CA2215272A1 - Novel compositions for use in embolizing blood vessels - Google Patents
Novel compositions for use in embolizing blood vessels Download PDFInfo
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- CA2215272A1 CA2215272A1 CA002215272A CA2215272A CA2215272A1 CA 2215272 A1 CA2215272 A1 CA 2215272A1 CA 002215272 A CA002215272 A CA 002215272A CA 2215272 A CA2215272 A CA 2215272A CA 2215272 A1 CA2215272 A1 CA 2215272A1
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- embolizing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/08—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0404—X-ray contrast preparations containing barium sulfate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
- A61K49/0414—Particles, beads, capsules or spheres
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
Abstract
Disclosed are compositions suitable for use in embolizing blood vessels which compositions comprise an ethylene vinyl alcohol copolymer, a biocompatible solvent and a water insoluble contrasting agent selected from the group consisting of tantalum, tantalum oxide and barium sulfate. Also disclosed are methods for embolizing a blood vessel using the compositions described herein.
Description
CA 022l5272 l997-09-l2 W O 97104656 PCTrUS96/I2435 NOVEL COMPOSITIONS
FOR USE IN E~IBOLIZING BLOOD VF~FT.~;;
BACKGROI~ND OF TEIE INVENTION
Field of the Invention This invention is dil~cLed to co"l~os;l;~ n~ s~it~hle for use in emholi7in~ blood vessels. In particular, this invention is dire.;~d to ~mholi7in~ c4...~ n~ cQmrri~in~ an ethylene vinyl alcohol copolymer, a 5 biocol~ ble solvent and a water in~olllble contrasting agent. The c4...l~0~;l;t~n~ of this invention find particular utility in embolizing blood vessels in, for eY~mrle, the tre~tmPnt of aneurysms and in ablating .li~ tissues.
R~r-t~ ces The following publir~ti~ n~ are cited in this applir~tilm as :~U~)el~;lil)t nnmhPrs:
Casarett and Doull's Toxicology, Amdur et al., Editors, Pergamon Press, New York, pp. 661-664 (1975) 2 Taki, et al., NA New Liquid M~t~ri~l for Emboli7~ti--n of Arteriovenous Malform~tion~N, American Society of Neuroradiology, 11:163-168 (1990) 3 Terada, et al., "Emboli7~tion of Arteriovenous Malformations with p~ h,., l Aneurysms Using Ethylene Vinyl Alcohol Copolymer", J. Neurosurg., 75:655-660 (1991) All of the above references are herein incorporated by reference in their elltil~;ly to the same extent as if each individual reference was spe~-ifir~lly and individually inrlic~t~ to be incorporated herein by reference in its e~ Ly.
State of the Art W O 97/04656 PCT~US96/12435 It is desirable in many clinical ~itll~tion~ to embolize blood vessels to prevent/control bleeding (e.g., organ bl~pe~ling~ ga~LIoi~ l bleeding, vascular bleeding, hlPeAin~ ~C~ pd with an aneurysm) or to ablate P~cpd tissue (e.g., tumors, etc.). Emboli7~tinn of blood vessels has 5 h~rt:loror~ employed polymer col,lpo~;tinns and particulates, e.g., ~iliCQnP, mPt~llic coils, sclerosing m~t~ri~l~ and the like. Polymeric m~tPri~l~
employed in the polymeric colllpos;l;on~ include those which polymerize in situ at the vascular site (e.g., cyanoacrylates) and those wherein a l.,c r~....~ polymer in situ pl~~jpi~ s from a carrier solution at the 10 vascular site.
The in situ polymP-ri7~tinn of cyanoacrylates delivered via a c~thetPr causes complic~tinn~ due to pl~llldlur~ polymPri7~tinn and/or adhesion of the polymer to the c~thetPr. Accordingly, there has been recent focus on ih~col~ldtillg ~ler(j~llled polymeric m~t~ri~l~ into embnli7~tinn 15 composition~ Ideally, such collll)osiLions should be easy to deliver (e.g., low viscosity) and should cause rapid embolization in the intpnde~d vascular site. Ad~litinn~lly~ these co~ osil;nn~ should be sterile, stable, biocol,~aLible and radiopaque. This last ~r~lly is nP~es~ry in order to moni~or injection of the embolizing co...~ ;nn into the vascular site and 20 to confirm its presence after the procedure is complete.
Current embolizing col..pos;l;ons employing ~rerolllled polymers typically fail to meet one or more of the requirements of ideal embolizing composition~ and a col"pr~ ",ise must be made in sPlPcting the embolizing agents relative to the given clinical case. At times, embolization of the 25 blood vessel, although called for by the clinical condition of the subject, is not p~,rorllled due to difficulties in sPl~o~ting an embolizing composition suitable for use in the given case.
CA 0221't272 1997-09-12 Failure of such embolizing col..positions to meet these ideal ,~uilcl,lents often arises from the particular comhin~tif~n of embolizing t and corlt~ct agents used in the embolizing co.. l~c;~ n Sper-ifir~lly~ the bioco---~lible embolizing agent should produce a well defined coherent S plug/solid upon contact with blood and the contrast agent should be ene~rs~ t~d in the formed solid in order to pennit adequate ~lefinition of the loc~tinn of embolism formation. While certain co---~os;l;nnc comrricin~ an embolizing agent, a cQntr~ct agent and a bioco...l ~lihle solvent such as dimethylsulfoxide (DMSO) have hc~elufo~e been ~iicr,lose~d, 10 the choice of embolizing agent in combination with contrast agent is criticalto sucr~c~irul use in embolizing cQntlitionc. For ey~mrle~ the s~ ted el..boliziilg agent must be biocc,...p.l;h1~-, capable of rapid p~ tinn to form a solid, space-filling m~tPri~l and co---l-~lible with the selç~tçd co..~ l agent. ~ itinn~lly, the rec--lting solid m~teri~l must be 15 s~lffiri~ontly coh~ l so as to minimi7P fr~mPnt~tion which results in smaller solid m~t~ri~lc being incc,l~uldled within the circ~ tinn system.
As is a~ nl, the presence of solid m~t~ri~lc in the circulation system can lead to embnli7~tinn of blood vessels at undesired locations. In the extreme, uninten~çd emboli7~til n of çc~nti~l blood vessels can lead to 20 subject death.
The choice of contrast agent relative to the embolizing agent is particularly critical and contrast agents hele~o~l~ employed for gasLloi.~le~ l tract applications and intravascular injections are not always s~it~hle for use in embolizing blood vessels. For example, while bismuth 25 trioYir1e is a well known contr~ct agent, recent evidence in~ tPs that e~pos~re to this agent can lead to progressive mental confusion, irregular myoclonic jerks, a ~lictinctive pattern of disordered gait, and a variable degree of dy~lhlia which was fatal to subjects who continlled its usel.
Contrast agents which interfere with or retard solid/plug formation for a 30 particular embolizing agent are also not desirable. Moreover, the contr~ct WO 97/04656 PCTrUS96/12435 agent should be water in~oluble and must be encapsulated into the res--lting le otherwise adverse mPAir~l problems can arise. Comrlir~tion~
arising from the use of a water in~oluble cQntr~t agents which are not çn~ tP~ into the formed p,~il);l~le include particles of contr~t agent S migr~ting Ih~ h the circ~ tion system causing embo1i7~tinn of unint~n~ed blood vessels. Complir~tinn~ arising from the use of water soluble eontr~t agents include r~ ltion of these agents into the blood upon injection into the vascular site leading to polential systemic side effects in the treated subject. Ad~1iti( n~lly, the use of water soluble 10 contr~t agents limits the rliniri~n's ability to eontimlously monitor the injection of the embolizing agent into the blood vessel bec~n~e, upon contact with the blood, the contra~t agent is dissolved and removed from the site of injection. As still a further complir~tion, the contr~t agent selçct~i must not alter the physical ~ro~cllies of the solution, e.g, 15 viscosity, in such a ~--a,mer as to render the composition lmcllit~hle for vascular use.
In view of the above, whether an embolizing agent and contr~t agent will be sllit~ in r~-..bin~ n to embolize a blood vessel is very emririr~l and s ~b~ ;on of one emboli7in~ agent for another or one 20 contr~t agent with another often leads to ~lPl~teri~ us results. This problemis not particularly surprising because ultim~tely a s~l~cçs~ful combination of embolizing agent and contr~t agent l~UilcS co~ libility between these co."pollents in producing the requisite coherent ~,cci~ilate having the contr~ct agent Pn~rS~ tP~i therein as well as m~int~ining the requisite 25 ~,o~c,lies for vascular use. When, for example, one contrast agent is replaced by another contrast agent, the chP-mi~l and physical prol)el~ies of each co~tr~t agent will dictate whether it is compatible with the selected embolizing agent. Accordingly, it is not unexpected that contr~t agents having different ch~-.mic~1 and/or physical pro~cl~ies will result in ch~nges 30 in the overall properties of the embolizing co,l.~osilion.
W O 97/046~6 PCT~US96/lZ435 This invention is directed to our discovery of a novel injectable liquid embolizing co~ o~ilion compri~in~ an ethylene vinyl alcohol ~, copolymer dissolved in a bioco.. p~l;hle solvent and a water insoluble cont~t agent sçl~tecl from either t~nt~ m, t~nt~ m oxide, or barium 5 sulfate. Surpri~in~ly, this embolizing cG~ osiLion is easily delivered to the vascular site and rapidly forms a coherent solid m~tPri~l which readily Pnr~ps~ tPs the cont~a~t agent.
He~ ,rore, Taki, et al.2 ~ rl~se an example of an embolizing co...l)os;l;rn collt;~ h-~ an ethylene vinyl alcohol copolymer (67 mole 0 ~llt ethylene and 33 mole ~lcenl vinyl alcohol) and a water soluble c~ntr~t agent (m~l.;,;...i~lP,) in DMSO. An a~l)a~e,llly similar co~ o~ ion was also di~lose~ by Terada, et al.3 However, the water soluble conL~
agents ~ r1~sed in these references ~ignifir~ntly limit the s~ hility of these cG...l o~;l;on~ for use in embolizing blood vessels. Moreover, as 15 above, the apriori ~ubs~ ;Qn of a water in~ lb1e contr~t agents for mPtri7~mil1e is inherently problematic because it is unl)re~lirt~hl~p what affect the different rhPmir~l and/or physical ~,o~ ies of the water insoluble contrast agent as co",~a.cd to the soluble contrast agent will have on the ultim~tr ~o~lLies of the rçs--lting composition~
SUMMARY OF THE INVENTION
As above, this invention is directed to our discovery of a novel injectable liquid Pmholi7ing composition comprising an ethylene vinyl alcohol copolymer dissolved in dimethylsulfoxide or other suitable bioco..lpatible solvent and a water insoluble contrast agent SPlP~t~d from 25 t~nt~ll-m, t~nt~lllm oxide, or barium sulfate.
Accordingly, in one of its co",posiLion aspects, this invention is directed to an embolizing composition comprising:
W O 97/04656 PCT~US96/12435 (a) from about 2.5 to about 8 weight percent of an ethylene vinyl alcohol copolymer çmholi7ing agent;
(b) from about 10 to about 40 weight percent of a water in.~nlnble Contr~t agent sPhP~te~l from the group con~i~ting of t~nt~lnm, 5 t~nt~lllm oxide and barium sulfate;
(c) from about 52 to about 87.5 weight percent of a bioco...~ ;hlP solvent wl.clcin the weight percent of each of the components is based on the total weight of the cornrlPtP composition.
In one of its method aspects, this invention is directed to a method for embolizing a blood vessel by injecting into said blood vessel a s--ffi~iPnt ~mol-nt of an embolizing co...~,o:jilion compri~ing:
(a) from about 2.5 to about 8 weight percent of an ethylene vinyl alcohol copolymer emboli_ing agent;
(b) from about 10 to about 40 weight percent of a water insoluble c~ntr~t agent se-lP~tPd from the group cQ~ ting of t~nt~lllm, t~nt~lllm oxide and barium sulfate;
(c) from about 52 to about 87.5 weight percent of a bioco~ ;ble solvent wherein the weight percent of each of the con.ponents is based on the total weight of the complete composition under con~litinn~ wherein a ~ ip;~te is formed which embolizes the blood vessel.
In a plerellcd emb~limPnt the molecular weight of the ethylene vinyl alcohol copolymer col"~osi~ion is SPlP~tP~i such that a solution of 6 weight percent of the ethylene vinyl alcohol composition, 35 weight percent of a t~nt~l-lm contrast agent in DMSO has a viscosity equal to or less than 60 centipoise at 20~C and more preferably 40 ccnlil)oise or less at 20~C.
In another p~c;r~ d embo ~iment, the ethylene vinyl alcohol copolymer W O 97/04656 PCT~US96/lZ435 comrositinn comprises from about 25 to about 60 mole percent of ethylene and from about 40 to about 75 mole percent of vinyl alcohol.
~ereldbly, the biocG.~ atible solvent is dimethylsulfoxide.
,, DETA~ l~n DESCRIPTION OF l~E INVENTION
This invention is dilc;~;~d to spe~ific embolizing comro~citi~nc comrricing a sre~-ific embolizing agent, cre~ific con~ct agents and a bioco~ atible solvent.
Prior to ~i~cu~ing this invention in further detail, the following terms will first be dt--fined The term "embolizing" as used in conjunction with "embolizing co,~l~,oc;l;~ nc" and "emh~1i7ing agents" refers to a process wherein a m~t~ri~1 is injected into a blood vessel which th-lcaÇl~r fills or plugs the blood vessel and/or enc~uldges clot form~tion so that blood flow ll-l~ugh the vessel ceases. The emb~1i7~ti~ n of the blood vessel is im~l~ in preventing/controlling bleeding (e.g., organ bleeding, ga~ r~
bl~lin~, vascular b1ee~ling, bleeding ~csoci~t~ with an aneurysm) or to ablate .licP~c~ tissue (e.g., tumors, etc.) by cutting off its blood supply.
The term "ethylene vinyl alcohol copolymers" refers to copolymers cQmrricing residues of both ethylene and vinyl alcohol monomers. Small amounts (e.g., less than 5 mole percent) of additional monomers can be in~ -ie~ in the polymer structure or grafted thereon provided such litil~n~1 monomers do not alter the embolizing pr~elLies of the composition. Such ~ ition~1 monomers include, by way of example only, maleic anhydride, styrene, propylene, acrylic acid, vinyl acetate and the like.
Ethylene vinyl alcohol copolymers used herein are either c4mmP-rcially available or can be prepared by art recognized procedures.
~cr~,~bly, the ethylene vinyl alcohol copolymer coll,posiLion is s~Plected such that a soll-tion of 6 weight percent of the ethylene vinyl alcohol 5 copolymer, 35 weight percent of a t~nt~lllm c~ntraet agent in DMSO has a viscosity equal to or less than 60 cenli~ise at 20~C. As is a~c lt to one skilled in the art, with all other factors being equal, copolymers having a lower molcclll~r weight will impart a lower viscosity to the comrositinn as cc,lll~ucd to higher mnlecul~r weight copolymers. Accordingly, adj~
10 of the viscosity of the co"~posiLion as nP~P~y for ç~thPtPr delivery can be readily achieved by mere adjl~tmPnt of the mole~ul~r weight of the copolymer compo~itinn.
As is also a~ Gnl, the ratio of ethylene to vinyl alcohol in the copolymer affects the overall hyd~hobicity/hydl~hilicity of the 15 co-"l)osilion which, in turn, affects the relative water solubility/insolubility of the co~po~;l;nn as well as the rate of precipitation of the copolymer in an aqueous sQllltinll (e.g., blood). In a particularly pl~GrGlled embo limPnt the copolymers employed herein comprise a mole percent of ethylene of from about 25 to about 60 and a mole percent of vinyl alcohol of from 20 about 40 to about 75. These co~ ;l;on~ provide for requisite pla iril;~t;c)n rates suitable for use in embolizing blood vessels.
The term '~CQ~tr~t agent" refers to a radiopaque m~tPri~l capable of being monitored during injection into a m~mm5li~n subject by, for PY~mpl~, r~tliogr~phy. The term "water insoluble contrast agent" refers to 25 cont~ct agents which are e~enti~lly insoluble in water (i.e., having a water solubility of less than 0.01 mg/ml at 20~C). The water insoluble contr~t t-agents incl~lded within the scope of this invention are t~nt~lllm, t~nt~ m oxide and barium sulfate, each of which is commercially available in the W O 97/046',6 PCTrUS96/12435 proper form for in vivo inrl~ ing a particle size of about 10 ~Lm or less.
Other cont~ct agents sllit~hle for use herein include gold and pl~tinum.
a The term "biocc,~ alible solvent" refers to an organic m~tPri~l liquid at least at body le~ .dtu,c of the m~mm~l in which the ethylene 5 vinyl alcohol copolymer is soluble and, in the amounts used, is ~,..bsl~..t;~lly non-toxic. Suitable bioco---~lible solvents inclllde, by way ofeY~mple, dimethylsulfoxide, analogues/homologues of dimethylsulfoxide, and the like. Preferably, the bioco---pdlible solvent is dimethylsulfoxide.
The term Nencaps~ tion" as used relative to the contrast agent being 10 ~n~ trA in the ~reril);l~tP is not meant to infer any physical e -L-d~---ent of the contract agent within the pl~;pil~le much as a capsule enr~rs~ t~s a m~Air~mrnt Rather, this term is used to mean that the contract agent and copolymer form an integ~l coherent ple~ le which does not se;~
into a copolymer co...l~nent and a contr~ct agent co...pollel t.
15 Cc,--,~o~ilions The comrositions of this invention are ~lc~cd by conventi~
mrth~lc whereby each of the co~ ~nl~ntc is added and the res--lting co...l)osiLion mixed together until the overall composition is subst~nti~lly homogeneous. Specifically, s--ffieient amounts of the ethylene vinyl 20 alcohol copolymer are added to the bioco.l.palible solvent to achieve the effective concPntr~tit n for the complete embolizing composition.
Preferably, the embolizing composition will comprise from about 2.5 to about 8 weight percent of the ethylene vinyl alcohol copolymer composition based on the total weight of the embolizing co---posilion and more 25 preferably from about 4 to about 5.2 weight percent. If n~c~.y, gentle heating and stirring can be used to effect tliccolllti~n of the copolymer into the bioco...l.~l;hle solvent, e.g., 12 hours at 50~C.
W O 97/04656 PCT~US96/12435 S~fflciPnt amounts of the contr~t agent are then added to the bioco...l~t;blP solvent to achieve the effective conA~-ntr~tinn for the cornp'A-~e embolizing co...los;l;~n. Preferably, the embolizing cc"ll~osilion will comprise from about 10 to about 40 weight percent of the cAntr~t 5 agent and more preferably from about 20 to about 40 weight percent and even more ~Jtert~bly 35 weight percent. Insofar as the contrast agent is not soluble in the biocclll~dLible solvent, stirring is employed to effect ho...~e-~;ly of the rp~lllting s~srpn~inn. In order to Pnh~nee fonn~Atinn of the s~rPnQ;nn~ the particle size of the contr~t agent is pl~rtldlily 10 Ill~inl~ P~ at about 10 ,um or less and more preferably at from about 1 to about 5 ~m (e.g., an average size of about 2 ~m).
The particular order of ~ tion of colllpollents to the biocolllpatible solvent is not critical and stirring of the resnlting sl-spçn~inn is con~ cted as ne~.y to achieve homogeneity of the composition. Preferably, 15 mixing/stirring of the col~s;l;on is con~ctP~1 under an anhydrous atmosphere at ambient pres~ulc;. The rçs--lting colllpcsiLion is heat stPrili7f~d and then stored preferably in sealed amber bottles or vials until n~ed Methods The co",~o~iLions described above are then employed in methods for embolizing ~ n blood vessels. Spe~-ifi~ lly, a snfficient amount of this composition is introduced into the sPlP~ted blood vessel by co"v~ l;nn~l means (e.g., injection or c~th~tt-r delivery under fluoroscopy) so that upon ~ on of the ethylene vinyl alcohol copolymer, the blood vessel is embolized. The particular amount of embolizing composition employed is dictated by the total volume of the v~c~ t--re to be embolized, the concentration of copolymer in the composition, the rate of pl~;p;l~;on (solids formation) of the copolymer, etc. Such factors are well within the skill of the art. The rate of ~l~ipiLation can be controlled by ~h~n~in,~ the overall hydr~)hobicity/hydrophilicity of the copolymer with faster pr~;~ ; tion rates being achieved by a more hydrophobic o copolymer cc,~ ion which, in turn, can be achieved by increasing the ethylene content of the copolymer composition.
One particularly prer~.led method for delivering the embolizing col~ n~ of this invention to the sPl~ted vascular site is via a small .... t~ . m~ic~l c~ . The particular c~theter employed is not critical provided that polymeric c~th~ter con,pol-ents are co~ )atible with the embolizing co--~po~ilion (i.e., the c~thett--r co~ onents will not readily 10 tlP~ l.o in the embolizing co~ osition). In this regard, it is pl~rell~d to use polyethylene in the c~thet~r co"~ ents because of its inertness in the ~;sence of the ~mboli~in~ co--l~osiLion described herein. Other m~t~.ri~l~
~",~aLible with the embolizing cG,,,posili~n~ can be readily determined by the skilled artisan and incl~lde, for eY~mrl~, other polyolefins, 15 iluolul)olymers (e.g., TeflonTM), silicone, etc.
When delivered by c~th~ter, the injection rate ~lict~t~s, in part, the form of the ~ at the vascular site. Spes-ific~lly, low injection rates of a~ Xim~t~ly 0.05 to 0.3 cc/minute will provide for a ~r~;pil~l~ in the form of a kernel or nodule which is particularly benlofici~l for site specifi 20 embolization bec~ e the l. ~s~ P forms prim~rily at the point of injection. Contr~rily~ high injection rates of about 0.1 to 0.5 or more cc/several s~on~l~ (e.g., up to ten seconds) will provide for a fil~m.ont like mass projecting down stream from the c~thete tip which is particularly bent~-fici~l for providing the embolizing agent deep into the vascular tree.
25 Such procedures are suitable for embolizing tumor masses, organs and arteriovenous malformations (AVM).
When introduced into the vascular site, the biocolllpaLible solvent diffuses rapidly into the blood and a solid pre5-ipit~te forms which W O 97/04656 PCT~US96/12435 preriritAtP is the ethylene vinyl alcohol copolymer with the contrast agent enc~rslllAt~A therein. Without being limited to any theory, it is believed that initially, a soft gel to spongy solid ~lccip;~A~e forms upon contact with the blood which ~ )ilAte is open and fibrous in structure. This 5 ~rec;l.ilAte then restricts blood flow, enlld~ g red cells thereby causing clot emholi7Ati~n of the blood vessel.
Utility The col-lpo-~ n~ described herein are useful in embolizing m~mmAliAn blood vessels which, in turn, can be used to prevent/control 10 bleeding (e.g., organ b1ePA;ng, gasL~ f ~ Al hlPPAing, vascular ble ding, blPeAing A~c;~A with an ant;uly~l,l) or to ablate ~ PA~PC1 tissue (e.g., tumors, etc.). Accoldingly, these colll~o~;l;nn~ find use in human and other mAmmAli~n subjects l~uiling embolization of blood vessels.
~d~lition~lly~ these compositions provide an a~lu~liate vehicle for 15 the delivery of a medicament to the vascular site. Spe~ifi~lly, a s-litAhle mPAiCAmPnt e.g., a chemotheldl~eulic agent, growth factor agents, anti-inflA~ Alo~ y agents, anti-s~mAtic agents, etc. which are compatible with the embolizing collll)osiLion can be in~ dPA in this composition in th~.Al~-l;C levels and delivered directly to the vascular site.
The following eYAmrles are set forth to illustrate the cl~imPA
invention and are not to be construed as a limit~tinn thereof.
EXAMPLES
Unless otherwise stated, all tell-~ldlu~es are in degrees Celsius.
Also, in these eyAmrl~s~ unless otherwise defined below, the abbreviations employed have their generally accepted m~Aning cc = cubic cPntimPtP~r DMSO = dimethylsulfoxide EVOH = ethylene vinyl alcohol copolymer gm = gram mL = millilitPrs mm = millimPt.or psi = pounds per square inch FY7/mple 1 The l~ul~ose of this eY~mple is to ~çmon~tr~t~p the suitability of 10 ethylene vinyl alcohol copolymer co~ ;I;nn~ in DMSO as em~olizing agents. The tests were cnn~luctP~ by addition of the copolymer solution into saline and d~;Lt;~ illg the plc~ ;on parameters. Rapid formation of a coherent l ~c~ip;li~l;on evidences suitability of the copolymer ~ osiLion as an embolizing agent.
Spe~ifi~lly~ five ethylene vinyl alcohol copolymer resins were employed of varying con~Pntr~tion~ - 27, 32, 38, 44 and 48 mole percent ethylene (available from EVAL Co",l)a.,y of ~mer~ Lisle, Tllinoi~, USA) having a viscosity grade as defined by a melt index of about 4-15 (gm/10 -s) at 210~C. The resin a~pe~ as clean, trAn~ cent cylin~lrir~l 20 particles about 1 x 2 mm. S~mplPs were pre~aled at 5.2% concPntrAtiQn in DMSO (obtained from Aldrich ChP-mi~ l Company, Milwaukee, Wi~con~in, USA as M8180-2, 99+ % purity). Di~ol~ltinn was complete within 24 hours at 52~C.
Approxim~tP~y 0.1 to 0.5 mL of each solution was added by 25 needle/syringe to a normal saline solution at 37~C or at room k;".~ldture.
All five samples immP~ tPly ge~nP~tP~l a white mass or string of polymer upon contact with saline. As the ethylene content in the sample increased, the res--lting ~JleCi~)itdtt; was whiter, tougher and more dense. The two W O 97/04656 PCT~US96/12435 lowest ethylene content resins a~ared to yield a weaker, more gelatinous mass, which nevertheless were suitable for use as embolizing agents.
Accordingly, these results in~ t~o that EVOH copolymers are snit~hle embolizing agents.
S Flow rates were ~SP~Pd for each of these s~mplPs at 10 psi and 37~C over 3 "~ ,t~ s using a 3 French Infusion c~thPtPr (available from Micro Th~ ;r-s, Inc., Aliso Viejo, California, USA) in order to assess suitability for C~thPtPr delivery of these composition~ to the vascular site.
The results of this analysis are set forth in Table I below:
TABLE I
Ethylene ContPnt inFlow Rate EVOH Copolymer 27% 0.22 cc/min 32% 0.25 cc/min lS 38% 0.20 cc/min 44 % 0.25 cc/min 48% 0.30 cc/min The above results in-lic~tP that these composition~ possess flow rates ~-lit~hlP for c~thtotPr delivery to the vascular site. These results also 20 suggest that preferable results are achieved using a more hydrophobic EVOH composition (e.g., about 48 mole % ethylene content) at a con~PntrAtion of about 2.5 to about 8.0 weight percent.
Example 2 W O 97/04656 PCTrUS96/12435 The ~ull~ose of this eY~mple is to illustrate that not all polymers are suitable as embolizing agents. Sperific~lly, in this eY~mple, the EVOH
copolymers desr-rihe~ above were replaced with polyufe:~halle (DOW
PELLETHANE 2363-80A, Dow Ch~mi~l Co~ y, Mi~ ntl, Mil~.hig~n, S USA), poly~ ylmPth~crylate (available from Rohm & Haas, Phil~delrhi~ Pe;~ sylvania, USA), polycarbonate (MOBAY MAKROLON
2558-1112, Mobay ChPmi~l Co---pally, Bayer Inc., Pil~l ul~h, Pennsylv;~ia, USA), two dirr~ t cell~ se (li~ret~tps [CP11I11O~P Acetate NF CA 320-S (~32% acetyl content) and ~e~ s~ Acetate NF CA 398-10 10 (--39.8 acetyl content) both available from FMC Corp., Pharm~euti~
Division, Phil~lPlphia, Pennsylvania, USA)] and cP~ lose tri~cet~te (C~ se Acetate NF CA 435-75S (~43.5% acetyl content) -- FMC
Corp., Pharm~uti~l Division, phil~ )hi~ Pennsylvania, USA).
The results of this analysis inrli~t~l that polyurell-alle ~mpl~s were 15 slow to dissolve in DMSO at 52~C and, upon cooling to room ~e~ e, formed a high viscosity sollltinnlgel nn~llit~hle for injection. In the case of the polymethylm~th~-rylate, the polymer dissolved in DMSO but the .~-il,il~le formed upon ~ ition to saline was lln~nit~hle for use as an embolizing agent because it lacked cohesiveness and easily fr~gmpn~çd In 20 the case of the poly~l,olla~e, the polymer failed to dissolve in DMSO at 52~C over 3 days. The c~-lll-lose tri~ePte sample provided too high a viscosity for effective delivery via a c~thPt~r at a concentration s~fficie-nt to effectively embolize a blood vessel and reduction of the conce-ntration to less than 2.5 weight percent resulted in ~l~ ipili1t~ formation which was 25 un~lit~hle for vascular embolization. Only the celll~lnse ~ et~ttos provided suitability for vascular emboli7~tion in a manner similar to EVOH
and the use of such polymers as embolizing agents is described in further detail in U.S. Patent Application Serial No. filed con~;u,lc;lllly herewith as Attorney Docket No. 018413-003 entitled "CELLULOSE
30 DIACETATE CO~aPOSlTl~LS FOB USE IN EMBOLIZING BLOOD
WO 97/04656 PCT~US96/12435 VF.~.SF-T~~" which app1ir~tion is incorporated herein by reference in its cn~lcly.
FY,~rle 3 The yulyOSc of this example is to co..lpale in vitro results achieved S by ih~colpn~ a water soluble cQntr~ct agent and a water incolllbl~P
cont~ct agent of this invention into an embolizing composition co.~ hiii-g EVOH in DMSO. .Syerifir~lly~ in this eY~mple, an EVOH col--yosiLion (44 mole percent ethylene) was dissolved into DMSO to provide for an 6.8 weight percent co~-ce~.L~Lion of the copolymer in DMSO. To this sQluti~m 10 was added either t~nt~lum (10 weight percent, available from Leico ~nllnctriPs, New York, New York, USA, 99.95% purity, less than 43 ~Lm in size) as a water insoluble contrast agent or metri7~mi~1ç (38.5 weight percent, available from Aldrich ChPmi~l Company, Milwaukee, Wicr-oncin, USA) as a water soluble contr~ct agent. Rer~llse these results 15 are in ~vitro results, the t~nt~l-lm particle size is not LlyOlL~It and the larger particles size is not c;~ye~iled to affect these results.
In the t~nt~lllm co~poc;l;on~ t~nt~lum settling can result from prolcnge l st~nrling. Srnifir~tion may help but thorough mixing prior to use is required.
Approxim~tPly 0.2 mL of the each composition was then added by syringe/needle to a saline solution at 37~C and the char~-tericti~s of the rçs--ltin~ ylc~'ip;l~ç eY~minPIl In the case of the tantalum ~mplP, a precipitate immP~i~tely formed which was çh~ tPri7P~I by firm spongy 25 fil~mPntc and nodlllPs The metri7~mide sample on the other hand did not form a well defined solid mass as the mçtri7~mide rapidly diffused away.
_ W O 97/04656 PCT~US96/12435 Example 4 The pu-~ose of this PY~mple is to illl-ctr~te that certain embolizing agent/c~nt~ct agent combin~tinnc provide for physical pro~cllies which makes injection of the comhin~tion into vascular sites .cignifit~ntly more 5 ~iffie llt Spe~-ifi~lly, in this eY~mrle, a col.")osilion compricin~ 6.8 weight pc~ l of EVOH (44 mole percent ethylene) in DMSO was p~c;~u~l. The viscosity of this cGIll~?osilion was al)pn"~ ely 60 c~ e at 20~C. Upon ~drlitinn of 38.5 weight ~.;cll~ of m~.~.;,i...~irl~
to this cGI~l~osi~ion, the viscosity increased cignifi~ntly to a~;~p~...;m~t~ly 145 ce--l;~ e at 20~C.
t~s)ntr~rily, the addition of 35 weight percent of t~nt~lllm or barium sulfate to a similar EVOH/DMSO co",posi~ion did not m~tP.ri~lly alter the viscosity of the co,--~)osiLion.
The above results intlic~te that the use of t~nt~ m as the contr~ct 15 agent provides for cG---l)osi~ions with cignific~ntly lower viscosity than those employing mPtri7~mi-1e. In turn, such lower vi.ccociti~s render the co...~osil;nn.c easier to deliver either by injection or by c~thPt~r to the vascular site thereby ~,~,lionally redur-ing the lik.o.lihood of vascular inJury.
FY~mrle 5 The ~ull~ose of this eY~mple is to illustrate an in vivo applic~tion of the embolizing composition of this invention.
In this eY~mrle, a 50 pound male hound was plcpalcd for blood vessel emboli7~tinn using an embolic composition comprising 5.8 weight pcl~n~ EVOH polymer (col.ti~in;ng 48 weight percent ethylene), 20 weight pel~nl t~nt~lllm in DMSO was loaded into a syringe. Embolization of the left kidney proceeded by p~ .mlo.nt of a 3F micro c~theter into the kidney WO 97/046S6 PCT~US96/12435 through a SF AngioDynamics ~ hllnt~r c~thPtPr. The c~theter was advanced into the renal artery, flushed with cnntr~t agent to identify the 1t c~tion and then flushed with DMSO, followed by 0.3 cc of the EVOH
co...po~;l;on ~es-rihe~ above, followed yet by more DMSO within the S c~thPter. The EVOH co...po~ n was quickly injected into the renal artery. After delivery of about 0.2 cc of EVOH composition, the upper pole of the kidney was blocked. Delivery of the ~ h~ g EVOH
co...l o~;l;on resulted in the entire kidney being embolized.
The above results indic~te that the coll.po~i~ions of this invention are 10 suitable for in YiYo emboli7~tion of blood vessels in m~mm~ n subjects.
From the l'olegoing description, various mo~lifi~tions and changes in the c-....l o~;l;on and method will occur to those skilled in the art. All such morlifir~tion~ coming within the scope of the appended claims are intende~l to be inrlllded therein.
FOR USE IN E~IBOLIZING BLOOD VF~FT.~;;
BACKGROI~ND OF TEIE INVENTION
Field of the Invention This invention is dil~cLed to co"l~os;l;~ n~ s~it~hle for use in emholi7in~ blood vessels. In particular, this invention is dire.;~d to ~mholi7in~ c4...~ n~ cQmrri~in~ an ethylene vinyl alcohol copolymer, a 5 biocol~ ble solvent and a water in~olllble contrasting agent. The c4...l~0~;l;t~n~ of this invention find particular utility in embolizing blood vessels in, for eY~mrle, the tre~tmPnt of aneurysms and in ablating .li~ tissues.
R~r-t~ ces The following publir~ti~ n~ are cited in this applir~tilm as :~U~)el~;lil)t nnmhPrs:
Casarett and Doull's Toxicology, Amdur et al., Editors, Pergamon Press, New York, pp. 661-664 (1975) 2 Taki, et al., NA New Liquid M~t~ri~l for Emboli7~ti--n of Arteriovenous Malform~tion~N, American Society of Neuroradiology, 11:163-168 (1990) 3 Terada, et al., "Emboli7~tion of Arteriovenous Malformations with p~ h,., l Aneurysms Using Ethylene Vinyl Alcohol Copolymer", J. Neurosurg., 75:655-660 (1991) All of the above references are herein incorporated by reference in their elltil~;ly to the same extent as if each individual reference was spe~-ifir~lly and individually inrlic~t~ to be incorporated herein by reference in its e~ Ly.
State of the Art W O 97/04656 PCT~US96/12435 It is desirable in many clinical ~itll~tion~ to embolize blood vessels to prevent/control bleeding (e.g., organ bl~pe~ling~ ga~LIoi~ l bleeding, vascular bleeding, hlPeAin~ ~C~ pd with an aneurysm) or to ablate P~cpd tissue (e.g., tumors, etc.). Emboli7~tinn of blood vessels has 5 h~rt:loror~ employed polymer col,lpo~;tinns and particulates, e.g., ~iliCQnP, mPt~llic coils, sclerosing m~t~ri~l~ and the like. Polymeric m~tPri~l~
employed in the polymeric colllpos;l;on~ include those which polymerize in situ at the vascular site (e.g., cyanoacrylates) and those wherein a l.,c r~....~ polymer in situ pl~~jpi~ s from a carrier solution at the 10 vascular site.
The in situ polymP-ri7~tinn of cyanoacrylates delivered via a c~thetPr causes complic~tinn~ due to pl~llldlur~ polymPri7~tinn and/or adhesion of the polymer to the c~thetPr. Accordingly, there has been recent focus on ih~col~ldtillg ~ler(j~llled polymeric m~t~ri~l~ into embnli7~tinn 15 composition~ Ideally, such collll)osiLions should be easy to deliver (e.g., low viscosity) and should cause rapid embolization in the intpnde~d vascular site. Ad~litinn~lly~ these co~ osil;nn~ should be sterile, stable, biocol,~aLible and radiopaque. This last ~r~lly is nP~es~ry in order to moni~or injection of the embolizing co...~ ;nn into the vascular site and 20 to confirm its presence after the procedure is complete.
Current embolizing col..pos;l;ons employing ~rerolllled polymers typically fail to meet one or more of the requirements of ideal embolizing composition~ and a col"pr~ ",ise must be made in sPlPcting the embolizing agents relative to the given clinical case. At times, embolization of the 25 blood vessel, although called for by the clinical condition of the subject, is not p~,rorllled due to difficulties in sPl~o~ting an embolizing composition suitable for use in the given case.
CA 0221't272 1997-09-12 Failure of such embolizing col..positions to meet these ideal ,~uilcl,lents often arises from the particular comhin~tif~n of embolizing t and corlt~ct agents used in the embolizing co.. l~c;~ n Sper-ifir~lly~ the bioco---~lible embolizing agent should produce a well defined coherent S plug/solid upon contact with blood and the contrast agent should be ene~rs~ t~d in the formed solid in order to pennit adequate ~lefinition of the loc~tinn of embolism formation. While certain co---~os;l;nnc comrricin~ an embolizing agent, a cQntr~ct agent and a bioco...l ~lihle solvent such as dimethylsulfoxide (DMSO) have hc~elufo~e been ~iicr,lose~d, 10 the choice of embolizing agent in combination with contrast agent is criticalto sucr~c~irul use in embolizing cQntlitionc. For ey~mrle~ the s~ ted el..boliziilg agent must be biocc,...p.l;h1~-, capable of rapid p~ tinn to form a solid, space-filling m~tPri~l and co---l-~lible with the selç~tçd co..~ l agent. ~ itinn~lly, the rec--lting solid m~teri~l must be 15 s~lffiri~ontly coh~ l so as to minimi7P fr~mPnt~tion which results in smaller solid m~t~ri~lc being incc,l~uldled within the circ~ tinn system.
As is a~ nl, the presence of solid m~t~ri~lc in the circulation system can lead to embnli7~tinn of blood vessels at undesired locations. In the extreme, uninten~çd emboli7~til n of çc~nti~l blood vessels can lead to 20 subject death.
The choice of contrast agent relative to the embolizing agent is particularly critical and contrast agents hele~o~l~ employed for gasLloi.~le~ l tract applications and intravascular injections are not always s~it~hle for use in embolizing blood vessels. For example, while bismuth 25 trioYir1e is a well known contr~ct agent, recent evidence in~ tPs that e~pos~re to this agent can lead to progressive mental confusion, irregular myoclonic jerks, a ~lictinctive pattern of disordered gait, and a variable degree of dy~lhlia which was fatal to subjects who continlled its usel.
Contrast agents which interfere with or retard solid/plug formation for a 30 particular embolizing agent are also not desirable. Moreover, the contr~ct WO 97/04656 PCTrUS96/12435 agent should be water in~oluble and must be encapsulated into the res--lting le otherwise adverse mPAir~l problems can arise. Comrlir~tion~
arising from the use of a water in~oluble cQntr~t agents which are not çn~ tP~ into the formed p,~il);l~le include particles of contr~t agent S migr~ting Ih~ h the circ~ tion system causing embo1i7~tinn of unint~n~ed blood vessels. Complir~tinn~ arising from the use of water soluble eontr~t agents include r~ ltion of these agents into the blood upon injection into the vascular site leading to polential systemic side effects in the treated subject. Ad~1iti( n~lly, the use of water soluble 10 contr~t agents limits the rliniri~n's ability to eontimlously monitor the injection of the embolizing agent into the blood vessel bec~n~e, upon contact with the blood, the contra~t agent is dissolved and removed from the site of injection. As still a further complir~tion, the contr~t agent selçct~i must not alter the physical ~ro~cllies of the solution, e.g, 15 viscosity, in such a ~--a,mer as to render the composition lmcllit~hle for vascular use.
In view of the above, whether an embolizing agent and contr~t agent will be sllit~ in r~-..bin~ n to embolize a blood vessel is very emririr~l and s ~b~ ;on of one emboli7in~ agent for another or one 20 contr~t agent with another often leads to ~lPl~teri~ us results. This problemis not particularly surprising because ultim~tely a s~l~cçs~ful combination of embolizing agent and contr~t agent l~UilcS co~ libility between these co."pollents in producing the requisite coherent ~,cci~ilate having the contr~ct agent Pn~rS~ tP~i therein as well as m~int~ining the requisite 25 ~,o~c,lies for vascular use. When, for example, one contrast agent is replaced by another contrast agent, the chP-mi~l and physical prol)el~ies of each co~tr~t agent will dictate whether it is compatible with the selected embolizing agent. Accordingly, it is not unexpected that contr~t agents having different ch~-.mic~1 and/or physical pro~cl~ies will result in ch~nges 30 in the overall properties of the embolizing co,l.~osilion.
W O 97/046~6 PCT~US96/lZ435 This invention is directed to our discovery of a novel injectable liquid embolizing co~ o~ilion compri~in~ an ethylene vinyl alcohol ~, copolymer dissolved in a bioco.. p~l;hle solvent and a water insoluble cont~t agent sçl~tecl from either t~nt~ m, t~nt~ m oxide, or barium 5 sulfate. Surpri~in~ly, this embolizing cG~ osiLion is easily delivered to the vascular site and rapidly forms a coherent solid m~tPri~l which readily Pnr~ps~ tPs the cont~a~t agent.
He~ ,rore, Taki, et al.2 ~ rl~se an example of an embolizing co...l)os;l;rn collt;~ h-~ an ethylene vinyl alcohol copolymer (67 mole 0 ~llt ethylene and 33 mole ~lcenl vinyl alcohol) and a water soluble c~ntr~t agent (m~l.;,;...i~lP,) in DMSO. An a~l)a~e,llly similar co~ o~ ion was also di~lose~ by Terada, et al.3 However, the water soluble conL~
agents ~ r1~sed in these references ~ignifir~ntly limit the s~ hility of these cG...l o~;l;on~ for use in embolizing blood vessels. Moreover, as 15 above, the apriori ~ubs~ ;Qn of a water in~ lb1e contr~t agents for mPtri7~mil1e is inherently problematic because it is unl)re~lirt~hl~p what affect the different rhPmir~l and/or physical ~,o~ ies of the water insoluble contrast agent as co",~a.cd to the soluble contrast agent will have on the ultim~tr ~o~lLies of the rçs--lting composition~
SUMMARY OF THE INVENTION
As above, this invention is directed to our discovery of a novel injectable liquid Pmholi7ing composition comprising an ethylene vinyl alcohol copolymer dissolved in dimethylsulfoxide or other suitable bioco..lpatible solvent and a water insoluble contrast agent SPlP~t~d from 25 t~nt~ll-m, t~nt~lllm oxide, or barium sulfate.
Accordingly, in one of its co",posiLion aspects, this invention is directed to an embolizing composition comprising:
W O 97/04656 PCT~US96/12435 (a) from about 2.5 to about 8 weight percent of an ethylene vinyl alcohol copolymer çmholi7ing agent;
(b) from about 10 to about 40 weight percent of a water in.~nlnble Contr~t agent sPhP~te~l from the group con~i~ting of t~nt~lnm, 5 t~nt~lllm oxide and barium sulfate;
(c) from about 52 to about 87.5 weight percent of a bioco...~ ;hlP solvent wl.clcin the weight percent of each of the components is based on the total weight of the cornrlPtP composition.
In one of its method aspects, this invention is directed to a method for embolizing a blood vessel by injecting into said blood vessel a s--ffi~iPnt ~mol-nt of an embolizing co...~,o:jilion compri~ing:
(a) from about 2.5 to about 8 weight percent of an ethylene vinyl alcohol copolymer emboli_ing agent;
(b) from about 10 to about 40 weight percent of a water insoluble c~ntr~t agent se-lP~tPd from the group cQ~ ting of t~nt~lllm, t~nt~lllm oxide and barium sulfate;
(c) from about 52 to about 87.5 weight percent of a bioco~ ;ble solvent wherein the weight percent of each of the con.ponents is based on the total weight of the complete composition under con~litinn~ wherein a ~ ip;~te is formed which embolizes the blood vessel.
In a plerellcd emb~limPnt the molecular weight of the ethylene vinyl alcohol copolymer col"~osi~ion is SPlP~tP~i such that a solution of 6 weight percent of the ethylene vinyl alcohol composition, 35 weight percent of a t~nt~l-lm contrast agent in DMSO has a viscosity equal to or less than 60 centipoise at 20~C and more preferably 40 ccnlil)oise or less at 20~C.
In another p~c;r~ d embo ~iment, the ethylene vinyl alcohol copolymer W O 97/04656 PCT~US96/lZ435 comrositinn comprises from about 25 to about 60 mole percent of ethylene and from about 40 to about 75 mole percent of vinyl alcohol.
~ereldbly, the biocG.~ atible solvent is dimethylsulfoxide.
,, DETA~ l~n DESCRIPTION OF l~E INVENTION
This invention is dilc;~;~d to spe~ific embolizing comro~citi~nc comrricing a sre~-ific embolizing agent, cre~ific con~ct agents and a bioco~ atible solvent.
Prior to ~i~cu~ing this invention in further detail, the following terms will first be dt--fined The term "embolizing" as used in conjunction with "embolizing co,~l~,oc;l;~ nc" and "emh~1i7ing agents" refers to a process wherein a m~t~ri~1 is injected into a blood vessel which th-lcaÇl~r fills or plugs the blood vessel and/or enc~uldges clot form~tion so that blood flow ll-l~ugh the vessel ceases. The emb~1i7~ti~ n of the blood vessel is im~l~ in preventing/controlling bleeding (e.g., organ bleeding, ga~ r~
bl~lin~, vascular b1ee~ling, bleeding ~csoci~t~ with an aneurysm) or to ablate .licP~c~ tissue (e.g., tumors, etc.) by cutting off its blood supply.
The term "ethylene vinyl alcohol copolymers" refers to copolymers cQmrricing residues of both ethylene and vinyl alcohol monomers. Small amounts (e.g., less than 5 mole percent) of additional monomers can be in~ -ie~ in the polymer structure or grafted thereon provided such litil~n~1 monomers do not alter the embolizing pr~elLies of the composition. Such ~ ition~1 monomers include, by way of example only, maleic anhydride, styrene, propylene, acrylic acid, vinyl acetate and the like.
Ethylene vinyl alcohol copolymers used herein are either c4mmP-rcially available or can be prepared by art recognized procedures.
~cr~,~bly, the ethylene vinyl alcohol copolymer coll,posiLion is s~Plected such that a soll-tion of 6 weight percent of the ethylene vinyl alcohol 5 copolymer, 35 weight percent of a t~nt~lllm c~ntraet agent in DMSO has a viscosity equal to or less than 60 cenli~ise at 20~C. As is a~c lt to one skilled in the art, with all other factors being equal, copolymers having a lower molcclll~r weight will impart a lower viscosity to the comrositinn as cc,lll~ucd to higher mnlecul~r weight copolymers. Accordingly, adj~
10 of the viscosity of the co"~posiLion as nP~P~y for ç~thPtPr delivery can be readily achieved by mere adjl~tmPnt of the mole~ul~r weight of the copolymer compo~itinn.
As is also a~ Gnl, the ratio of ethylene to vinyl alcohol in the copolymer affects the overall hyd~hobicity/hydl~hilicity of the 15 co-"l)osilion which, in turn, affects the relative water solubility/insolubility of the co~po~;l;nn as well as the rate of precipitation of the copolymer in an aqueous sQllltinll (e.g., blood). In a particularly pl~GrGlled embo limPnt the copolymers employed herein comprise a mole percent of ethylene of from about 25 to about 60 and a mole percent of vinyl alcohol of from 20 about 40 to about 75. These co~ ;l;on~ provide for requisite pla iril;~t;c)n rates suitable for use in embolizing blood vessels.
The term '~CQ~tr~t agent" refers to a radiopaque m~tPri~l capable of being monitored during injection into a m~mm5li~n subject by, for PY~mpl~, r~tliogr~phy. The term "water insoluble contrast agent" refers to 25 cont~ct agents which are e~enti~lly insoluble in water (i.e., having a water solubility of less than 0.01 mg/ml at 20~C). The water insoluble contr~t t-agents incl~lded within the scope of this invention are t~nt~lllm, t~nt~ m oxide and barium sulfate, each of which is commercially available in the W O 97/046',6 PCTrUS96/12435 proper form for in vivo inrl~ ing a particle size of about 10 ~Lm or less.
Other cont~ct agents sllit~hle for use herein include gold and pl~tinum.
a The term "biocc,~ alible solvent" refers to an organic m~tPri~l liquid at least at body le~ .dtu,c of the m~mm~l in which the ethylene 5 vinyl alcohol copolymer is soluble and, in the amounts used, is ~,..bsl~..t;~lly non-toxic. Suitable bioco---~lible solvents inclllde, by way ofeY~mple, dimethylsulfoxide, analogues/homologues of dimethylsulfoxide, and the like. Preferably, the bioco---pdlible solvent is dimethylsulfoxide.
The term Nencaps~ tion" as used relative to the contrast agent being 10 ~n~ trA in the ~reril);l~tP is not meant to infer any physical e -L-d~---ent of the contract agent within the pl~;pil~le much as a capsule enr~rs~ t~s a m~Air~mrnt Rather, this term is used to mean that the contract agent and copolymer form an integ~l coherent ple~ le which does not se;~
into a copolymer co...l~nent and a contr~ct agent co...pollel t.
15 Cc,--,~o~ilions The comrositions of this invention are ~lc~cd by conventi~
mrth~lc whereby each of the co~ ~nl~ntc is added and the res--lting co...l)osiLion mixed together until the overall composition is subst~nti~lly homogeneous. Specifically, s--ffieient amounts of the ethylene vinyl 20 alcohol copolymer are added to the bioco.l.palible solvent to achieve the effective concPntr~tit n for the complete embolizing composition.
Preferably, the embolizing composition will comprise from about 2.5 to about 8 weight percent of the ethylene vinyl alcohol copolymer composition based on the total weight of the embolizing co---posilion and more 25 preferably from about 4 to about 5.2 weight percent. If n~c~.y, gentle heating and stirring can be used to effect tliccolllti~n of the copolymer into the bioco...l.~l;hle solvent, e.g., 12 hours at 50~C.
W O 97/04656 PCT~US96/12435 S~fflciPnt amounts of the contr~t agent are then added to the bioco...l~t;blP solvent to achieve the effective conA~-ntr~tinn for the cornp'A-~e embolizing co...los;l;~n. Preferably, the embolizing cc"ll~osilion will comprise from about 10 to about 40 weight percent of the cAntr~t 5 agent and more preferably from about 20 to about 40 weight percent and even more ~Jtert~bly 35 weight percent. Insofar as the contrast agent is not soluble in the biocclll~dLible solvent, stirring is employed to effect ho...~e-~;ly of the rp~lllting s~srpn~inn. In order to Pnh~nee fonn~Atinn of the s~rPnQ;nn~ the particle size of the contr~t agent is pl~rtldlily 10 Ill~inl~ P~ at about 10 ,um or less and more preferably at from about 1 to about 5 ~m (e.g., an average size of about 2 ~m).
The particular order of ~ tion of colllpollents to the biocolllpatible solvent is not critical and stirring of the resnlting sl-spçn~inn is con~ cted as ne~.y to achieve homogeneity of the composition. Preferably, 15 mixing/stirring of the col~s;l;on is con~ctP~1 under an anhydrous atmosphere at ambient pres~ulc;. The rçs--lting colllpcsiLion is heat stPrili7f~d and then stored preferably in sealed amber bottles or vials until n~ed Methods The co",~o~iLions described above are then employed in methods for embolizing ~ n blood vessels. Spe~-ifi~ lly, a snfficient amount of this composition is introduced into the sPlP~ted blood vessel by co"v~ l;nn~l means (e.g., injection or c~th~tt-r delivery under fluoroscopy) so that upon ~ on of the ethylene vinyl alcohol copolymer, the blood vessel is embolized. The particular amount of embolizing composition employed is dictated by the total volume of the v~c~ t--re to be embolized, the concentration of copolymer in the composition, the rate of pl~;p;l~;on (solids formation) of the copolymer, etc. Such factors are well within the skill of the art. The rate of ~l~ipiLation can be controlled by ~h~n~in,~ the overall hydr~)hobicity/hydrophilicity of the copolymer with faster pr~;~ ; tion rates being achieved by a more hydrophobic o copolymer cc,~ ion which, in turn, can be achieved by increasing the ethylene content of the copolymer composition.
One particularly prer~.led method for delivering the embolizing col~ n~ of this invention to the sPl~ted vascular site is via a small .... t~ . m~ic~l c~ . The particular c~theter employed is not critical provided that polymeric c~th~ter con,pol-ents are co~ )atible with the embolizing co--~po~ilion (i.e., the c~thett--r co~ onents will not readily 10 tlP~ l.o in the embolizing co~ osition). In this regard, it is pl~rell~d to use polyethylene in the c~thet~r co"~ ents because of its inertness in the ~;sence of the ~mboli~in~ co--l~osiLion described herein. Other m~t~.ri~l~
~",~aLible with the embolizing cG,,,posili~n~ can be readily determined by the skilled artisan and incl~lde, for eY~mrl~, other polyolefins, 15 iluolul)olymers (e.g., TeflonTM), silicone, etc.
When delivered by c~th~ter, the injection rate ~lict~t~s, in part, the form of the ~ at the vascular site. Spes-ific~lly, low injection rates of a~ Xim~t~ly 0.05 to 0.3 cc/minute will provide for a ~r~;pil~l~ in the form of a kernel or nodule which is particularly benlofici~l for site specifi 20 embolization bec~ e the l. ~s~ P forms prim~rily at the point of injection. Contr~rily~ high injection rates of about 0.1 to 0.5 or more cc/several s~on~l~ (e.g., up to ten seconds) will provide for a fil~m.ont like mass projecting down stream from the c~thete tip which is particularly bent~-fici~l for providing the embolizing agent deep into the vascular tree.
25 Such procedures are suitable for embolizing tumor masses, organs and arteriovenous malformations (AVM).
When introduced into the vascular site, the biocolllpaLible solvent diffuses rapidly into the blood and a solid pre5-ipit~te forms which W O 97/04656 PCT~US96/12435 preriritAtP is the ethylene vinyl alcohol copolymer with the contrast agent enc~rslllAt~A therein. Without being limited to any theory, it is believed that initially, a soft gel to spongy solid ~lccip;~A~e forms upon contact with the blood which ~ )ilAte is open and fibrous in structure. This 5 ~rec;l.ilAte then restricts blood flow, enlld~ g red cells thereby causing clot emholi7Ati~n of the blood vessel.
Utility The col-lpo-~ n~ described herein are useful in embolizing m~mmAliAn blood vessels which, in turn, can be used to prevent/control 10 bleeding (e.g., organ b1ePA;ng, gasL~ f ~ Al hlPPAing, vascular ble ding, blPeAing A~c;~A with an ant;uly~l,l) or to ablate ~ PA~PC1 tissue (e.g., tumors, etc.). Accoldingly, these colll~o~;l;nn~ find use in human and other mAmmAli~n subjects l~uiling embolization of blood vessels.
~d~lition~lly~ these compositions provide an a~lu~liate vehicle for 15 the delivery of a medicament to the vascular site. Spe~ifi~lly, a s-litAhle mPAiCAmPnt e.g., a chemotheldl~eulic agent, growth factor agents, anti-inflA~ Alo~ y agents, anti-s~mAtic agents, etc. which are compatible with the embolizing collll)osiLion can be in~ dPA in this composition in th~.Al~-l;C levels and delivered directly to the vascular site.
The following eYAmrles are set forth to illustrate the cl~imPA
invention and are not to be construed as a limit~tinn thereof.
EXAMPLES
Unless otherwise stated, all tell-~ldlu~es are in degrees Celsius.
Also, in these eyAmrl~s~ unless otherwise defined below, the abbreviations employed have their generally accepted m~Aning cc = cubic cPntimPtP~r DMSO = dimethylsulfoxide EVOH = ethylene vinyl alcohol copolymer gm = gram mL = millilitPrs mm = millimPt.or psi = pounds per square inch FY7/mple 1 The l~ul~ose of this eY~mple is to ~çmon~tr~t~p the suitability of 10 ethylene vinyl alcohol copolymer co~ ;I;nn~ in DMSO as em~olizing agents. The tests were cnn~luctP~ by addition of the copolymer solution into saline and d~;Lt;~ illg the plc~ ;on parameters. Rapid formation of a coherent l ~c~ip;li~l;on evidences suitability of the copolymer ~ osiLion as an embolizing agent.
Spe~ifi~lly~ five ethylene vinyl alcohol copolymer resins were employed of varying con~Pntr~tion~ - 27, 32, 38, 44 and 48 mole percent ethylene (available from EVAL Co",l)a.,y of ~mer~ Lisle, Tllinoi~, USA) having a viscosity grade as defined by a melt index of about 4-15 (gm/10 -s) at 210~C. The resin a~pe~ as clean, trAn~ cent cylin~lrir~l 20 particles about 1 x 2 mm. S~mplPs were pre~aled at 5.2% concPntrAtiQn in DMSO (obtained from Aldrich ChP-mi~ l Company, Milwaukee, Wi~con~in, USA as M8180-2, 99+ % purity). Di~ol~ltinn was complete within 24 hours at 52~C.
Approxim~tP~y 0.1 to 0.5 mL of each solution was added by 25 needle/syringe to a normal saline solution at 37~C or at room k;".~ldture.
All five samples immP~ tPly ge~nP~tP~l a white mass or string of polymer upon contact with saline. As the ethylene content in the sample increased, the res--lting ~JleCi~)itdtt; was whiter, tougher and more dense. The two W O 97/04656 PCT~US96/12435 lowest ethylene content resins a~ared to yield a weaker, more gelatinous mass, which nevertheless were suitable for use as embolizing agents.
Accordingly, these results in~ t~o that EVOH copolymers are snit~hle embolizing agents.
S Flow rates were ~SP~Pd for each of these s~mplPs at 10 psi and 37~C over 3 "~ ,t~ s using a 3 French Infusion c~thPtPr (available from Micro Th~ ;r-s, Inc., Aliso Viejo, California, USA) in order to assess suitability for C~thPtPr delivery of these composition~ to the vascular site.
The results of this analysis are set forth in Table I below:
TABLE I
Ethylene ContPnt inFlow Rate EVOH Copolymer 27% 0.22 cc/min 32% 0.25 cc/min lS 38% 0.20 cc/min 44 % 0.25 cc/min 48% 0.30 cc/min The above results in-lic~tP that these composition~ possess flow rates ~-lit~hlP for c~thtotPr delivery to the vascular site. These results also 20 suggest that preferable results are achieved using a more hydrophobic EVOH composition (e.g., about 48 mole % ethylene content) at a con~PntrAtion of about 2.5 to about 8.0 weight percent.
Example 2 W O 97/04656 PCTrUS96/12435 The ~ull~ose of this eY~mple is to illustrate that not all polymers are suitable as embolizing agents. Sperific~lly, in this eY~mple, the EVOH
copolymers desr-rihe~ above were replaced with polyufe:~halle (DOW
PELLETHANE 2363-80A, Dow Ch~mi~l Co~ y, Mi~ ntl, Mil~.hig~n, S USA), poly~ ylmPth~crylate (available from Rohm & Haas, Phil~delrhi~ Pe;~ sylvania, USA), polycarbonate (MOBAY MAKROLON
2558-1112, Mobay ChPmi~l Co---pally, Bayer Inc., Pil~l ul~h, Pennsylv;~ia, USA), two dirr~ t cell~ se (li~ret~tps [CP11I11O~P Acetate NF CA 320-S (~32% acetyl content) and ~e~ s~ Acetate NF CA 398-10 10 (--39.8 acetyl content) both available from FMC Corp., Pharm~euti~
Division, Phil~lPlphia, Pennsylvania, USA)] and cP~ lose tri~cet~te (C~ se Acetate NF CA 435-75S (~43.5% acetyl content) -- FMC
Corp., Pharm~uti~l Division, phil~ )hi~ Pennsylvania, USA).
The results of this analysis inrli~t~l that polyurell-alle ~mpl~s were 15 slow to dissolve in DMSO at 52~C and, upon cooling to room ~e~ e, formed a high viscosity sollltinnlgel nn~llit~hle for injection. In the case of the polymethylm~th~-rylate, the polymer dissolved in DMSO but the .~-il,il~le formed upon ~ ition to saline was lln~nit~hle for use as an embolizing agent because it lacked cohesiveness and easily fr~gmpn~çd In 20 the case of the poly~l,olla~e, the polymer failed to dissolve in DMSO at 52~C over 3 days. The c~-lll-lose tri~ePte sample provided too high a viscosity for effective delivery via a c~thPt~r at a concentration s~fficie-nt to effectively embolize a blood vessel and reduction of the conce-ntration to less than 2.5 weight percent resulted in ~l~ ipili1t~ formation which was 25 un~lit~hle for vascular embolization. Only the celll~lnse ~ et~ttos provided suitability for vascular emboli7~tion in a manner similar to EVOH
and the use of such polymers as embolizing agents is described in further detail in U.S. Patent Application Serial No. filed con~;u,lc;lllly herewith as Attorney Docket No. 018413-003 entitled "CELLULOSE
30 DIACETATE CO~aPOSlTl~LS FOB USE IN EMBOLIZING BLOOD
WO 97/04656 PCT~US96/12435 VF.~.SF-T~~" which app1ir~tion is incorporated herein by reference in its cn~lcly.
FY,~rle 3 The yulyOSc of this example is to co..lpale in vitro results achieved S by ih~colpn~ a water soluble cQntr~ct agent and a water incolllbl~P
cont~ct agent of this invention into an embolizing composition co.~ hiii-g EVOH in DMSO. .Syerifir~lly~ in this eY~mple, an EVOH col--yosiLion (44 mole percent ethylene) was dissolved into DMSO to provide for an 6.8 weight percent co~-ce~.L~Lion of the copolymer in DMSO. To this sQluti~m 10 was added either t~nt~lum (10 weight percent, available from Leico ~nllnctriPs, New York, New York, USA, 99.95% purity, less than 43 ~Lm in size) as a water insoluble contrast agent or metri7~mi~1ç (38.5 weight percent, available from Aldrich ChPmi~l Company, Milwaukee, Wicr-oncin, USA) as a water soluble contr~ct agent. Rer~llse these results 15 are in ~vitro results, the t~nt~l-lm particle size is not LlyOlL~It and the larger particles size is not c;~ye~iled to affect these results.
In the t~nt~lllm co~poc;l;on~ t~nt~lum settling can result from prolcnge l st~nrling. Srnifir~tion may help but thorough mixing prior to use is required.
Approxim~tPly 0.2 mL of the each composition was then added by syringe/needle to a saline solution at 37~C and the char~-tericti~s of the rçs--ltin~ ylc~'ip;l~ç eY~minPIl In the case of the tantalum ~mplP, a precipitate immP~i~tely formed which was çh~ tPri7P~I by firm spongy 25 fil~mPntc and nodlllPs The metri7~mide sample on the other hand did not form a well defined solid mass as the mçtri7~mide rapidly diffused away.
_ W O 97/04656 PCT~US96/12435 Example 4 The pu-~ose of this PY~mple is to illl-ctr~te that certain embolizing agent/c~nt~ct agent combin~tinnc provide for physical pro~cllies which makes injection of the comhin~tion into vascular sites .cignifit~ntly more 5 ~iffie llt Spe~-ifi~lly, in this eY~mrle, a col.")osilion compricin~ 6.8 weight pc~ l of EVOH (44 mole percent ethylene) in DMSO was p~c;~u~l. The viscosity of this cGIll~?osilion was al)pn"~ ely 60 c~ e at 20~C. Upon ~drlitinn of 38.5 weight ~.;cll~ of m~.~.;,i...~irl~
to this cGI~l~osi~ion, the viscosity increased cignifi~ntly to a~;~p~...;m~t~ly 145 ce--l;~ e at 20~C.
t~s)ntr~rily, the addition of 35 weight percent of t~nt~lllm or barium sulfate to a similar EVOH/DMSO co",posi~ion did not m~tP.ri~lly alter the viscosity of the co,--~)osiLion.
The above results intlic~te that the use of t~nt~ m as the contr~ct 15 agent provides for cG---l)osi~ions with cignific~ntly lower viscosity than those employing mPtri7~mi-1e. In turn, such lower vi.ccociti~s render the co...~osil;nn.c easier to deliver either by injection or by c~thPt~r to the vascular site thereby ~,~,lionally redur-ing the lik.o.lihood of vascular inJury.
FY~mrle 5 The ~ull~ose of this eY~mple is to illustrate an in vivo applic~tion of the embolizing composition of this invention.
In this eY~mrle, a 50 pound male hound was plcpalcd for blood vessel emboli7~tinn using an embolic composition comprising 5.8 weight pcl~n~ EVOH polymer (col.ti~in;ng 48 weight percent ethylene), 20 weight pel~nl t~nt~lllm in DMSO was loaded into a syringe. Embolization of the left kidney proceeded by p~ .mlo.nt of a 3F micro c~theter into the kidney WO 97/046S6 PCT~US96/12435 through a SF AngioDynamics ~ hllnt~r c~thPtPr. The c~theter was advanced into the renal artery, flushed with cnntr~t agent to identify the 1t c~tion and then flushed with DMSO, followed by 0.3 cc of the EVOH
co...po~;l;on ~es-rihe~ above, followed yet by more DMSO within the S c~thPter. The EVOH co...po~ n was quickly injected into the renal artery. After delivery of about 0.2 cc of EVOH composition, the upper pole of the kidney was blocked. Delivery of the ~ h~ g EVOH
co...l o~;l;on resulted in the entire kidney being embolized.
The above results indic~te that the coll.po~i~ions of this invention are 10 suitable for in YiYo emboli7~tion of blood vessels in m~mm~ n subjects.
From the l'olegoing description, various mo~lifi~tions and changes in the c-....l o~;l;on and method will occur to those skilled in the art. All such morlifir~tion~ coming within the scope of the appended claims are intende~l to be inrlllded therein.
Claims (15)
1. A composition comprising:
(a) from about 2.5 to about 8.0 weight percent of an ethylene vinyl alcohol copolymer embolizing agent;
(b) from about 10 to about 40 weight percent of a water insoluble contrast agent selected from the group consisting of tantalum, tantalum oxide and barium sulfate;
(c) from about 52 to about 87.5 weight percent of a biocompatible solvent wherein the weight percent of each of the components is based on the total weight of the complete composition.
(a) from about 2.5 to about 8.0 weight percent of an ethylene vinyl alcohol copolymer embolizing agent;
(b) from about 10 to about 40 weight percent of a water insoluble contrast agent selected from the group consisting of tantalum, tantalum oxide and barium sulfate;
(c) from about 52 to about 87.5 weight percent of a biocompatible solvent wherein the weight percent of each of the components is based on the total weight of the complete composition.
2. The composition according to Claim 1 wherein said ethylene vinyl alcohol copolymer comprises from about 25 to about 60 mole percent of ethylene and from about 40 to about 75 mole percent of vinyl alcohol.
3. The composition according to Claim 2 wherein said biocompatible solvent is DMSO.
4. The composition according to Claim 3 wherein said contrast agent is tantalum.
5. The composition according to Claim 3 wherein said contrast agent is tantalum oxide.
6. The composition according to Claim 3 wherein said contrast agent is barium sulfate.
7. A method for embolizing a blood vessel by injecting into said blood vessel a sufficient amount of an embolizing composition comprising:
(a) from about 2.5 to about 8.0 weight percent of an ethylene vinyl alcohol copolymer embolizing agent;
(b) from about 10 to about 40 weight percent of a water insoluble contrast agent selected from the group consisting of tantalum, tantalum oxide and barium sulfate;
(c) from about 52 to about 87.5 weight percent of a biocompatible solvent wherein the weight percent of each of the components is based on the total weight of the complete composition under conditions wherein a precipitate is formed which embolizes the blood vessel.
(a) from about 2.5 to about 8.0 weight percent of an ethylene vinyl alcohol copolymer embolizing agent;
(b) from about 10 to about 40 weight percent of a water insoluble contrast agent selected from the group consisting of tantalum, tantalum oxide and barium sulfate;
(c) from about 52 to about 87.5 weight percent of a biocompatible solvent wherein the weight percent of each of the components is based on the total weight of the complete composition under conditions wherein a precipitate is formed which embolizes the blood vessel.
8. The method according to Claim 7 wherein said ethylene vinyl alcohol copolymer comprises from about 25 to about 60 mole percent of ethylene and from about 40 to about 75 mole percent of vinyl alcohol.
9. The method according to Claim 8 wherein said biocompatible solvent is DMSO.
10. The method according to Claim 9 wherein said contrast agent is tantalum,
11. The method according to Claim 9 wherein said contrast agent is tantalum oxide.
12. The method according to Claim 9 wherein said contrast agent is barium sulfate.
13. The method according to Claim 7 wherein the embolizing composition is injected into the blood vessel at a rate of about 0.05 to 0.3 cc/minute.
14. The method according to Claim 7 wherein the embolizing composition is injected into the blood vessel at a rate of at least 0.6 cc/minute.
15. The method according to Claim 14 wherein the injection rate of at least 0.6 cc/minute is employed to form a filament like mass projecting down stream from the catheter tip for embolizing tumor masses, organs and arteriovenous malformations (AVM).
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|---|---|---|---|
| US08/507,863 | 1995-07-27 | ||
| US08/507,863 US5667767A (en) | 1995-07-27 | 1995-07-27 | Compositions for use in embolizing blood vessels |
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| CA2215272A1 true CA2215272A1 (en) | 1997-02-13 |
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| CA002215272A Abandoned CA2215272A1 (en) | 1995-07-27 | 1996-07-29 | Novel compositions for use in embolizing blood vessels |
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|---|---|
| US (2) | US5667767A (en) |
| EP (1) | EP0841854B1 (en) |
| JP (1) | JP4240533B2 (en) |
| AT (1) | ATE216602T1 (en) |
| AU (1) | AU6604296A (en) |
| CA (1) | CA2215272A1 (en) |
| DE (1) | DE69620886T2 (en) |
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| WO (1) | WO1997004656A1 (en) |
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| JP3203382B2 (en) * | 1992-03-13 | 2001-08-27 | 国立循環器病センター総長 | Polymer solution for artificial emboli formation |
| JP2736339B2 (en) * | 1992-09-30 | 1998-04-02 | 株式会社日本感光色素研究所 | Liquid embolic material for aneurysms |
| US5443454A (en) * | 1992-12-09 | 1995-08-22 | Terumo Kabushiki Kaisha | Catheter for embolectomy |
-
1995
- 1995-07-27 US US08/507,863 patent/US5667767A/en not_active Expired - Lifetime
-
1996
- 1996-07-29 WO PCT/US1996/012435 patent/WO1997004656A1/en active IP Right Grant
- 1996-07-29 JP JP50784197A patent/JP4240533B2/en not_active Expired - Lifetime
- 1996-07-29 AU AU66042/96A patent/AU6604296A/en not_active Abandoned
- 1996-07-29 EP EP96925567A patent/EP0841854B1/en not_active Expired - Lifetime
- 1996-07-29 ES ES96925567T patent/ES2175113T3/en not_active Expired - Lifetime
- 1996-07-29 CA CA002215272A patent/CA2215272A1/en not_active Abandoned
- 1996-07-29 AT AT96925567T patent/ATE216602T1/en active
- 1996-07-29 DE DE69620886T patent/DE69620886T2/en not_active Expired - Lifetime
-
1997
- 1997-02-14 US US08/800,677 patent/US5851508A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997004656A1 (en) | 1997-02-13 |
| EP0841854A4 (en) | 2000-01-26 |
| US5851508A (en) | 1998-12-22 |
| ES2175113T3 (en) | 2002-11-16 |
| JP4240533B2 (en) | 2009-03-18 |
| US5667767A (en) | 1997-09-16 |
| DE69620886T2 (en) | 2002-11-14 |
| EP0841854B1 (en) | 2002-04-24 |
| DE69620886D1 (en) | 2002-05-29 |
| EP0841854A1 (en) | 1998-05-20 |
| JP2000502321A (en) | 2000-02-29 |
| AU6604296A (en) | 1997-02-26 |
| ATE216602T1 (en) | 2002-05-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |