WO2014009674A1 - Bone substitute composition - Google Patents
Bone substitute composition Download PDFInfo
- Publication number
- WO2014009674A1 WO2014009674A1 PCT/FR2013/051683 FR2013051683W WO2014009674A1 WO 2014009674 A1 WO2014009674 A1 WO 2014009674A1 FR 2013051683 W FR2013051683 W FR 2013051683W WO 2014009674 A1 WO2014009674 A1 WO 2014009674A1
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- WO
- WIPO (PCT)
- Prior art keywords
- solid phase
- composition according
- syringe
- liquid phase
- particles
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 121
- 239000000316 bone substitute Substances 0.000 title claims abstract description 66
- 239000007790 solid phase Substances 0.000 claims abstract description 79
- 239000002245 particle Substances 0.000 claims abstract description 46
- 239000007791 liquid phase Substances 0.000 claims abstract description 40
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 30
- 239000001506 calcium phosphate Substances 0.000 claims abstract description 23
- 229910000389 calcium phosphate Inorganic materials 0.000 claims abstract description 23
- 235000011010 calcium phosphates Nutrition 0.000 claims abstract description 23
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims abstract description 23
- ZOMBKNNSYQHRCA-UHFFFAOYSA-J calcium sulfate hemihydrate Chemical compound O.[Ca+2].[Ca+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O ZOMBKNNSYQHRCA-UHFFFAOYSA-J 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000004014 plasticizer Substances 0.000 claims abstract description 12
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 11
- 239000003708 ampul Substances 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229920001249 ethyl cellulose Polymers 0.000 claims description 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
- 239000010440 gypsum Substances 0.000 claims description 4
- 229910052602 gypsum Inorganic materials 0.000 claims description 4
- 229920000609 methyl cellulose Polymers 0.000 claims description 4
- 239000001923 methylcellulose Substances 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 238000009826 distribution Methods 0.000 claims description 3
- 239000008240 homogeneous mixture Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000011159 matrix material Substances 0.000 claims description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 2
- 229930182566 Gentamicin Natural products 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- BAQCROVBDNBEEB-UBYUBLNFSA-N Metrizamide Chemical compound CC(=O)N(C)C1=C(I)C(NC(C)=O)=C(I)C(C(=O)N[C@@H]2[C@H]([C@H](O)[C@@H](CO)OC2O)O)=C1I BAQCROVBDNBEEB-UBYUBLNFSA-N 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 229920006217 cellulose acetate butyrate Polymers 0.000 claims description 2
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 150000001879 copper Chemical class 0.000 claims description 2
- 229960002518 gentamicin Drugs 0.000 claims description 2
- 239000003102 growth factor Substances 0.000 claims description 2
- 229920002674 hyaluronan Polymers 0.000 claims description 2
- 229960003160 hyaluronic acid Drugs 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- BDAGIHXWWSANSR-NJFSPNSNSA-N hydroxyformaldehyde Chemical compound O[14CH]=O BDAGIHXWWSANSR-NJFSPNSNSA-N 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 claims description 2
- 229960001025 iohexol Drugs 0.000 claims description 2
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 claims description 2
- 229960004647 iopamidol Drugs 0.000 claims description 2
- 229960000554 metrizamide Drugs 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 235000011151 potassium sulphates Nutrition 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 150000003378 silver Chemical class 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229910000018 strontium carbonate Inorganic materials 0.000 claims description 2
- 159000000008 strontium salts Chemical class 0.000 claims description 2
- 229960004989 tetracycline hydrochloride Drugs 0.000 claims description 2
- 229960000707 tobramycin Drugs 0.000 claims description 2
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 claims description 2
- -1 vinyl alcohols Chemical class 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- PASHVRUKOFIRIK-UHFFFAOYSA-L calcium sulfate dihydrate Chemical compound O.O.[Ca+2].[O-]S([O-])(=O)=O PASHVRUKOFIRIK-UHFFFAOYSA-L 0.000 claims 2
- 229960002900 methylcellulose Drugs 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 15
- 238000012360 testing method Methods 0.000 description 13
- 239000007972 injectable composition Substances 0.000 description 9
- 239000008187 granular material Substances 0.000 description 7
- 235000011132 calcium sulphate Nutrition 0.000 description 6
- 238000002513 implantation Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 230000006835 compression Effects 0.000 description 5
- 238000007906 compression Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000012530 fluid Substances 0.000 description 4
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 239000001175 calcium sulphate Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000011837 pasties Nutrition 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000012798 spherical particle Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002324 minimally invasive surgery Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
-
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
-
- 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
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Definitions
- the present invention relates to a bone substitute composition, injectable and / or moldable.
- Injectable bone substitute compositions now represent a considerable part of the bone substitutes market. They are bioactive, absorbable and have a catch effect.
- compositions adapt perfectly to the forms of bone deficiencies.
- the blocks must be reshaped to correspond approximately to that of the gap to fill.
- the pellets are stacked randomly to fill the gap.
- the newly formed bone stabilizes only after several months in the bone gap.
- the present invention provides a bone substitute composition that perfectly fulfills these objectives.
- the bone substitute composition according to the invention is cohesive and easily injectable and / or moldable (as needed). It also has the advantage of having a working time, a hardening time and a setting time adapted to surgical needs, namely a working time preferably greater than 4 minutes (that the composition is injectable or moldable), or even at 10 minutes when it is an injectable composition, for a curing time preferably less than 30 minutes (that the composition is injectable or modelable) and a setting time (VICAT) preferably less than 1 h20 (that the composition is injectable or moldable), or even 45 minutes when it is a modelable composition, it being understood that a setting time of 30 minutes can quite be obtained for an injectable composition according to the invention.
- Working time refers to the time available for the surgeon to inject the bone substitute composition into the gap before it hardens.
- the present invention firstly provides an injectable and / or moldable bone substitute composition which comprises:
- a liquid phase comprising sterilized water; a solid phase which contains:
- a solid first phase comprising:
- ⁇ optionally from 0.1 to 20% of an accelerator or a weight of setting retarder relative to the total weight of said first solid phase
- a second solid phase comprising 0.1 to 20% of at least one plasticizer by weight relative to the weight of the liquid phase, the liquid phase / solid phase ratio being between 0.1 and 0.8 ml / g, preferably between 0.4 and 0.8 ml / g (for example when it is desired to obtain an injectable composition) or else between 0.1 and 0.6 ml / g (for example when it is desired to obtain a modelable composition) or between 0.5 and 0.7 mL / g.
- injectable is meant here a composition whose physico-chemical properties (especially rheological) make it suitable (thanks in particular to sufficient fluidity) to be administered by flow, for example by means of a syringe.
- modelable refers to a malleable, pasty composition, the consistency of which is sufficiently strong and sufficiently fluid to be able to be modeled, especially manually, in any useful form, before or during the administration of the composition.
- said particles can therefore be formed solely of porous particles of calcium phosphate, or only of porous particles of human or animal (for example bovine) demineralized or non-demineralised bone, or of a mixture of phosphate particles. calcium and bone particles.
- the elements described here are valid, unless stated otherwise, for each of the three cases of particles referred to above (calcium phosphate particles, human or animal bone particles, mixture of calcium phosphate particles and particulate matter 'bone).
- said particles are, at least for a part of them, of substantially spherical shape, and are thus preferably in the form of microporous spherical particles.
- This spherical shape is entirely appropriate for the injectability of the bone substitute composition according to the invention.
- said particles are substantially all substantially spherical in shape.
- said porous particles consist essentially exclusively of calcium phosphate particles in the form of porous spherical particles.
- the particle size distribution of the particles is preferably as follows: D 10 is greater than or equal to 40 micrometers; D 50 is between 70 micrometers and 90 micrometers, and D 90 is less than or equal to 150 micrometers.
- Alpha calcium sulfate hemihydrate is in the form of a powder.
- the inventors have discovered a synergistic effect between alpha calcium sulfate hemihydrate and calcium phosphate (or bone) which is particularly advantageous for osteogenesis once the bone substitute composition according to the invention has been injected into the patient's body.
- calcium sulphate hemihydrate aipha which is in this case a powder forms around the porous particles (formed for example of calcium phosphate granules) a matrix which hardens on contact with water to form calcium sulfate dihydrate.
- the alpha calcium sulphate hemihydrate matrix is reabsorbed in a few weeks to make room to a network of interconnected pores (for example calcium phosphate) which will be a stable growth support for the neoformed bone.
- These pores are the spaces between the particles (formed for example of calcium phosphate granules) whose size is favorable for bone regrowth.
- the particles formed for example of calcium phosphate granules
- the particles being themselves microporous, once the alpha calcium sulfate hemihydrate has resorbed, the adhesion of the bone cells and their growth in the network of particles (formed for example calcium phosphate granules) are favored.
- the space between the particles (formed for example of calcium phosphate granules) will allow the osteoblasts to come and rebuild the bone inside the substitute.
- the microporosities will promote the penetration of fluids and thus the total resorption of the bone substitute in the long term.
- alpha calcium sulfate hemihydrate is combined with porous particles which are exclusively calcium phosphate particles makes it possible to overcome the need for the bone substitute composition to comprise demineralized bone. Thus it secures the safety of the bone substitute composition for the patient.
- the injectable and / or modelable bone substitute composition according to the invention advantageously has the following technical characteristics:
- a working time preferably greater than 4 minutes (the composition is injectable or moldable), or even 10 minutes when it is an injectable composition. This allows the surgeon to have enough time to shape the bone substitute and prepare the implantation site;
- a setting time preferably less than 1 h 20 (whether the composition is injectable or moldable), or even 45 minutes in the case of a moldable composition, it being understood that a setting time of about 30 minutes can be obtained for an injectable composition according to the invention;
- the compressive strength is substantially greater than 3 MPa (for an injectable composition), or even substantially greater than 10 MPa (for a moldable composition), or is approximately between 4 and
- the bone substitute according to the invention is resistant to the environment constituted by the human body (blood pressure, dissolution, disintegration by human fluids, etc.).
- Standardized water means that the water has been distilled and is sterile and at a neutral pH. This is water commonly used in the technical field of bone substitute compositions (including injectable).
- the function of the plasticizer is to modify the rheology of the bone substitute composition so as to make the composition more homogeneous and to limit the quantity of sterilized water required so that, for example, the said composition can be injected with the aid of a syringe. or modeled by hand by a surgeon.
- the addition of the plasticizer makes it possible to increase the viscosity of the bone substitute composition according to the invention. In the absence of plasticizer in the bone substitute composition according to the invention, there is a risk of segregation between the solid phase and the liquid phase. The composition may therefore not be homogeneous.
- the plasticizer is advantageously chosen from cellulose derivatives, and more preferentially from the group consisting of carboxymethylcellulose, hydroxypropyl-methylcellulose (HPMC), methylcellulose (MC), hydroxyethylcellulose (HPC), hydroxypropylcellulose, ethylcellulose (EC), cellulose acetate butyrate.
- the plasticizer may also be selected from high molecular weight alcohols such as glycerol, vinyl alcohols, stearic acid or hyaluronic acid.
- the plasticizer is hydroxy-propyl-methylcellulose (HPMC or hypromellose).
- the composition according to the invention is such that said first solid phase contains between approximately 40 and 60% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase and substantially between 40 and 60% of porous particles (of calcium phosphate and / or bone) in weight relative to the total weight of said first solid phase, whereas said second solid phase contains between approximately 2 and 20% of HPMC by weight relative to the weight of the liquid phase.
- said composition advantageously has the following characteristics:
- its first solid phase contains between approximately 40 and 60% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase
- first solid phase contains between 40 and 60% of porous particles, preferably formed of hydroxyapatite particles by weight relative to the total weight of said first solid phase
- second solid phase contains between 2 and 10% of HPMC by weight relative to the weight of the liquid phase
- liquid phase / solid phase ratio is between 0.4 and 0.8 mlJg.
- composition according to the invention which has a modelable character
- said composition advantageously has the following characteristics:
- its first solid phase contains between approximately 40 and 60% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase
- its first solid phase contains between approximately 40 and 60% of porous particles, preferably formed of hydroxyapatite particles, by weight relative to the total weight of said first solid phase
- its second solid phase contains between approximately 2 and 20% of HPMC by weight relative to the weight of the liquid phase
- liquid phase / solid phase ratio is between 0.1 and 0.6 ml / g.
- the injectable and / or moldable bone substitute composition may further comprise at least one setting accelerator as selected from sodium chloride, sodium sulfate, potassium sulfate, BMA (i.e., a mixture of gypsum and starch) or crushed gypsum or a setting retarder such as calcium sulfate dihydrate.
- at least one setting accelerator as selected from sodium chloride, sodium sulfate, potassium sulfate, BMA (i.e., a mixture of gypsum and starch) or crushed gypsum or a setting retarder such as calcium sulfate dihydrate.
- the injectable and / or sharable bone substitute composition further comprises at least one therapeutic agent.
- it is an agent having a bactericidal or bacteriostatic effect such as tetracyclines (tetracycline hydrochloride), gentamicin, tobramycin, or silver salts or copper salts. It may also be a therapeutic agent having an action on bone metabolism such as strontium salts, peptides or growth factors.
- the injectable and / or modelable bone substitute composition may also comprise at least one radio-opaque agent such as strontium carbonate, iohexol, iopamidol, or metrizamide.
- the radiopaque agent allows the bone substitute to be visible to radiology after implantation. This makes it possible to follow the resorption of the implant.
- the present invention also relates to a process for preparing the injectable and / or modelable bone substitute composition as described above, wherein said liquid phase and said solid phase are mixed so that the liquid phase / solid phase ratio is included between 0.1 and 0.8 mL / g as described above.
- the method comprises the following steps:
- a suitable amount of the liquid phase of said bone substitute composition is provided.
- an appropriate amount of the solid phase of said bone substitute composition is disposed.
- the two syringes are attached end to end using a connector.
- the syringes are arranged horizontally so that the solid phase spreads in the second syringe.
- the second syringe is vigorously agitated so as to obtain a homogeneous mixture of the solid phase and the liquid phase in the said second syringe.
- the mixture is transferred at least once from one syringe to the other, in order to perfect the homogenization of the mixture.
- the transfer is carried out three to four times.
- the system is disassembled and a needle is attached to said syringe.
- the bone substitute composition is then ready for injection.
- the bone substitute composition is thus in this advantageous variant immediately ready for injection once the mixture is complete. There is therefore no loss of time or additional manipulations for the surgeon before implantation of the bone substitute. In addition, there is no risk of external contamination.
- the injectability of the bone substitute composition is in this case advantageously easy during the first 10 minutes. This therefore leaves the surgeon a few minutes between the preparation and the injection of said bone substitute composition.
- the amount of bone substitute composition according to the invention that can be injected is for example between about 0.5 and 20 cm 3 , and for example:
- the present invention also relates to a kit for the preparation of a bone substitute composition according to the present invention as described above, said kit comprising:
- a first container for example an ampoule filled with the liquid phase of said composition
- a second container for example a syringe filled with the solid phase of said composition.
- the kit according to the invention further comprises two syringes, a syringe connector, a syringe cap, a needle and at least one ampoule of sterilized water.
- the ampoule was screwed onto the tip of an empty syringe.
- the cap of a second syringe was removed which contained the solid phase described above.
- the two syringes were attached end to end using a connector.
- the syringes were placed horizontally so that the powder is spread in the 2 nd syringe.
- the assembly consisting of the two syringes and the connector was vigorously agitated so as to obtain a homogeneous mixture of the powder and the sterilized water.
- the mixture was transferred three times from one syringe to the other. Then all the mixture was collected in a single syringe. Then both syringes were disconnected.
- a needle was screwed onto the syringe containing the mixture.
- the syringe was disposed in a support in the form of a PVC tube disposed in the compression machine and configured so that the compressive stress is applied only to the plunger of the syringe.
- Compression stress was applied to the syringe plunger with a displacement speed of 2.5 mm / min.
- the resulting force was measured as a function of time.
- the stopwatch was stopped when the force reached was 120 N (which corresponds to maximum manual human strength).
- the time thus determined by the stopwatch corresponded to the working time. There was obtained a 16 minute working time for the 1 st series of tests and 32 minutes for the 2nd series of tests.
- the working time of a bone substitute composition according to the invention subjected to a standard irradiation dose will be between about fifteen minutes and half an hour; which corresponds to a time long enough to allow the surgeon time to prepare the implantation site before injecting said bone substitute composition.
- the Vicat apparatus is equipped with a needle, on which rests a normed mass. This needle was deposited on the surface of the sample of bone substitute composition according to the invention during its setting.
- the degree of insertion of the needle into the sample made it possible to determine the progress of the setting. To do this, the samples were prepared in the same way as for measuring the working time.
- the stopwatch was triggered when the water came in contact with the powder. Once the mixture homogenized, the two syringes were disconnected.
- the bone substitute composition according to the invention was slowly poured into cells provided for this purpose, so as to avoid the formation of bubbles.
- the cells were filled to the brim.
- the Vicat setting time is the time after which the needle no longer sinks to the bottom of the sample.
- Vicat time taken for the 1 st series of tests was 51 minutes and 59 minutes for the 2 nd series of tests.
- the samples were prepared in the same manner as for the working time and setting measurements detailed above.
- the injectable bone substitute composition according to the invention was cast in previously oiled molds, so as to avoid the formation of bubbles in the mold.
- Some injectable bone substitute composition protruded out of the mold to compensate for the shrinkage.
- the surface of the injectable bone substitute composition was smoothed with abrasive paper so that the surface of the injectable bone substitute composition could be perfectly aligned with that of the mold.
- the injectable bone substitute compositions were demolded and then placed in an oven at 45 ° C for at least 12 hours. These were the samples of this experiment. The samples were taken out of the oven only when measuring the compressive strength.
- the measurement was carried out by applying a compressive stress on the sample at a speed of 1 mm / min until the sample was broken.
- the compressive strength was the maximum stress reached during the measurement.
- the compressive strength for the 1 st series of tests was 5 MPa and 6 MPa for 2 nd series of tests.
- its first solid phase contains substantially 50% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase
- its first solid phase contains substantially 50% hydroxyapatite by weight relative to the total weight of said first solid phase, in the form of porous particles,
- its second solid phase contains substantially 10% of HP C by weight relative to the weight of the liquid phase
- liquid phase / solid phase ratio is approximately 0.6 ml / g. and on the other hand a modelable composition according to the invention having the following characteristics:
- its first solid phase contains substantially 50% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase; its first solid phase contains substantially 50% hydroxyapatite by weight relative to the total weight of said first solid phase, in the form of porous particles, its second solid phase contains substantially 13.5% HPMC weight relative to the weight of the liquid phase, the liquid phase / solid phase ratio is about 0.3 mL / g.
- the invention finds its industrial application in the development, manufacture and use of bone substitutes, injectable and / or modelable.
Abstract
The invention concerns an injectable and/or modellable bone substitute composition which comprises: - a liquid phase comprising sterilised water; - a solid phase which contains: • a first solid phase comprising: ■ 10 to 90% of alpha hemihydrate calcium sulphate by weight, relative to the total weight of said first solid phase; ■ 10 to 90 % of porous particles by weight, relative to the total weight of said first solid phase, said particles being calcium phosphate and/or bone particles; • a second solid phase comprising 0.1 to 20% of at least one plasticiser by weight, relative to the weight of the liquid phase, the liquid phase/solid phase ratio being between 0.1 and 0.8 mL/g. Injectable and/or modellable bone substitute compositions.
Description
COMPOSITION DE SUBSTITUT OSSEUX BONE SUBSTITUTE COMPOSITION
DOMAINE TECHNIQUE TECHNICAL AREA
La présente invention concerne une composition de substitut osseux, injectable et/ou modelable. TECHNIQUE ANTERIEURE The present invention relates to a bone substitute composition, injectable and / or moldable. PRIOR ART
Les compositions de substitut osseux injectable représentent aujourd'hui une part considérable du marché des substituts osseux. Elles sont bioactives, résorbables et présentent un effet de prise. Injectable bone substitute compositions now represent a considerable part of the bone substitutes market. They are bioactive, absorbable and have a catch effect.
En effet, ces compositions de substituts osseux qui sont implantabies par injection répondent aux besoins de la chirurgie mini-invasive et présentent les avantages suivants : Indeed, these bone substitute compositions which are implantable by injection meet the needs of minimally invasive surgery and have the following advantages:
- Ces compositions s'adaptent parfaitement aux formes des lacunes osseuses.- These compositions adapt perfectly to the forms of bone deficiencies.
- Cela permet un contact plus étroit avec les tissus osseux et évite le déchaussement que l'on peut observer avec des blocs ou des granulés. En effet, pour être implantés, les blocs doivent être retaillés de manière à correspondre approximativement à celle de la lacune à combler. Les granulés sont empilés de manière aléatoire pour remplir la lacune. De plus, avec ces techniques de blocs ou de granulés, l'os nouvellement formé ne se stabilise qu'au bout de plusieurs mois dans la lacune osseuse. - This allows a closer contact with bone tissue and avoids loosening that can be observed with blocks or granules. Indeed, to be implanted, the blocks must be reshaped to correspond approximately to that of the gap to fill. The pellets are stacked randomly to fill the gap. In addition, with these blocking or granulating techniques, the newly formed bone stabilizes only after several months in the bone gap.
- Elles sont constituées de cristallites très fines et sont donc plus résorbables que les matériaux frittés à base de phosphate de calcium, dont les phases les plus résorbables ne se substituent qu'au bout de quelques mois. - They consist of very fine crystallites and are therefore more absorbable than sintered calcium phosphate-based materials, the most resorbable phases do not replace after a few months.
Il est possible de mélanger pendant le gâchage un principe actif comme agent de croissance ou un antibiotique. It is possible to mix during the mixing an active ingredient as a growth agent or an antibiotic.
- Elles durcissent après l'implantation, ce qui permet de les implanter par voie mini-mvasive.
Il existe des compositions de substituts osseux injectables qui sont constituées essentiellement de phosphate de calcium. Cependant, de telles compositions présentent souvent les inconvénients suivants : - They harden after implantation, which allows them to be implanted by minimally invasive methods. There are injectable bone substitutes compositions which consist essentially of calcium phosphate. However, such compositions often have the following disadvantages:
- Elles sont difficilement injectables à travers une seringue ; - Leur prise est lente pour la majorité; - They are difficult to inject through a syringe; - Their catch is slow for the majority;
- Elles ont une faible cohésion après injection dans un site ouvert, - They have a weak cohesion after injection in an open site,
- Elles sont peu recolonisées par l'os en raison de leur faible porosité ; - They are little recolonized by the bone because of their low porosity;
- Elles sont peu résorbables. - They are not absorbable.
11 existe aussi des compositions de substituts osseux injectables qui sont constituées essentiellement de sulfate de calcium. De telles compositions ont généralement une résorption trop rapide pour permettre une recolonisation du défaut osseux par l'os néoformé. A cet égard, la publication intitulée « No effect of Osteoset ®, a bone graft substitute on bone healing in humans », Acta Orthopedia, 2002, 73(5) : 575-578 de Petruskevicius détaille cet inconvénient occasionné par des compositions de substituts osseux contenant essentiellement du sulfate de calcium. En effet, la résorption du sulfate de calcium seul est trop rapide par rapport à la vitesse de repousse de l'os naturel (dans le cas de la présente invention, le tibia). En conséquence, il a été observé que le groupe de patients sans substitut osseux possédait davantage d'os naturellement renouvelé que celui dans lequel avait été implanté un substitut à base de sulfate de calcium. De la même manière, ia publication intitulée « In vivo évaluation of calcium sulfate as a bone graft substitute for lumbar spinal fusion » The Spine Journal,There are also injectable bone substitutes compositions which consist essentially of calcium sulfate. Such compositions generally have resorption too fast to allow recolonization of the bone defect by the neoformed bone. In this regard, the publication "No effect of Osteoset ®, a bone graft substitute on bone healing in humans", Acta Orthopedia, 2002, 73 (5): 575-578 of Petruskevicius details this disadvantage caused by bone substitute compositions. containing mainly calcium sulphate. Indeed, the resorption of calcium sulfate alone is too fast compared to the speed of regrowth of natural bone (in the case of the present invention, the tibia). As a result, it was observed that the group of patients without bone substitutes had more bone naturally renewed than that in which a calcium sulphate substitute had been implanted. Similarly, the publication entitled "In vivo evaluation of calcium sulfate as a substitute bone for lumbar spinal fusion" The Spine Journal,
12 Novembre 2001 , 395-401 de Paul A Glazer, démontre que le sulfate de calcium se résorbe sous 4 semaines après implantation chez le lapin et qu'aucune reconstruction osseuse n'est observée. En outre, il existe aussi des compositions de substituts osseux injectables ou pâteuses (pour application manuelle) qui comprennent de l'hémihydrate de sulfate de calcium, un agent plastifiant tel que l'HPMC et de l'os déminéralisé. November 12, 2001, 395-401 by Paul A Glazer, demonstrates that calcium sulphate reabsorb within 4 weeks after implantation in rabbits and that no bone reconstruction is observed. In addition, there are also injectable or pasty bone substitute compositions (for manual application) which include calcium sulfate hemihydrate, a plasticizer such as HPMC and demineralized bone.
La demande internationale WO-2004/000334 A1 décrit une telle composition, laquelle pourrait toutefois encore être optimisée relativement à différents paramètres de mise en
œuvre (compromis entre temps de travail/temps de prise/temps de durcissement/comportement mécanique/biorésorbabilité, etc.). The international application WO-2004/000334 A1 describes such a composition, which could, however, still be optimized with respect to various parameters of implementation. (compromise between working time / setting time / hardening time / mechanical behavior / bioabsorbability, etc.).
Il existe donc un réel besoin de disposer d'une composition de substitut osseux qui pallie l'ensemble des inconvénients détaillés ci-dessus. EXPOSE DE L'INVENTION There is therefore a real need to have a bone substitute composition that overcomes all the disadvantages detailed above. SUMMARY OF THE INVENTION
La présente invention propose une composition de substitut osseux qui remplit parfaitement ces objectifs. The present invention provides a bone substitute composition that perfectly fulfills these objectives.
En effet, la composition de substitut osseux selon l'invention est cohésive et facilement injectable et/ou modelable (selon le besoin). Elle présente en outre l'avantage de présenter un temps de travail, un temps de durcissement et un temps de prise adaptés aux besoins chirurgicaux, à savoir un temps de travail préférentiellement supérieur à 4 minutes (que la composition soit injectable ou modelable), voire même à 10 minutes lorsqu'il s'agit d'une composition injectable, pour un temps de durcissement préférentiellement inférieur à 30 minutes (que la composition soit injectable ou modelable) et un temps de prise (VICAT) préférentiellement inférieur à 1 h20 (que la composition soit injectable ou modelable), voire même à 45 minutes lorsqu'il s'agit d'une composition modelable, étant entendu qu'un temps de prise de l'ordre de 30 minutes peut tout à fait être obtenu pour une composition injectable selon l'invention. Par temps de travail, on entend le temps dont dispose le chirurgien pour injecter la composition de substitut osseux dans la lacune avant qu'elle ne durcisse.
MEILLEURE MANIERE DE REALISER L'INVENTION Indeed, the bone substitute composition according to the invention is cohesive and easily injectable and / or moldable (as needed). It also has the advantage of having a working time, a hardening time and a setting time adapted to surgical needs, namely a working time preferably greater than 4 minutes (that the composition is injectable or moldable), or even at 10 minutes when it is an injectable composition, for a curing time preferably less than 30 minutes (that the composition is injectable or modelable) and a setting time (VICAT) preferably less than 1 h20 (that the composition is injectable or moldable), or even 45 minutes when it is a modelable composition, it being understood that a setting time of 30 minutes can quite be obtained for an injectable composition according to the invention. Working time refers to the time available for the surgeon to inject the bone substitute composition into the gap before it hardens. BEST MODE OF REALIZING THE INVENTION
La présente invention a pour premier objet une composition de substitut osseux injectable et/ou modelable qui comprend : The present invention firstly provides an injectable and / or moldable bone substitute composition which comprises:
- une phase liquide comprenant de l'eau stérilisée ; - une phase solide qui contient : a liquid phase comprising sterilized water; a solid phase which contains:
• une première phase solide comprenant : A solid first phase comprising:
■ 10 à 90 % d'hémihydrate de sulfate de calcium alpha en poids par rapport au poids total de ladite première phase solide; ■ 10 to 90% calcium sulfate hemihydrate alpha by weight relative to the total weight of said first solid phase;
■ 10 à 90 % de particules poreuses en poids, par rapport au poids total de ladite première phase solide, lesdites particules étant des particules de phosphate de calcium et/ou d'os (humain ou animal); ■ 10 to 90% porous particles by weight, based on the total weight of said first solid phase, said particles being particles of calcium phosphate and / or bone (human or animal);
■ optionnellement de 0,1 à 20% d'un accélérateur ou d'un retardateur de prise en poids par rapport au poids total de ladite première phase solide ; ■ optionally from 0.1 to 20% of an accelerator or a weight of setting retarder relative to the total weight of said first solid phase;
• une deuxième phase solide comprenant 0, 1 à 20 % d'au moins un plastifiant en poids par rapport au poids de la phase liquide, le ratio phase liquide/phase solide étant compris entre 0, 1 et 0,8 mL/g, de préférence entre 0,4 et 0,8 mL/g (par exemple lorsqu'on désire obtenir une composition injectable) ou encore entre 0, 1 et 0,6 mL/g (par exemple lorsqu'on désire obtenir une composition modelable), ou encore entre 0,5 et 0,7 mL/g. A second solid phase comprising 0.1 to 20% of at least one plasticizer by weight relative to the weight of the liquid phase, the liquid phase / solid phase ratio being between 0.1 and 0.8 ml / g, preferably between 0.4 and 0.8 ml / g (for example when it is desired to obtain an injectable composition) or else between 0.1 and 0.6 ml / g (for example when it is desired to obtain a modelable composition) or between 0.5 and 0.7 mL / g.
Par « injectable » on désigne ici une composition dont les propriétés physico-chimiques (notamment rhéologiques) la rendent apte (grâce notamment à une fluidité suffisante) à être administrée par écoulement, par exemple au moyen d'une seringue. Le terme « modelable » fait quant à lui référence à une composition malléable, pâteuse, dont la consistance à la fois suffisamment solide et suffisamment fluide la rend apte à être modelée, notamment manuellement, selon toute forme utile, préalablement ou pendant l'administration de la composition.
Conformément à l'invention, lesdites particules peuvent donc être formées uniquement de particules poreuses de phosphate de calcium, ou uniquement de particules poreuses d'os humain ou animal (par exemple bovin) déminéralisé ou non, ou d'un mélange de particules de phosphate de calcium et de particules d'os. Les éléments de description exposés ici sont valables, sauf mention contraire, pour chacun des trois cas de particules visés ci-avant (particules de phosphate de calcium, particules d'os humain ou animal, mélange de particules de phosphate de calcium et de particules d'os). By "injectable" is meant here a composition whose physico-chemical properties (especially rheological) make it suitable (thanks in particular to sufficient fluidity) to be administered by flow, for example by means of a syringe. The term "modelable" refers to a malleable, pasty composition, the consistency of which is sufficiently strong and sufficiently fluid to be able to be modeled, especially manually, in any useful form, before or during the administration of the composition. According to the invention, said particles can therefore be formed solely of porous particles of calcium phosphate, or only of porous particles of human or animal (for example bovine) demineralized or non-demineralised bone, or of a mixture of phosphate particles. calcium and bone particles. The elements described here are valid, unless stated otherwise, for each of the three cases of particles referred to above (calcium phosphate particles, human or animal bone particles, mixture of calcium phosphate particles and particulate matter 'bone).
Avantageusement, lesdites particules (constituées de phosphate de calcium et/ou d:os) sont, au moins pour une partie d'entre elles, de forme sensiblement sphérique, et se présentent ainsi de préférence sous la forme de particules sphériques microporeuses. Cette forme sphérique est tout à fait appropriée pour l'injectabilité de la composition de substitut osseux selon l'invention. Advantageously, said particles (consisting of calcium phosphate and / or d : bone) are, at least for a part of them, of substantially spherical shape, and are thus preferably in the form of microporous spherical particles. This spherical shape is entirely appropriate for the injectability of the bone substitute composition according to the invention.
De préférence, afin de maximiser l'injectabilité, lesdites particules sont sensiblement toutes de forme sensiblement sphérique. De façon préférentielle, notamment lorsqu'on souhaite disposer d'une composition injectable, lesdites particules poreuses sont sensiblement exclusivement constituées de particules de phosphate de calcium se présentant sous la forme de particules sphériques poreuses. Preferably, in order to maximize the injectability, said particles are substantially all substantially spherical in shape. Preferably, especially when it is desired to have an injectable composition, said porous particles consist essentially exclusively of calcium phosphate particles in the form of porous spherical particles.
La répartition granulométrique des particules est de manière préférée la suivante : D10 est supérieur ou égal à 40 micromètres ; D50 est compris entre 70 micromètres et 90 micromètres, et D90 est inférieur ou égal à 150 micromètres. The particle size distribution of the particles is preferably as follows: D 10 is greater than or equal to 40 micrometers; D 50 is between 70 micrometers and 90 micrometers, and D 90 is less than or equal to 150 micrometers.
L'hémihydrate de sulfate de calcium alpha se présente sous la forme d'une poudre. Alpha calcium sulfate hemihydrate is in the form of a powder.
De plus, les inventeurs ont découvert un effet synergique entre l'hémihydrate de sulfate de calcium alpha et le phosphate de calcium (ou l'os) particulièrement avantageux pour l'ostéogénèse une fois que la composition de substitut osseux selon l'invention a été injectée dans le corps du patient. In addition, the inventors have discovered a synergistic effect between alpha calcium sulfate hemihydrate and calcium phosphate (or bone) which is particularly advantageous for osteogenesis once the bone substitute composition according to the invention has been injected into the patient's body.
Plus précisément, lors de la préparation du mélange des composés de la phase solide dans la phase liquide, l'hémihydrate de sulfate de calcium aipha qui est en l'espèce une
poudre forme autour des particules poreuses (formées par exemple de granules de phosphate de calcium) une matrice qui durcit au contact de l'eau en formant du dihydrate de sulfate de calcium. Après administration (par exemple injection) de la composition selon l'invention, et du fait des vitesses de résorption différentes de l'hémihydrate de sulfate de calcium alpha d'une part et du phosphate de calcium ou de l'os d'autre part (l'hémihydrate de sulfate de calcium alpha se résorbe en quelques semaines alors que par exemple le phosphate de calcium se résorbe au bout d'une année), la matrice d'hémihydrate de sulfate de calcium alpha se résorbe en quelques semaines pour laisser place à un réseau de pores interconnectés (par exemple de phosphate de calcium) qui va être un support de croissance stable pour l'os néoformé. Ces pores sont les espaces entre les particules (formées par exemple de granules de phosphate de calcium) dont la taille est propice à la repousse osseuse. More specifically, during the preparation of the mixture of the compounds of the solid phase in the liquid phase, calcium sulphate hemihydrate aipha which is in this case a powder forms around the porous particles (formed for example of calcium phosphate granules) a matrix which hardens on contact with water to form calcium sulfate dihydrate. After administration (for example injection) of the composition according to the invention, and because of the resorption rates different from alpha calcium sulfate hemihydrate on the one hand and calcium phosphate or bone on the other hand (Alpha calcium sulphate hemihydrate reabsorbs in a few weeks, while for example calcium phosphate resorbs after one year), the alpha calcium sulphate hemihydrate matrix is reabsorbed in a few weeks to make room to a network of interconnected pores (for example calcium phosphate) which will be a stable growth support for the neoformed bone. These pores are the spaces between the particles (formed for example of calcium phosphate granules) whose size is favorable for bone regrowth.
De plus, les particules (formées par exemple de granules de phosphate de calcium) étant eux-mêmes microporeuses, une fois l'hémihydrate de sulfate de calcium alpha résorbé, l'adhésion des cellules osseuses et leur croissance dans le réseau de particules (formées par exemple de granules de phosphate de calcium) sont favorisées. In addition, the particles (formed for example of calcium phosphate granules) being themselves microporous, once the alpha calcium sulfate hemihydrate has resorbed, the adhesion of the bone cells and their growth in the network of particles (formed for example calcium phosphate granules) are favored.
En d'autres termes, l'espace entre les particules (formées par exemple de granules de phosphate de calcium) permettra aux ostéoblastes de venir reconstruire l'os à l'intérieur du substitut. Les microporosités favoriseront la pénétration des fluides et donc la résorption totale du substitut osseux à long terme. In other words, the space between the particles (formed for example of calcium phosphate granules) will allow the osteoblasts to come and rebuild the bone inside the substitute. The microporosities will promote the penetration of fluids and thus the total resorption of the bone substitute in the long term.
Le mode de réalisation avantageux où l'hémihydrate de sulfate de calcium alpha est associé avec des particules poreuses qui sont exclusivement des particules de phosphate de calcium permet de s'affranchir de la nécessité que la composition de substitut osseux comprenne de l'os déminéralisé. Ainsi cela sécurise l'innocuité de la composition de substitut osseux pour le patient. The advantageous embodiment where alpha calcium sulfate hemihydrate is combined with porous particles which are exclusively calcium phosphate particles makes it possible to overcome the need for the bone substitute composition to comprise demineralized bone. Thus it secures the safety of the bone substitute composition for the patient.
Aussi, la composition de substitut osseux injectable et/ou modelable selon l'invention présente avantageusement les caractéristiques techniques suivantes : Also, the injectable and / or modelable bone substitute composition according to the invention advantageously has the following technical characteristics:
- Un temps de travail préférentiellement supérieur à 4 minutes (que la composition soit injectable ou modelable), voire même à 10 minutes lorsqu'il s'agit d'une composition injectable. Cela permet au chirurgien de disposer de
suffisamment de temps pour mettre en forme le substitut osseux et préparer le site d'implantation ; - A working time preferably greater than 4 minutes (the composition is injectable or moldable), or even 10 minutes when it is an injectable composition. This allows the surgeon to have enough time to shape the bone substitute and prepare the implantation site;
- Un temps de prise (VICAT) préférentiellement inférieur à 1 h20 (que la composition soit injectable ou modelable), voire même à 45 minutes lorsqu'il s'agit d'une composition modelable, étant entendu qu'un temps de prise d'environ 30 minutes peut tout à fait être obtenu pour une composition injectable selon l'invention ; A setting time (VICAT) preferably less than 1 h 20 (whether the composition is injectable or moldable), or even 45 minutes in the case of a moldable composition, it being understood that a setting time of about 30 minutes can be obtained for an injectable composition according to the invention;
- La résistance à la compression est sensiblement supérieure à 3 MPa (pour une composition injectable), voire même sensiblement supérieure à 10 MPa (pour une composition modelable), ou encore est environ comprise entre 4 et- The compressive strength is substantially greater than 3 MPa (for an injectable composition), or even substantially greater than 10 MPa (for a moldable composition), or is approximately between 4 and
8 MPa : le substitut osseux selon l'invention résiste à l'environnement constitué par le corps humain (pression sanguine, dissolution, désintégration par les fluides humains...). 8 MPa: the bone substitute according to the invention is resistant to the environment constituted by the human body (blood pressure, dissolution, disintegration by human fluids, etc.).
Par « eau stérilisée », on entend que l'eau a été distillée et qu'elle est stérile et à pH neutre. Il s'agit de l'eau couramment utilisée dans le domaine technique des compositions de substitut osseux (notamment injectable). "Sterilized water" means that the water has been distilled and is sterile and at a neutral pH. This is water commonly used in the technical field of bone substitute compositions (including injectable).
Le plastifiant a pour fonction de modifier la rhéologie de la composition de substitut osseux de manière à rendre la composition plus homogène et à limiter la quantité d'eau stérilisée requise pour que par exemple ladite composition puisse être injectée à l'aide d'une seringue ou modelée à la main par un chirurgien. L'ajout du plastifiant permet d'augmenter la viscosité de la composition de substitut osseux selon l'invention. En l'absence de plastifiant dans la composition de substitut osseux selon l'invention, on risquerait d'observer une ségrégation entre la phase solide et la phase liquide. La composition risquerait donc de ne pas être homogène. Le plastifiant est avantageusement choisi parmi les dérivés de cellulose, et plus préférentiellement dans le groupe constitué par le carboxymethylcellulose, l'hydroxy- propyl-methyl-cellulose (HPMC), le méthylcellulose (MC), l'hydroxyethylcellulose (HPC), hydroxypropylcellulose, l'ethylcellulose (EC), l'acétate butyrate de cellulose. The function of the plasticizer is to modify the rheology of the bone substitute composition so as to make the composition more homogeneous and to limit the quantity of sterilized water required so that, for example, the said composition can be injected with the aid of a syringe. or modeled by hand by a surgeon. The addition of the plasticizer makes it possible to increase the viscosity of the bone substitute composition according to the invention. In the absence of plasticizer in the bone substitute composition according to the invention, there is a risk of segregation between the solid phase and the liquid phase. The composition may therefore not be homogeneous. The plasticizer is advantageously chosen from cellulose derivatives, and more preferentially from the group consisting of carboxymethylcellulose, hydroxypropyl-methylcellulose (HPMC), methylcellulose (MC), hydroxyethylcellulose (HPC), hydroxypropylcellulose, ethylcellulose (EC), cellulose acetate butyrate.
Le plastifiant peut aussi être choisi parmi des alcools à haut poids moléculaire tels que le glycérol, les alcools viny!iques, l'acide stéarique ou l'acide hyaluronique.
De manière préférée, le plastifiant est l'hydroxy-propyl-methyi-cellulose (HPMC ou hypromellose). The plasticizer may also be selected from high molecular weight alcohols such as glycerol, vinyl alcohols, stearic acid or hyaluronic acid. Preferably, the plasticizer is hydroxy-propyl-methylcellulose (HPMC or hypromellose).
De préférence, la composition selon l'invention est telle que ladite première phase solide contient entre sensiblement 40 et 60% d'hémihydrate de sulfate de calcium alpha en poids par rapport au poids total de ladite première phase solide et entre sensiblement 40 et 60% de particules poreuses (de phosphate de calcium et/ou d'os) en poids par rapport au poids total de ladite première phase solide, tandis que ladite deuxième phase solide contient entre sensiblement 2 et 20% de HPMC en poids par rapport au poids de la phase liquide. Par exemple, lorsqu'on souhaite obtenir une composition selon l'invention qui présente un caractère injectable, ladite composition présente avantageusement les caractéristiques suivantes : Preferably, the composition according to the invention is such that said first solid phase contains between approximately 40 and 60% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase and substantially between 40 and 60% of porous particles (of calcium phosphate and / or bone) in weight relative to the total weight of said first solid phase, whereas said second solid phase contains between approximately 2 and 20% of HPMC by weight relative to the weight of the liquid phase. For example, when it is desired to obtain a composition according to the invention which has an injectable character, said composition advantageously has the following characteristics:
- sa première phase solide contient entre sensiblement 40 et 60% d'hémihydrate de sulfate de calcium alpha en poids par rapport au poids total de ladite première phase solide, its first solid phase contains between approximately 40 and 60% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase,
- sa première phase solide contient entre sensiblement 40 et 60% de particules poreuses, formées préférentiellement de particules d'hydroxyapatite en poids par rapport au poids total de ladite première phase solide, - sa deuxième phase solide contient entre sensiblement 2 et 10% de HPMC en poids par rapport au poids de la phase liquide, - Its first solid phase contains between 40 and 60% of porous particles, preferably formed of hydroxyapatite particles by weight relative to the total weight of said first solid phase, - its second solid phase contains between 2 and 10% of HPMC by weight relative to the weight of the liquid phase,
- le ratio phase liquide/phase solide est compris entre 0,4 et 0,8 mLJg. the liquid phase / solid phase ratio is between 0.4 and 0.8 mlJg.
Selon un autre exemple, lorsqu'on souhaite obtenir une composition selon l'invention qui présente un caractère modelable, ladite composition présente avantageusement les caractéristiques suivantes : According to another example, when it is desired to obtain a composition according to the invention which has a modelable character, said composition advantageously has the following characteristics:
- sa première phase solide contient entre sensiblement 40 et 60% d'hémihydrate de sulfate de calcium alpha en poids par rapport au poids total de ladite première phase solide,
- sa première phase solide contient entre sensiblement 40 et 60% de particules poreuses, formées préférentiellement de particules d'hydroxyapatite, en poids par rapport au poids total de ladite première phase solide, - sa deuxième phase solide contient entre sensiblement 2 et 20% de HPMC en poids par rapport au poids de la phase liquide, its first solid phase contains between approximately 40 and 60% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase, its first solid phase contains between approximately 40 and 60% of porous particles, preferably formed of hydroxyapatite particles, by weight relative to the total weight of said first solid phase; its second solid phase contains between approximately 2 and 20% of HPMC by weight relative to the weight of the liquid phase,
- le ratio phase liquide/phase solide est compris entre 0, 1 et 0,6 mL/g. the liquid phase / solid phase ratio is between 0.1 and 0.6 ml / g.
La composition de substitut osseux injectable et/ou modelable peut en outre comprendre au moins un accélérateur de prise tel que choisi parmi le chlorure de sodium, le sulfate de sodium, le sulfate de potassium, le BMA (à savoir un mélange de gypse et d'amidon) ou encore le gypse broyé ou un retardateur de prise tel que le sulfate de calcium dihydraté. The injectable and / or moldable bone substitute composition may further comprise at least one setting accelerator as selected from sodium chloride, sodium sulfate, potassium sulfate, BMA (i.e., a mixture of gypsum and starch) or crushed gypsum or a setting retarder such as calcium sulfate dihydrate.
Dans un mode de réalisation de l'invention, la composition de substitut osseux injectable et/ou modeiable comprend en outre au moins un agent thérapeutique. Avantageusement, il s'agit d'un agent ayant un effet bactéricide ou bactériostatique tel que les tetracyclines (la teîracycline hydrochloride), la gentamicine, la tobramycine, ou encore des sels d'argent ou des sels de cuivre. Il peut aussi s'agir d'un agent thérapeutique ayant une action sur le métabolisme osseux tel que les sels de strontium, les peptides ou encore les facteurs de croissance. La composition de substitut osseux injectable et/ou modelable peut aussi comprendre au moins un agent radio-opaque tel que du carbonate de strontium, de l'iohexol, de l'iopamidol, ou encore de la metrizamide. L'agent radio-opaque permet au substitut osseux d'être visibie à la radiologie après l'implantation. Cela permet donc de réaliser un suivi de la résorption de l'implant. La présente invention concerne aussi un procédé de préparation de la composition de substitut osseux injectable et/ou modelable telle que décrite ci-dessus, dans lequel on mélange ladite phase liquide et ladite phase solide de façon que le ratio phase liquide/phase solide soit compris entre 0,1 et 0,8 mL/g comme exposé ci-avant.
Avantageusement, le procédé comprend les étapes suivantes : In one embodiment of the invention, the injectable and / or sharable bone substitute composition further comprises at least one therapeutic agent. Advantageously, it is an agent having a bactericidal or bacteriostatic effect such as tetracyclines (tetracycline hydrochloride), gentamicin, tobramycin, or silver salts or copper salts. It may also be a therapeutic agent having an action on bone metabolism such as strontium salts, peptides or growth factors. The injectable and / or modelable bone substitute composition may also comprise at least one radio-opaque agent such as strontium carbonate, iohexol, iopamidol, or metrizamide. The radiopaque agent allows the bone substitute to be visible to radiology after implantation. This makes it possible to follow the resorption of the implant. The present invention also relates to a process for preparing the injectable and / or modelable bone substitute composition as described above, wherein said liquid phase and said solid phase are mixed so that the liquid phase / solid phase ratio is included between 0.1 and 0.8 mL / g as described above. Advantageously, the method comprises the following steps:
- On dispose dans une première seringue d'une quantité appropriée de la phase liquide de ladite composition de substitut osseux. In a first syringe, a suitable amount of the liquid phase of said bone substitute composition is provided.
- On dispose dans une deuxième seringue d'une quantité appropriée de la phase solide de ladite composition de substitut osseux. In a second syringe, an appropriate amount of the solid phase of said bone substitute composition is disposed.
- On fixe les deux seringues bout à bout à l'aide d'un connecteur. - The two syringes are attached end to end using a connector.
- On dispose les seringues horizontalement de manière à ce que la phase solide s'étale dans la deuxième seringue. - The syringes are arranged horizontally so that the solid phase spreads in the second syringe.
- On pousse sur le piston de la première seringue remplie de la phase liquide en tirant simultanément sur le piston de la deuxième seringue remplie de la phase solide. - One pushes on the piston of the first syringe filled with the liquid phase by simultaneously pulling on the piston of the second syringe filled with the solid phase.
- On agite énergiquement la deuxième seringue de manière à obtenir un mélange homogène de la phase solide et de la phase liquide dans ladite deuxième seringue. On effectue au moins une fois le transfert du mélange d'une seringue à l'autre, afin de parfaire l'homogénéisation du mélange. De manière avantageuse, le transfert est effectué trois à quatre fois. The second syringe is vigorously agitated so as to obtain a homogeneous mixture of the solid phase and the liquid phase in the said second syringe. The mixture is transferred at least once from one syringe to the other, in order to perfect the homogenization of the mixture. Advantageously, the transfer is carried out three to four times.
Ensuite, on démonte le système et on fixe une aiguille sur ladite seringue. La composition de substitut osseux est alors prête à l'injection. Then, the system is disassembled and a needle is attached to said syringe. The bone substitute composition is then ready for injection.
La composition de substitut osseux est ainsi dans cette variante avantageuse immédiatement prête à l'injection une fois le mélange terminé. Il n'y a donc pas de perte de temps ou de manipulations supplémentaires pour le chirurgien avant l'implantation du substitut osseux. De plus, il n'y a pas de risques de contamination externe. The bone substitute composition is thus in this advantageous variant immediately ready for injection once the mixture is complete. There is therefore no loss of time or additional manipulations for the surgeon before implantation of the bone substitute. In addition, there is no risk of external contamination.
L'injectabilité de la composition de substitut osseux est en l'espèce avantageusement aisée durant les 10 premières minutes. Cela laisse donc au chirurgien quelques minutes entre la préparation et l'injection de ladite composition de substitut osseux.
La quantité de composition de substitut osseux selon l'invention qui peut être injectée est par exemple comprise entre environ 0,5 et 20 cm3, et par exemple : The injectability of the bone substitute composition is in this case advantageously easy during the first 10 minutes. This therefore leaves the surgeon a few minutes between the preparation and the injection of said bone substitute composition. The amount of bone substitute composition according to the invention that can be injected is for example between about 0.5 and 20 cm 3 , and for example:
- lorsqu'il s'agit d'une composition injectable entre 0,5 et 16 cm3, voire entre 1 cm3 et 8 cm3, when it is an injectable composition between 0.5 and 16 cm 3 , or even between 1 cm 3 and 8 cm 3 ,
- et lorsqu'il s'agit d'une composition modelable, entre 0,5 et 20 cm3. and when it is a modelable composition, between 0.5 and 20 cm 3 .
La présente invention concerne aussi un kit destiné à (a préparation d'une composition de substitut osseux selon la présente invention telle que décrite ci-dessus, ledit kit comprenant : The present invention also relates to a kit for the preparation of a bone substitute composition according to the present invention as described above, said kit comprising:
- un premier récipient (par exemple une ampoule) rempli de la phase liquide de ladite composition ; a first container (for example an ampoule) filled with the liquid phase of said composition;
- un deuxième récipient (par exemple une seringue) rempli de la phase solide de ladite composition. a second container (for example a syringe) filled with the solid phase of said composition.
Avantageusement, le kit selon l'invention comprend en outre deux seringues, un connecteur de seringues, un bouchon de seringue, une aiguille et au moins une ampoule d'eau stérilisée. Advantageously, the kit according to the invention further comprises two syringes, a syringe connector, a syringe cap, a needle and at least one ampoule of sterilized water.
Des expérimentations ont été réalisées sur une composition de substitut osseux selon l'invention qui comprenait : Experiments were carried out on a bone substitute composition according to the invention which included:
- une phase liquide d'eau stérilisée ; a liquid phase of sterilized water;
- une phase solide qui contenait : - a solid phase that contained:
• une première phase solide contenant 50% d'hémihydrate de sulfate de calcium alpha en poids par rapport au poids total de ladite première phase solide ; A first solid phase containing 50% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase;
50% de phosphate de calcium, sous la forme de granules poreuses et sphériques, en poids par rapport au poids total de ladite première phase solide; 50% calcium phosphate, in the form of porous and spherical granules, by weight relative to the total weight of said first solid phase;
• une deuxième phase solide contenant 10% d'HPMC en poids par rapport au poids de la phase liquide,
et le ratio phase liquide/phase solide était de 0,6 ml_/g. A second solid phase containing 10% HPMC by weight relative to the weight of the liquid phase, and the liquid phase / solid phase ratio was 0.6 ml / g.
Etant donné que la dose de stérilisation (par irradiation gamma) a une influence sur les propriétés de la composition de substitut osseux selon l'invention, les deux séries d'essais de caractérisation suivantes ont été réalisées : - une 1 lère série à la dose minimale de stérilisation, à savoir à 20-25 kGy ; Since the sterilization dose (by gamma irradiation) has an influence on the properties of the bone substitute composition according to the invention, the following two series of characterization tests were carried out: a first series at the dose minimal sterilization, ie, 20-25 kGy;
- une 2ieme série à la dose maximale, à savoir à 40-50 kGy. - A 2 th series at the highest dose, ie 40-50 kGy.
Les échantillons des 1 iere et 2lème série étaient strictement identiques quant à leur composition, seule la dose d'irradiation était différentes. Samples of 1 st and 2 -th series were strictly identical in their composition, only the irradiation dose was different.
Les valeurs de 20-25 kGy et de 40-50 kGy ont été choisies de manière à se situer de part et d'autre de la dose standard appliquée sur de tels produits qui est de 25-40 kGy et donc d'étudier les caractéristiques de composition de substitut osseux avec des doses d'irradiation aux valeurs extrêmes (inférieure et supérieure). The values of 20-25 kGy and 40-50 kGy were chosen so as to be on either side of the standard dose applied to such products which is 25-40 kGy and thus to study the characteristics of bone substitute composition with irradiation doses at extreme values (lower and upper).
A partir de ces deux séries d'essais de composition de substitut osseux selon l'invention, on a mesuré : i. Le temps de travail ; ii. Le temps de prise ; iii. La résistance en compression. From these two series of tests for bone substitute composition according to the invention, it was measured: i. Work time ; ii. The setting time; iii. Resistance in compression.
A) Description du protocole de mesure du temps de travail : A) Description of the protocol for measuring working time:
L'essai a été réalisé à l'aide d'une machine de compression qui avait les caractéristiques suivantes : The test was carried out using a compression machine which had the following characteristics:
- Capteur de force : 100kN, - Force sensor: 100kN,
- Force: + 2%- Vitesse d'avancement = 2,5 ± 0,6 mm/min L'échantillon a été préparé de la manière suivante : stérilisée était contenue dans une ampoule.
La capsule a été ôtée de l'ampoule. - Force: + 2% - Feeding speed = 2.5 ± 0.6 mm / min The sample was prepared as follows: sterilized was contained in a vial. The capsule has been removed from the ampoule.
L'ampoule a été vissée sur l'embout d'une 1 seringue vide. The ampoule was screwed onto the tip of an empty syringe.
De l'eau a été aspirée plusieurs fois en effectuant des va-et-vient avec le piston de la seringue de manière à éliminer les bulles d'air. On a prélevé environ 2 mL d'eau stérilisée, puis l'ampoule a été dévissée de la seringue. Water was sucked several times by reciprocating with the plunger of the syringe to remove air bubbles. Approximately 2 mL of sterilized water was removed and the ampule was unscrewed from the syringe.
On a rejeté l'excédent d'eau stérilisée pour ne garder dans la seringue que 1 ,2 mL. The excess sterilized water was discarded to keep only 1.2 mL in the syringe.
On a ôté le bouchon d'une deuxième seringue qui contenait la phase solide décrite ci- dessus. On a fixé les deux seringues bout à bout à l'aide d'un connecteur. The cap of a second syringe was removed which contained the solid phase described above. The two syringes were attached end to end using a connector.
Les seringues ont été disposées horizontalement de manière à ce que la poudre s'étale dans la 2ième seringue. The syringes were placed horizontally so that the powder is spread in the 2 nd syringe.
On a poussé sur le piston de la 1 lère seringue tout en tirant simultanément sur le piston de la 2ieme seringue. Au moment où l'eau stérilisée est entrée en contact avec la poudre, le chronomètre a été déclenché. Was grown on the plunger of the syringe 1 era while simultaneously pulling on the plunger of the syringe 2 nd. By the time the sterilized water came into contact with the powder, the stopwatch was triggered.
On a agité énergiquement l'ensemble constitué par les deux seringues et le connecteur de manière à obtenir un mélange homogène de la poudre et de l'eau stérilisée. The assembly consisting of the two syringes and the connector was vigorously agitated so as to obtain a homogeneous mixture of the powder and the sterilized water.
Une fois homogénéisé, le mélange a été transféré trois fois d'une seringue à l'autre. Puis, tout le mélange a été rassemblé dans une seule seringue. Ensuite, les deux seringues ont été déconnectées. Once homogenized, the mixture was transferred three times from one syringe to the other. Then all the mixture was collected in a single syringe. Then both syringes were disconnected.
Une aiguille a été vissée sur la seringue contenant le mélange.
La seringue a été disposée dans un support sous la forme d'un tube en PVC disposé dans la machine de compression et configuré de manière à ce que la contrainte en compression ne soit appliquée que sur le piston de la seringue. A needle was screwed onto the syringe containing the mixture. The syringe was disposed in a support in the form of a PVC tube disposed in the compression machine and configured so that the compressive stress is applied only to the plunger of the syringe.
Une contrainte en compression a été appliquée sur le piston de la seringue, avec une vitesse de déplacement de 2,5 mm/min. Compression stress was applied to the syringe plunger with a displacement speed of 2.5 mm / min.
La force résultante a été mesurée en fonction du temps. The resulting force was measured as a function of time.
Le chronomètre a été arrêté au moment où la force atteinte était de 120 N (ce qui correspond à une force humaine manuelle maximale). The stopwatch was stopped when the force reached was 120 N (which corresponds to maximum manual human strength).
Le temps ainsi déterminé par le chronomètre correspondait au temps de travail. On a obtenu un temps de travail de 16 minutes pour la 1iere série d'essais et de 32 minutes pour la 2ième série d'essais. The time thus determined by the stopwatch corresponded to the working time. There was obtained a 16 minute working time for the 1 st series of tests and 32 minutes for the 2nd series of tests.
On peut en conclure que le temps de travail d'une composition de substitut osseux selon l'invention soumis à une dose d'irradiation standard se situera entre environ une quinzaine de minutes et une demi-heure ; ce qui correspond à une durée suffisamment longue pour laisser au chirurgien le temps de préparer le site d'implantation avant d'injecter ladite composition de substitut osseux. It can be concluded that the working time of a bone substitute composition according to the invention subjected to a standard irradiation dose will be between about fifteen minutes and half an hour; which corresponds to a time long enough to allow the surgeon time to prepare the implantation site before injecting said bone substitute composition.
B) Description du protocole de mesure du temps de prise VICAT : B) Description of the VICAT setting time measurement protocol:
Cet essai a été réalisé conformément à la norme ASTM C472. This test was performed in accordance with ASTM C472.
L'appareil Vicat est muni d'une aiguille, sur laquelle repose une masse normée. Cette aiguille a été déposée sur la surface de l'échantillon de composition de substitut osseux selon l'invention durant sa prise. The Vicat apparatus is equipped with a needle, on which rests a normed mass. This needle was deposited on the surface of the sample of bone substitute composition according to the invention during its setting.
Le degré d'enfoncement de l'aiguille dans l'échantillon a permis de déterminer l'état d'avancement de la prise.
Pour ce faire, les échantillons ont été préparés de la même manière que pour la mesure du temps de travail. The degree of insertion of the needle into the sample made it possible to determine the progress of the setting. To do this, the samples were prepared in the same way as for measuring the working time.
De même, le chronomètre a été déclenché au moment où l'eau est entrée en contact avec la poudre, Une fois le mélange homogénéisé, les deux seringues ont été déconnectées. Similarly, the stopwatch was triggered when the water came in contact with the powder. Once the mixture homogenized, the two syringes were disconnected.
La composition de substitut osseux selon l'invention a été coulée lentement dans des alvéoles prévues à cet effet, de manière à éviter la formation de bulles. The bone substitute composition according to the invention was slowly poured into cells provided for this purpose, so as to avoid the formation of bubbles.
Les alvéoles ont été remplies jusqu'à ras-bord. The cells were filled to the brim.
Ensuite, les échantillons ont été mis à l'étuve à 37°C. Lorsqu'il s'est écoulé 40 minutes sur le chronomètre, les échantillons ont été sortis de Tétuve et ont été disposés sur le plateau de l'appareil Vicat. Then the samples were put in an oven at 37 ° C. After 40 minutes on the stopwatch, the samples were taken out of the oven and placed on the Vicat tray.
A la surface de chaque échantillon a été déposée délicatement l'aiguille de l'appareil Vicat. Puis, l'aiguille a été lâchée complètement. On the surface of each sample was gently deposited the needle of the Vicat device. Then, the needle was released completely.
La mesure a été réitérée toutes les 5 minutes. Le temps de prise Vicat est le temps au bout duquel l'aiguille ne s'enfonce plus jusqu'au fond de l'échantillon. The measurement was repeated every 5 minutes. The Vicat setting time is the time after which the needle no longer sinks to the bottom of the sample.
Le temps de prise Vicat pour la 1 ière série d'essais était de 51 minutes et de 59 minutes pour la 2ieme série d'essais. Vicat time taken for the 1 st series of tests was 51 minutes and 59 minutes for the 2 nd series of tests.
Ainsi, on conclut que la composition de substitut osseux selon l'invention durcit en moins d'une heure, c'est-à-dire avant que le patient ne se remette en mouvement La composition de substitut osseux selon l'invention peut donc parfaitement s'intégrer dans un mode opératoire sans en altérer son déroulement.
C) Description du protocole de mesure de la résistance en compression Thus, it is concluded that the bone substitute composition according to the invention cures in less than one hour, that is to say before the patient resumes movement The bone substitute composition according to the invention can therefore perfectly integrate into a procedure without altering its course. C) Description of the protocol for measuring the compressive strength
Capteur de force : 100kN, Force: ± 2% Vitesse d'avancement = 1 ,0 ± 0,01 mm/min Force sensor: 100kN, Force: ± 2% Travel speed = 1, 0 ± 0.01 mm / min
L'essai de résistance en compression a consisté à déterminer la résistance en compression d'une éprouvette cylindrique de composition de substitut osseux injectable selon l'invention (hauteur = 15mm et diamètre = 10mm). The compressive strength test consisted of determining the compressive strength of a cylindrical test specimen of injectable bone substitute composition according to the invention (height = 15 mm and diameter = 10 mm).
Les échantillons ont été préparés de la même manière que pour les mesures de temps de travail et de prise détaillées ci-dessus. The samples were prepared in the same manner as for the working time and setting measurements detailed above.
Une fois le mélange homogénéisé, les deux seringues ont été déconnectées. La composition de substitut osseux injectable selon l'invention a été coulée dans des moules préalablement huilés, de manière à éviter la formation de bulles dans le moule. Once the mixture homogenized, the two syringes were disconnected. The injectable bone substitute composition according to the invention was cast in previously oiled molds, so as to avoid the formation of bubbles in the mold.
Un peu de composition de substitut osseux injectable dépassait hors du moule pour compenser le retrait. Some injectable bone substitute composition protruded out of the mold to compensate for the shrinkage.
Au bout d'une heure, la surface de la composition de substitut osseux injectable a été égalisée avec du papier abrasif de manière à ce que la surface de la composition de substitut osseux injectable puisse être parfaitement alignée avec celle du moule. After one hour, the surface of the injectable bone substitute composition was smoothed with abrasive paper so that the surface of the injectable bone substitute composition could be perfectly aligned with that of the mold.
Les compositions de substitut osseux injectable ont été démoulées puis disposées à l'étuve à 45°C pendant au moins 12 heures. Cela constituait les échantillons de cette expérimentation. Les échantillons n'ont été sortis de l'étuve qu'au moment de la mesure de la résistance en compression. The injectable bone substitute compositions were demolded and then placed in an oven at 45 ° C for at least 12 hours. These were the samples of this experiment. The samples were taken out of the oven only when measuring the compressive strength.
La mesure a été réalisée en appliquant une contrainte en compression sur l'échantillon à une vitesse de 1 mm/min jusqu'à rupture de l'échantillon.
La résistance en compression était la contrainte maximale atteinte durant la mesure. The measurement was carried out by applying a compressive stress on the sample at a speed of 1 mm / min until the sample was broken. The compressive strength was the maximum stress reached during the measurement.
La résistance en compression pour la 1 ,ere série d'essais était de 5 MPa et de 6 MPa pour la 2ieme série d'essais. The compressive strength for the 1 st series of tests was 5 MPa and 6 MPa for 2 nd series of tests.
Ces résistances de compression ainsi obtenues sont particulièrement appropriées pour que ie substitut osseux selon l'invention résiste à l'environnement constitué par le corps humain (pression sanguine, dissolution, désintégration par les fluides humains...). These compression resistances thus obtained are particularly suitable for the bone substitute according to the invention to withstand the environment constituted by the human body (blood pressure, dissolution, disintegration by human fluids, etc.).
Des campagnes d'essais ont en outre permis d'établir les résultats exposés dans le tableau 1 ci-après, concernant : Test campaigns have also established the results set out in Table 1 below, relating to:
- d'une part une composition injectable selon l'invention présentant les caractéristiques suivantes : on the one hand an injectable composition according to the invention having the following characteristics:
- sa première phase solide contient sensiblement 50% d'hémihydrate de sulfate de calcium alpha en poids par rapport au poids total de ladite première phase solide, its first solid phase contains substantially 50% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase,
- sa première phase solide contient sensiblement 50% d'hydroxyapatite en poids par rapport au poids total de ladite première phase solide, sous forme de particules poreuses, its first solid phase contains substantially 50% hydroxyapatite by weight relative to the total weight of said first solid phase, in the form of porous particles,
- sa deuxième phase solide contient sensiblement 10% de HP C en poids par rapport au poids de la phase liquide, its second solid phase contains substantially 10% of HP C by weight relative to the weight of the liquid phase,
- le ratio phase liquide/phase solide est d'environ 0,6 mL/g. - et d'autre part une composition modelable selon l'invention présentant les caractéristiques suivantes : the liquid phase / solid phase ratio is approximately 0.6 ml / g. and on the other hand a modelable composition according to the invention having the following characteristics:
- sa première phase solide contient sensiblement 50% d'hémihydrate de sulfate de calcium alpha en poids par rapport au poids total de ladite première phase solide, - sa première phase solide contient sensiblement 50% d'hydroxyapatite en poids par rapport au poids total de ladite première phase solide, sous forme de particules poreuses,
sa deuxième phase solide contient sensiblement 13,5% de HPMC poids par rapport au poids de la phase liquide, le ratio phase liquide/phase solide est d'environ 0,3 mL/g. its first solid phase contains substantially 50% alpha calcium sulphate hemihydrate by weight relative to the total weight of said first solid phase; its first solid phase contains substantially 50% hydroxyapatite by weight relative to the total weight of said first solid phase, in the form of porous particles, its second solid phase contains substantially 13.5% HPMC weight relative to the weight of the liquid phase, the liquid phase / solid phase ratio is about 0.3 mL / g.
Tableau 1 Table 1
POSSIBILITE D'APPLICATION INDUSTRIELLE POSSIBILITY OF INDUSTRIAL APPLICATION
L'invention trouve son application industrielle dans l'élaboration, la fabrication et l'utilisation de substituts osseux, injectables et/ou modelables.
The invention finds its industrial application in the development, manufacture and use of bone substitutes, injectable and / or modelable.
Claims
REVENDICATIONS
Composition de substitut osseux injectable et/ou modelable qui comprend : Composition of injectable and/or moldable bone substitute which comprises:
- une phase liquide comprenant de l'eau stérilisée ; - a liquid phase comprising sterilized water;
- une phase solide qui contient : - a solid phase which contains:
• une première phase solide comprenant : • a first solid phase comprising:
■ 10 à 90 % d'hémihydrate de sulfate de calcium alpha en poids, par rapport au poids total de ladite première phase solide; ■ 10 to 90% of alpha calcium sulfate hemihydrate by weight, relative to the total weight of said first solid phase;
■ 10 à 90 % de particules poreuses en poids, par rapport au poids total de ladite première phase solide, lesdites particules étant des particules de phosphate de calcium et ou d'os ; ■ 10 to 90% of porous particles by weight, relative to the total weight of said first solid phase, said particles being particles of calcium phosphate and/or bone;
• une deuxième phase solide comprenant 0,1 à 20 % d'au moins un plastifiant en poids, par rapport au poids de la phase liquide, le ratio phase liquide/phase solide étant compris entre 0,1 et 0,8 mUg. • a second solid phase comprising 0.1 to 20% of at least one plasticizer by weight, relative to the weight of the liquid phase, the liquid phase/solid phase ratio being between 0.1 and 0.8 mUg.
Composition selon la revendication 1 caractérisée en ce que le ratio phase liquide/phase solide est compris entre 0,4 et 0,8 mL/g. Composition according to claim 1 characterized in that the liquid phase/solid phase ratio is between 0.4 and 0.8 mL/g.
Composition selon ia revendication 1 caractérisée en ce que le ratio phase liquide/phase solide est compris entre 0,1 et 0,Composition according to claim 1 characterized in that the liquid phase/solid phase ratio is between 0.1 and 0,
6 mUg. 6 mUg.
Composition selon la revendication 2 caractérisée en ce que le ratio phase liquide/phase solide est compris entre 0,5 et 0,7 mL/g. Composition according to claim 2, characterized in that the liquid phase/solid phase ratio is between 0.5 and 0.7 mL/g.
Composition selon l'une des revendications 1 à 4 caractérisé en ce que lesdites particules sont, au moins pour une partie d'entre elles, de forme sensiblement sphérique. Composition according to one of claims 1 to 4 characterized in that said particles are, at least for part of them, of substantially spherical shape.
Composition selon la revendication 5 caractérisée en ce que lesdites particules sont sensiblement toutes de forme sensiblement sphérique.
Composition according to claim 5 characterized in that said particles are substantially all of substantially spherical shape.
7. Composition selon l'une des revendications 1 à 6 caractérisée en ce que la répartition granulométrique desdites particules est la suivante : Di0 est supérieur ou égal à 10 micromètres et Dgo est inférieur ou égal à 150 micromètres. 7. Composition according to one of claims 1 to 6 characterized in that the particle size distribution of said particles is as follows: Di 0 is greater than or equal to 10 micrometers and Dgo is less than or equal to 150 micrometers.
8. Composition selon la revendication 7 caractérisée en ce que la répartition granulométrique desdites particules est la suivante : D10 est supérieur ou égal à 40 micromètres ; D50 est compris entre 70 micromètres et 90 micromètres, et D90 est inférieur ou égal à 150 micromètres. 8. Composition according to claim 7 characterized in that the particle size distribution of said particles is as follows: D 10 is greater than or equal to 40 micrometers; D 50 is between 70 micrometers and 90 micrometers, and D90 is less than or equal to 150 micrometers.
9. Composition selon l'une des revendications 1 à 8 caractérisée en ce que Γ hémihydrate de sulfate de calcium alpha se présente sous la forme d'une poudre qui, lors du mélange des composés de la phase solide dans la phase liquide, forme autour desdites particules une matrice qui durcit au contact de l'eau en formant du dihydrate de sulfate de calcium. 9. Composition according to one of claims 1 to 8 characterized in that the alpha calcium sulfate hemihydrate is in the form of a powder which, when mixing the compounds of the solid phase in the liquid phase, forms around said particles a matrix which hardens on contact with water forming calcium sulfate dihydrate.
10. Composition selon l'une des revendications 1 à 9, caractérisée en ce que ledit plastifiant est choisi dans le groupe constitué par le carboxymethylcellulose, l'hydroxy-propyl-methyl-ceilulose (HPMC), le méthylcellulose (MC), l'hydroxyethylcellulose (HPC), l'hydroxypropylcellulose, l'ethylcellulose (EC), l'acétate butyrate de cellulose, le glycérol, les alcools vinyliques, l'acide stéarique, l'acide hyaluronique. 10. Composition according to one of claims 1 to 9, characterized in that said plasticizer is chosen from the group consisting of carboxymethylcellulose, hydroxy-propyl-methyl-ceilulose (HPMC), methylcellulose (MC), hydroxyethylcellulose (HPC), hydroxypropylcellulose, ethylcellulose (EC), cellulose acetate butyrate, glycerol, vinyl alcohols, stearic acid, hyaluronic acid.
11. Composition de substitut osseux injectable selon la revendication 10, caractérisée en ce que le plastifiant est l'hydroxy-propyl-methyl-cellulose (HPMC). 11. Injectable bone substitute composition according to claim 10, characterized in that the plasticizer is hydroxy-propyl-methyl-cellulose (HPMC).
12. Composition selon l'une des revendications 1 à 11 caractérisée en ce que ladite première phase solide comprend de 0,1 à 20% d'au moins un accélérateur ou d'un retardateur de prise en poids par rapport au poids total de ladite première phase solide. 12. Composition according to one of claims 1 to 11 characterized in that said first solid phase comprises from 0.1 to 20% of at least one accelerator or a set retarder by weight relative to the total weight of said first solid phase.
13. Composition selon la revendication 12 caractérisée en ce que ledit accélérateur de prise est choisi parmi le chlorure de sodium, le sulfate de sodium, le sulfate de potassium, un mélange de gypse et d'amidon appelé BMA ou encore le gypse broyé.
13. Composition according to claim 12 characterized in that said setting accelerator is chosen from sodium chloride, sodium sulfate, potassium sulfate, a mixture of gypsum and starch called BMA or even crushed gypsum.
14. Composition selon la revendication 12 ou 13 caractérisé en ce que ledit retardateur de prise est le sulfate de calcium dihydraté. 14. Composition according to claim 12 or 13 characterized in that said setting retarder is calcium sulfate dihydrate.
15. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle comprend en outre au moins un agent thérapeutique. 15. Composition according to any one of the preceding claims, characterized in that it further comprises at least one therapeutic agent.
16. Composition selon la revendication 15, caractérisée en ce que ledit agent thérapeutique est choisi dans le groupe constitué par la tetracycline hydrochloride, la gentamicine, la tobramycine, les sels d'argent, les sels de cuivre, les sels de strontium, les peptides, les facteurs de croissance. 16. Composition according to claim 15, characterized in that said therapeutic agent is chosen from the group consisting of tetracycline hydrochloride, gentamicin, tobramycin, silver salts, copper salts, strontium salts, peptides , growth factors.
17. Composition selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle comprend en outre au moins un agent radio-opaque choisi dans le groupe constitué par le carbonate de strontium, l'iohexol, l'iopamidol, la metrizamide. 17. Composition according to any one of the preceding claims, characterized in that it further comprises at least one radiopaque agent chosen from the group consisting of strontium carbonate, iohexol, iopamidol, metrizamide.
18. Composition selon l'une quelconque des revendications précédentes caractérisée en ce que ladite première phase solide contient entre sensiblement 40 et 60% d'hémihydrate de sulfate de caicium alpha en poids par rapport au poids total de ladite première phase solide et entre sensiblement 40 et 60% de particules de phosphate de calcium et/ou d'os en poids par rapport au poids total de ladite première phase solide, tandis que ladite deuxième phase solide contient entre sensiblement 2 et 20% de HPMC en poids par rapport au poids de la phase liquide. 18. Composition according to any one of the preceding claims characterized in that said first solid phase contains between substantially 40 and 60% of alpha caicium sulfate hemihydrate by weight relative to the total weight of said first solid phase and between substantially 40 and 60% of calcium phosphate particles and/or bone by weight relative to the total weight of said first solid phase, while said second solid phase contains between substantially 2 and 20% of HPMC by weight relative to the weight of the liquid phase.
19. Procédé de préparation d'une composition selon l'une quelconque des revendications 1 à 17 dans lequel on mélange ladite phase liquide et ladite phase solide de façon que le ratio phase liquide/phase solide soit compris entre 0,1 et 0,8 mL/g. 19. Process for preparing a composition according to any one of claims 1 to 17 in which said liquid phase and said solid phase are mixed so that the liquid phase/solid phase ratio is between 0.1 and 0.8 mL/g.
20. Procédé de préparation selon la revendication 19 caractérisé en ce qu'il comprend les étapes suivantes : 20. Preparation process according to claim 19 characterized in that it comprises the following steps:
- On dispose dans une première seringue d'une quantité appropriée de !a phase liquide de ladite composition de substitut osseux.
- On dispose dans une deuxième seringue d'une quantité appropriée de !a phase solide requise de ladite composition de substitut osseux. - An appropriate quantity of the liquid phase of said bone substitute composition is placed in a first syringe. - An appropriate quantity of the required solid phase of said bone substitute composition is placed in a second syringe.
- On fixe les deux seringues bout à bout à l'aide d'un connecteur. - We attach the two syringes end to end using a connector.
- On dispose les seringues horizontales de manière à ce que la phase solide s'étale dans la deuxième seringue. - Place the syringes horizontally so that the solid phase spreads out in the second syringe.
- On pousse sur le piston de la première seringue remplie de la phase liquide en tirant simultanément sur le piston de la deuxième seringue remplie de la phase solide. - We push on the piston of the first syringe filled with the liquid phase while simultaneously pulling on the piston of the second syringe filled with the solid phase.
- On agite énergiquement la deuxième seringue de manière à obtenir un mélange homogène de la phase solide et de la phase liquide dans ladite deuxième seringue. - The second syringe is vigorously shaken so as to obtain a homogeneous mixture of the solid phase and the liquid phase in said second syringe.
- On effectue au moins une fois le transfert du mélange d'une seringue à l'autre. - The mixture is transferred from one syringe to another at least once.
21. Kit destiné à la préparation d'une composition selon l'une quelconque des revendications 1 à 18, ledit kit comprenant : 21. Kit intended for the preparation of a composition according to any one of claims 1 to 18, said kit comprising:
- un premier récipient rempli de la phase liquide de ladite composition ; - a first container filled with the liquid phase of said composition;
- un deuxième récipient rempli de la phase solide de ladite composition. - a second container filled with the solid phase of said composition.
22. Kit selon la revendication 21 caractérisé en ce que ledit premier récipient est une ampoule tandis que ledit deuxième récipient est une seringue. 22. Kit according to claim 21 characterized in that said first container is an ampoule while said second container is a syringe.
23. Kit selon la revendication 21 ou 22, caractérisé en ce que ledit kit comprend en outre deux seringues, un connecteur de seringues, un bouchon de seringue, une aiguille et au moins une ampoule d'eau stérilisée.
23. Kit according to claim 21 or 22, characterized in that said kit further comprises two syringes, a syringe connector, a syringe cap, a needle and at least one ampoule of sterilized water.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1256776 | 2012-07-13 | ||
| FR1256776A FR2993183B1 (en) | 2012-07-13 | 2012-07-13 | INJECTABLE BONE SUBSTITUTE COMPOSITION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014009674A1 true WO2014009674A1 (en) | 2014-01-16 |
Family
ID=46826818
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/FR2013/051683 WO2014009674A1 (en) | 2012-07-13 | 2013-07-12 | Bone substitute composition |
Country Status (2)
| Country | Link |
|---|---|
| FR (1) | FR2993183B1 (en) |
| WO (1) | WO2014009674A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9446170B2 (en) | 2013-12-13 | 2016-09-20 | Agnovos Healthcare, Llc | Multiphasic bone graft substitute material |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004000334A1 (en) * | 2002-06-24 | 2003-12-31 | Wright Medical Technology, Inc. | Bone graft substitute composition |
| US20060088601A1 (en) * | 2004-10-22 | 2006-04-27 | Wright Medical Technology, Inc. | Synthetic bone substitute material |
| US20120004594A1 (en) * | 2010-07-02 | 2012-01-05 | Wright Medical Technology, Inc. | Methods of treating degenerative bone conditions |
-
2012
- 2012-07-13 FR FR1256776A patent/FR2993183B1/en not_active Expired - Fee Related
-
2013
- 2013-07-12 WO PCT/FR2013/051683 patent/WO2014009674A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004000334A1 (en) * | 2002-06-24 | 2003-12-31 | Wright Medical Technology, Inc. | Bone graft substitute composition |
| US20060088601A1 (en) * | 2004-10-22 | 2006-04-27 | Wright Medical Technology, Inc. | Synthetic bone substitute material |
| US20120004594A1 (en) * | 2010-07-02 | 2012-01-05 | Wright Medical Technology, Inc. | Methods of treating degenerative bone conditions |
Non-Patent Citations (1)
| Title |
|---|
| HU GANGFENG ET AL.: "Study on injectable and degradable cement of calcium sulphate and calcium phosphate for bone repair", JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE, vol. 21, 2010, pages 627 - 634, XP002693694 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9446170B2 (en) | 2013-12-13 | 2016-09-20 | Agnovos Healthcare, Llc | Multiphasic bone graft substitute material |
| US10973949B2 (en) | 2013-12-13 | 2021-04-13 | Agnovos Healthcare, Llc | Multiphasic bone graft substitute material |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2993183B1 (en) | 2014-10-31 |
| FR2993183A1 (en) | 2014-01-17 |
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