-Dimer.
1240. The invention of claim 1 147, wherein said diagnostic test material comprises Dexamethasone suppression test/
1241 . The invention of claim 1 147, wherein said diagnostic test material comprises DHEA-S.
1242. The invention of claim 1 147, wherein said diagnostic test material comprises Dilute Russell viper venom.
1243. The invention of claim 1 147, wherein said diagnostic test material comprises Elliptocytes.
1244. The invention of claim 1 147, wherein said diagnostic test material comprises Eosinophil.
1245. The invention of claim 1 147, wherein said diagnostic test material comprises Erythrocyte sedimentation rate (ESR).
1246. The invention of claim 1 147, wherein said diagnostic test material comprises Estradiol.
1247. The invention of claim 1 147, wherein said diagnostic test material comprises Estriol.
1248. The invention of claim 1 147, wherein said diagnostic test material comprises Ethanol.
1249. The invention of claim 1 147, wherein said diagnostic test material comprises Ethylene glycol.
1250. The invention of claim 1 147, wherein said diagnostic test material comprises Euglobulin lysis.
1251 . The invention of claim 1 147, wherein said diagnostic test material comprises Factor V Leiden.
1252. The invention of claim 1 147, wherein said diagnostic test material comprises Factor VIII inhibitor.
1253. The invention of claim 1 147, wherein said diagnostic test material comprises Factor VIII level.
1254. The invention of claim 1 147, wherein said diagnostic test material comprises Ferritin.
1255. The invention of claim 1 147, wherein said diagnostic test material comprises Fibrin split products.
1256. The invention of claim 1 147, wherein said diagnostic test material comprises Fibrinogen.
1257. The invention of claim 1 147, wherein said diagnostic test material comprises Folate.
1258. The invention of claim 1 147, wherein said diagnostic test material comprises Folate (serum).
1259. The invention of claim 1 147, wherein said diagnostic test material comprises Fractional excretion of sodium (FENA).
1260. The invention of claim 1 147, wherein said diagnostic test material comprises FSH (follicle stimulating factor).
1261 . The invention of claim 1 147, wherein said diagnostic test material comprises FTA-ABS.
1262. The invention of claim 1 147, wherein said diagnostic test material comprises Gamma glutamyl transferase (GGT).
1263. The invention of claim 1 147, wherein said diagnostic test material comprises Gastrin.
1264. The invention of claim 1 147, wherein said diagnostic test material comprises GGTP (Gamma glutamyl transferase).
1265. The invention of claim 1 147, wherein said diagnostic test material comprises Glucose.
1266. The invention of claim 1 147, wherein said diagnostic test material comprises Growth hormone.
1267. The invention of claim 1 147, wherein said diagnostic test material comprises Haptoglobin.
1268. The invention of claim 1 147, wherein said diagnostic test material comprises HBeAg (Hepatitis Be antigen).
1269. The invention of claim 1 147, wherein said diagnostic test material comprises HBs-Ag (Hepatitis B surface antigen).
1270. The invention of claim 1 147, wherein said diagnostic test material comprises Helicobacter pylori .
1271 . The invention of claim 1 147, wherein said diagnostic test material comprises Hematocrit.
1272. The invention of claim 1 147, wherein said diagnostic test material comprises Hematocrit (HCT).
1273. The invention of claim 1 147, wherein said diagnostic test material comprises Hemoglobin.
1274. The invention of claim 1 147, wherein said diagnostic test material comprises Hemoglobin A1 C.
1275. The invention of claim 1 147, wherein said diagnostic test material comprises Hemoglobin electrophoresis.
1276. The invention of claim 1 147, wherein said diagnostic test material comprises Hepatitis A antibodies.
1277. The invention of claim 1 147, wherein said diagnostic test material comprises Hepatitis C antibodies.
1278. The invention of claim 1 147, wherein said diagnostic test material comprises IAT (Indirect antiglobulin test).
1279. The invention of claim 1 147, wherein said diagnostic test material comprises Immunofixation (IFE).
1280. The invention of claim 1 147, wherein said diagnostic test material comprises Iron.
1281 . The invention of claim 1 147, wherein said diagnostic test material comprises Lactate dehydrogenase (LDH).
1282. The invention of claim 1 147, wherein said diagnostic test material comprises Lactic acid (lactate).
1283. The invention of claim 1 147, wherein said diagnostic test material comprises LDH.
1284. The invention of claim 1 147, wherein said diagnostic test material comprises LH (Leutinizing hormone.
1285. The invention of claim 1 147, wherein said diagnostic test material comprises Lipase.
1286. The invention of claim 1 147, wherein said diagnostic test material comprises Lupus anticoagulant.
1287. The invention of claim 1 147, wherein said diagnostic test material comprises Lymphocyte.
1288. The invention of claim 1 147, wherein said diagnostic test material comprises Magnesium.
1289. The invention of claim 1 147, wherein said diagnostic test material comprises MCH (mean corpuscular hemoglobin.
1290. The invention of claim 1 147, wherein said diagnostic test material comprises MCHC (mean corpuscular hemoglobin concentration).
1291 . The invention of claim 1 147, wherein said diagnostic test material comprises MCV (mean corpuscular volume).
1292. The invention of claim 1 147, wherein said diagnostic test material comprises Methyl malonate.
1293. The invention of claim 1 147, wherein said diagnostic test material comprises Monocyte.
1294. The invention of claim 1 147, wherein said diagnostic test material comprises MPV (mean platelet volume).
1295. The invention of claim 1 147, wherein said diagnostic test material comprises Myoglobin.
1296. The invention of claim 1 147, wherein said diagnostic test material comprises Neutrophil.
1297. The invention of claim 1 147, wherein said diagnostic test material comprises Parathyroid hormone (PTH).
1298. The invention of claim 1 147, wherein said diagnostic test material comprises Phosphorus.
1299. The invention of claim 1 147, wherein said diagnostic test material comprises Platelets (pit).
1300. The invention of claim 1 147, wherein said diagnostic test material comprises Potassium.
1301 . The invention of claim 1 147, wherein said diagnostic test material comprises Prealbumin.
1302. The invention of claim 1 147, wherein said diagnostic test material comprises Prolactin.
1303. The invention of claim 1 147, wherein said diagnostic test material comprises Prostate specific antigen (PSA).
1304. The invention of claim 1 147, wherein said diagnostic test material comprises Protein C.
1305. The invention of claim 1 147, wherein said diagnostic test material comprises Protein S.
1306. The invention of claim 1 147, wherein said diagnostic test material comprises PSA (prostate specific antigen).
1307. The invention of claim 1 147, wherein said diagnostic test material comprises PT (Prothrombin time).
1308. The invention of claim 1 147, wherein said diagnostic test material comprises PTT (Partial thromboplastin time).
1309. The invention of claim 1 147, wherein said diagnostic test material comprises RDW (red cell distribution width).
1310. The invention of claim 1 147, wherein said diagnostic test material comprises Renin.
131 1 . The invention of claim 1 147, wherein said diagnostic test material comprises Rennin.
1312. The invention of claim 1 147, wherein said diagnostic test material comprises Reticulocyte count.
1313. The invention of claim 1 147, wherein said diagnostic test material comprises reticulocytes.
1314. The invention of claim 1 147, wherein said diagnostic test material comprises Rheumatoid factor (RF).
1315. The invention of claim 1 147, wherein said diagnostic test material comprises Sed Rate.
1316. The invention of claim 1 147, wherein said diagnostic test material comprises Serum glutamic-pyruvic transaminase (SGPT).
1317. The invention of claim 1 147, wherein said diagnostic test material comprises Serum protein electrophoresis (SPEP).
1318. The invention of claim 1 147, wherein said diagnostic test material comprises Sodium.
1319. The invention of claim 1 147, wherein said diagnostic test material comprises T3-resin uptake (T3RU).
1320. The invention of claim 1 147, wherein said diagnostic test material comprises T4, Free.
1321 . The invention of claim 1 147, wherein said diagnostic test material comprises Thrombin time.
1322. The invention of claim 1 147, wherein said diagnostic test material comprises Thyroid stimulating hormone (TSH).
1323. The invention of claim 1 147, wherein said diagnostic test material comprises Thyroxine (T4).
1324. The invention of claim 1 147, wherein said diagnostic test material comprises Total iron binding capacity (TIBC).
1325. The invention of claim 1 147, wherein said diagnostic test material comprises Total protein.
1326. The invention of claim 1 147, wherein said diagnostic test material comprises Transferrin.
1327. The invention of claim 1 147, wherein said diagnostic test material comprises Transferrin saturation.
1328. The invention of claim 1 147, wherein said diagnostic test material comprises Triglyceride (TG).
1329. The invention of claim 1 147, wherein said diagnostic test material comprises Troponin.
1330. The invention of claim 1 147, wherein said diagnostic test material comprises Uric acid.
1331 . The invention of claim 1 147, wherein said diagnostic test material comprises Vitamin B12.
1332. The invention of claim 1 147, wherein said diagnostic test material comprises White blood cells (WBC).
1333. The invention of claim 1 147, wherein said diagnostic test material comprises Widal test.
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US61/707,810 | 2012-09-28 | ||
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US201361753348P | 2013-01-16 | 2013-01-16 | |
US61/753,348 | 2013-01-16 | ||
US201361768334P | 2013-02-22 | 2013-02-22 | |
US61/768,334 | 2013-02-22 |
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WO2014052792A1 true WO2014052792A1 (en) | 2014-04-03 |
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PCT/US2013/062247 WO2014052792A1 (en) | 2012-09-28 | 2013-09-27 | Halogenated or parylene polymer coating |
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