EP4329713A1 - Biocompatible product having a matrix comprising a polysaccharide co-crosslinked with chitosan - Google Patents
Biocompatible product having a matrix comprising a polysaccharide co-crosslinked with chitosanInfo
- Publication number
- EP4329713A1 EP4329713A1 EP22719360.4A EP22719360A EP4329713A1 EP 4329713 A1 EP4329713 A1 EP 4329713A1 EP 22719360 A EP22719360 A EP 22719360A EP 4329713 A1 EP4329713 A1 EP 4329713A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- matrix
- chitosan
- salt
- composition
- hyaluronic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000011159 matrix material Substances 0.000 title claims abstract description 101
- 229920001661 Chitosan Polymers 0.000 title claims abstract description 73
- 150000004676 glycans Chemical class 0.000 title claims abstract description 19
- 229920001282 polysaccharide Polymers 0.000 title claims abstract description 19
- 239000005017 polysaccharide Substances 0.000 title claims abstract description 19
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims abstract description 50
- 229940006486 zinc cation Drugs 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 239000000203 mixture Substances 0.000 claims description 114
- 238000010438 heat treatment Methods 0.000 claims description 57
- 229920002674 hyaluronan Polymers 0.000 claims description 41
- 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 40
- 229960003160 hyaluronic acid Drugs 0.000 claims description 39
- 238000004132 cross linking Methods 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- 235000011478 zinc gluconate Nutrition 0.000 claims description 17
- 239000011670 zinc gluconate Substances 0.000 claims description 17
- 229960000306 zinc gluconate Drugs 0.000 claims description 17
- WHMDKBIGKVEYHS-IYEMJOQQSA-L Zinc gluconate Chemical compound [Zn+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O WHMDKBIGKVEYHS-IYEMJOQQSA-L 0.000 claims description 16
- 239000002537 cosmetic Substances 0.000 claims description 15
- 230000001954 sterilising effect Effects 0.000 claims description 15
- 238000004659 sterilization and disinfection Methods 0.000 claims description 15
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 15
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 13
- 239000003431 cross linking reagent Substances 0.000 claims description 13
- 230000001225 therapeutic effect Effects 0.000 claims description 13
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- 210000001519 tissue Anatomy 0.000 claims description 12
- 238000001356 surgical procedure Methods 0.000 claims description 11
- 150000003751 zinc Chemical class 0.000 claims description 11
- 229910052725 zinc Inorganic materials 0.000 claims description 11
- 239000011701 zinc Substances 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 9
- 206010013774 Dry eye Diseases 0.000 claims description 9
- 239000013060 biological fluid Substances 0.000 claims description 8
- 235000005074 zinc chloride Nutrition 0.000 claims description 8
- 239000011592 zinc chloride Substances 0.000 claims description 8
- -1 zinc saccharide Chemical class 0.000 claims description 8
- 229920001287 Chondroitin sulfate Chemical class 0.000 claims description 7
- 210000000845 cartilage Anatomy 0.000 claims description 7
- 229940050561 matrix product Drugs 0.000 claims description 7
- 235000009529 zinc sulphate Nutrition 0.000 claims description 7
- 239000011686 zinc sulphate Substances 0.000 claims description 7
- 238000002513 implantation Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 6
- 239000001913 cellulose Chemical class 0.000 claims description 5
- 229920002678 cellulose Chemical class 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 208000028006 Corneal injury Diseases 0.000 claims description 4
- 206010011026 Corneal lesion Diseases 0.000 claims description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 4
- 230000007547 defect Effects 0.000 claims description 4
- 230000000399 orthopedic effect Effects 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 210000001179 synovial fluid Anatomy 0.000 claims description 4
- 208000031737 Tissue Adhesions Diseases 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 3
- 238000002316 cosmetic surgery Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 208000018937 joint inflammation Diseases 0.000 claims description 3
- 230000001050 lubricating effect Effects 0.000 claims description 3
- 230000007170 pathology Effects 0.000 claims description 3
- 230000001172 regenerating effect Effects 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- 230000009469 supplementation Effects 0.000 claims description 3
- 230000000699 topical effect Effects 0.000 claims description 3
- 150000003904 phospholipids Chemical class 0.000 claims description 2
- 229920005862 polyol Polymers 0.000 claims description 2
- 150000003077 polyols Chemical class 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 239000003889 eye drop Substances 0.000 claims 1
- 239000000047 product Substances 0.000 description 69
- 238000009472 formulation Methods 0.000 description 57
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 239000011521 glass Substances 0.000 description 12
- 229920002385 Sodium hyaluronate Polymers 0.000 description 11
- 229940010747 sodium hyaluronate Drugs 0.000 description 11
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000007853 buffer solution Substances 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 6
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 description 5
- 230000003044 adaptive effect Effects 0.000 description 5
- 238000000502 dialysis Methods 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000005063 solubilization Methods 0.000 description 5
- 230000007928 solubilization Effects 0.000 description 5
- 239000013589 supplement Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- AOBIOSPNXBMOAT-UHFFFAOYSA-N 2-[2-(oxiran-2-ylmethoxy)ethoxymethyl]oxirane Chemical compound C1OC1COCCOCC1CO1 AOBIOSPNXBMOAT-UHFFFAOYSA-N 0.000 description 2
- 102100030089 ATP-dependent RNA helicase DHX8 Human genes 0.000 description 2
- 101000864666 Homo sapiens ATP-dependent RNA helicase DHX8 Proteins 0.000 description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N glucosamine group Chemical group OC1[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(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-MNSSHETKSA-N 0.000 description 2
- 229940099552 hyaluronan Drugs 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 229960004716 idoxuridine Drugs 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000001502 supplementing effect Effects 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 239000008154 viscoelastic solution Substances 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 206010015943 Eye inflammation Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical group N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 230000000193 eyeblink Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
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- A61K8/00—Cosmetics or similar toiletry preparations
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- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/736—Chitin; Chitosan; Derivatives thereof
-
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
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- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
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- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
Definitions
- the present invention relates to the field of biocompatible products for cosmetic and/or medical, in particular surgical, purposes. It relates most particularly to a biocompatible product with a matrix comprising a polysaccharide at least partly co-crosslinked with chitosan, preferably a chitosan derivative or a chitosan salt.
- viscoelastic products are also known which are used during ophthalmic surgeries in order to replace or supplement the aqueous humor (during cataract surgery or in the context of refractive surgery) or the vitreous humor ( in the case of a vitrectomy), as described in document US 4,716,154.
- a certain number of biocompatible products in particular products comprising cross-linked hyaluronic acid or a salt of cross-linked hyaluronic acid, have made it possible to fill, replace, increase the volume of a biological tissue and/or replace, supplement a biological fluid.
- some of them cannot be used effectively either in the cosmetic field or in the medical field because of their undesirable side effects and/or low efficacy.
- Products based on cross-linked hyaluronic acid or cross-linked hyaluronic acid salt have a relatively satisfactory viscosity after cross-linking.
- the viscosity of these products tends to decrease sharply after the completion of a heat treatment.
- these products must be sterilized before their use in a human or animal, and this sterilization is generally carried out by heat treatment (for example by means of an autoclave).
- Document US 10,898,613 B2 describes a biocompatible injectable hydrogel composition of cross-linked hyaluronic acid containing from 0.05 mM to 4 mM of zinc divalent cation to confer improved stability (evaluated by a viscosity parameter) after sterilization by autoclave.
- Document FR 3 096260 A1 describes a co-crosslinking of carboxymethyl chitosan with hyaluronan with the aim of combining the recognized moisturizing properties of hyaluronan with the protective properties against oxidative stress of chitosan.
- a problem proposed by the present invention is to provide a biocompatible product making it possible to better fill, replace, increase the volume of a biological tissue and/or replace, supplement a biological fluid.
- the invention aims to provide such a product having improved rheological properties, in particular in terms of viscosity after application of a heat treatment such as sterilization by autoclave.
- the invention provides a biocompatible product according to claim 1.
- biocompatible product within the meaning of the present invention, is meant any product which is well tolerated by a living organism and which does not cause a rejection reaction, a toxic reaction, a lesion or a harmful effect on its biological functions.
- chitosan derivative is intended to denote a substituted chitosan having a substitution of the D-glucosamine and/or N-acetyl-D-glucosamine units, and in which the substitution group is covalently bonded.
- the Applicant has found that a co-crosslinking of a polysaccharide (chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture of these ci) with chitosan, a chitosan derivative or a chitosan salt, which leads to the establishment in the matrix of covalent bonds between the polysaccharide and the chitosan, chitosan derivative or chitosan salt, makes it possible to very significantly increase the viscosity of the product relative to the cross-linked polysaccharide.
- a polysaccharide chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture of these ci
- the divalent zinc cation can be introduced by adding a zinc saccharide to be crosslinked in the matrix.
- crosslinked in the matrix within the meaning of the present invention, is understood to mean a bond to at least one of the constituents of the matrix by at least two covalent bonds.
- the divalent zinc cation can be introduced by adding a zinc saccharide to be grafted into the matrix.
- grafted into the matrix within the meaning of the present invention, means a bond to at least one of the constituents of the matrix by a covalent bond.
- the divalent zinc cation can preferably be dispersed in the matrix.
- the term "dispersed in the matrix” means an absence of covalent bond to the constituents of the matrix.
- a dispersion in the matrix of the divalent zinc cation provided excellent results in terms of viscosity.
- the manufacturing process is simpler than in the case of addition in view of a crosslinking or a graft, because zinc (in the form of a zinc salt or in the form of a zinc saccharide in particular) has a relatively poor solubility in the pH range necessary for a crosslinking or a graft.
- the concentration of divalent zinc cation in the matrix can be between
- the concentration of divalent zinc cation in the matrix can be less than or equal to 0.1% by weight relative to the total weight of the matrix.
- the concentration of divalent zinc cation in the matrix can be between 0.002% and 0.06% by weight relative to the total weight of the matrix, and preferably between 0.01% and 0.6% by weight. weight relative to the total weight of the matrix.
- concentration of divalent zinc cation in the matrix can be between 0.002% and 0.06% by weight relative to the total weight of the matrix, and preferably between 0.01% and 0.6% by weight. weight relative to the total weight of the matrix.
- the divalent zinc cation can be included in the matrix by the addition of a zinc salt or a zinc saccharide, preferably zinc gluconate, zinc chloride or zinc sulphate.
- Zinc gluconate helps to obtain a product with good transparency, in particular for applications requiring it (notably in the ophthalmological field or for injections close to the surface of the skin).
- Zinc chloride and zinc sulphate have proved interesting for applications in rheumatology, in orthopedic surgery, or for the treatment of osteoarthritis or the repair of a cartilage defect.
- the concentration of polysaccharide chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture thereof is between 0.01% and 3% by weight relative to the total weight of the matrix, and/or
- the concentration of chitosan, chitosan derivative, or chitosan salt is between 0.01% and 3% by weight relative to the total weight of the matrix.
- the chitosan derivative can be a carboxyalkyl chitosan.
- carboxyalkyl chitosan Good results have in particular been obtained with carboxymethyl chitosan.
- carboxya! ky! e chitosan is meant a chitosan having glucosamine units, N-acetyl-glucosamine units and glucosamine units substituted by a carboxyalkyl group. This is thus referred to as a chitosan derivative or a substituted chitosan.
- the polysaccharide can be hyaluronic acid or a salt of hyaluronic acid, and can preferably have a molecular weight of between 0.1 and 5 MDa.
- a cosmetic or pharmaceutical composition comprising a biocompatible product as previously described.
- This cosmetic or pharmaceutical composition can be in the form of a viscoelastic solution or a hydrogel.
- the cosmetic or pharmaceutical composition may comprise a physiologically acceptable buffer, preferably containing polyols (mannitol, sorbitol, glycerol) and/or phospholipids.
- a physiologically acceptable buffer preferably containing polyols (mannitol, sorbitol, glycerol) and/or phospholipids.
- said composition can be used in a method of cosmetic treatment or therapeutic treatment, comprising in particular topical application, implantation, instillation or injection by subcutaneous, intradermal, mucosal, ocular, intraocular, or intra-articular, of said composition.
- said composition can be used for the prevention and/or treatment of pathologies which can be improved or avoided by:
- said composition can be used for a method of treating osteoarthritis, or repairing a cartilage defect, the composition being for example formulated for administration by injection into the synovial fluid or for implantation in cartilage after mixing with blood, or for a method of treating dry eyes.
- said composition can be used in a therapeutic, surgical or cosmetic treatment method, including in particular a treatment in rheumatology, ophthalmology, gynecology, aesthetic medicine, plastic surgery, internal surgery, in orthopedic surgery, for the prevention of post-surgical tissue adhesions, in dermatology.
- the composition can be used in a therapeutic treatment of a dry eye syndrome, of a corneal lesion or of an ocular or articular inflammation.
- said composition can be used in a therapeutic treatment during which said composition is applied by instillation on the ocular surface to prevent or fight against a corneal lesion or a dry eye syndrome, in particular with the aim of lubricate or regenerate the ocular surface.
- an ophthalmic drop composition comprising a biocompatible product as previously described.
- a method for manufacturing a biocompatible product as described above or a composition as described above comprising the following steps: a. dissolve in the same aqueous solution: i. a polysaccharide selected from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulosic derivatives, and a mixture thereof, preferably hyaluronic acid or a salt of hyaluronic acid , ii. chitosan, preferably a chitosan derivative, or a chitosan salt, b. adding a crosslinking agent to said aqueous solution and causing crosslinking of the mixture to form a matrix, c. add a divalent zinc cation before and/or after step b.
- a polysaccharide selected from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulosic
- the invention is not limited to a particular covalent crosslinking method, but a method using a chemical molecule serving as crosslinking agent, also called crosslinking agent, such as 1,4-butanediol diglycidyl ether (BDDE) or polyethylene glycol diglycidyl ether (PEGDE) in particular.
- crosslinking agent such as 1,4-butanediol diglycidyl ether (BDDE) or polyethylene glycol diglycidyl ether (PEGDE) in particular.
- this addition can be in the form of a zinc saccharide, with a view to crosslinking and/or grafting into the matrix, or can be in the form of a zinc salt which will be dispersed in the matrix.
- step b When the divalent zinc cation is added after step b, this addition takes place in the form of zinc salt or zinc saccharide which is dispersed in the matrix.
- the pH of the biocompatible product or of the composition can be adjusted between 6 and 8, preferably to 7.
- the biocompatible product or the composition can be subjected to a heat treatment for sterilization, preferably a heat treatment at a temperature of between 120° C. and 140° C. for a period of between 1 and 20 minutes.
- each example or embodiment has a general scope.
- Figure 1 is a histogram of the viscosities of different formulations, measured before and after heat treatment.
- Figure 2 is a graph illustrating the evolution of the viscosities of different formulations and different products on the market as a function of the shear rate.
- CMCS carboxymethyl chitosan
- PEGDE polyethylene glycol diglycidyl ether
- a physiological buffer solution is prepared in deionized water to reach a pH of between 6 and 8 and an osmolality of between 250 and 350 mOsm/L.
- hyaluronic acid or a salt of hyaluronic acid is designated by “HA”.
- the crosslinking of the HA is carried out by dissolving the HA (for example sodium hyaluronate (NaHa)) in an aqueous solution of sodium hydroxide at 0.25 mol/L until complete solubilization.
- a crosslinking agent for example BDDE or PEGDE
- the crosslinking agent is then added and the mixture is mixed to homogenize.
- the mixture is sealed and placed in a water bath at 50° C. for 3 hours to induce a crosslinking reaction of the HA. Covalent bonds are thus created between the crosslinking agent and the HA. Bridges can thus be formed between two HA chains.
- the gel is then homogenized and neutralized in a container with the addition of an aqueous solution of hydrochloric acid to form a homogeneous and transparent phase. Dialysis is then performed to remove residual cross-linking agent and to stabilize pH and osmolarity.
- a cross-linked phase comprising a polysaccharide (namely hyaluronic acid or a salt of hyaluronic acid) with chitosan.
- a chitosan derivative or a chitosan salt To simplify the reader's understanding, hyaluronic acid or a salt of hyaluronic acid is designated by “HA”, while chitosan, a chitosan derivative or a salt of chitosan is designated by “CHITO”.
- the crosslinking of HA with CHITO is carried out by dissolving the HA (for example sodium hyaluronate (NaHa)) and a "CHITO" (for example a carboxyalkyl chitosan) in an aqueous solution of soda at 0 .25 mol/L until complete solubilization.
- a crosslinking agent for example BDDE or PEGDE
- the crosslinking mixture is sealed and placed in a water bath at 50° C. for 3 hours to induce a simultaneous crosslinking reaction (or co-crosslinking) of the HA and of the CHITO.
- silicates can be formed between two chains of HA, between two chains of CHITO, or between a chain of HA and a chain of CHITO.
- the gel is then homogenized and neutralized in a container with the addition of an aqueous solution of hydrochloric acid to form a homogeneous and transparent phase. Dialysis is then performed to remove residual cross-linking agent and to stabilize pH and osmolarity.
- hyaluronic acid or a salt of hyaluronic acid is designated by "HA”
- chitosan, a derivative of chitosan or a salt of chitosan is designated by "CHITO”.
- HA taken alone or with a CHITO, is dissolved in a physiological buffer solution until complete solubilization to form a transparent viscoelastic solution.
- a divalent cation of zinc can be added by incorporating (by dispersion) into the solution a zinc salt or a zinc saccharide (in particular zinc gluconate, zinc chloride or zinc sulphate) .
- a mixture dissolves and homogenizes the zinc salt in the linear phase.
- Each formulation undergoes a heat treatment corresponding to a sterilization cycle.
- This heat treatment is carried out in a laboratory autoclave HMT 260 MB from HMC EUROPE.
- the 1-minute sterilization tray is set at a temperature of 131°C.
- the total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes.
- the rheological characterizations are carried out using a Discovery "DHR2" hybrid rheometer from the company TA Instruments, equipped with a cone-plane geometry 40 mm in diameter and having an angle of 2 degrees, as well as a a truncation of 55 microns.
- the rheometer is also equipped with a Peltier plate in order to control the temperature of the sample during the measurement.
- the sample is placed on the lower plate and the geometry is lowered until it reaches the “trim gap” (105 ⁇ m). Excess product is removed with a spatula. Then the geometry went down to 55 ⁇ m from the lower plateau.
- the method used consists of a flow ramp at 35° C. by applying a shear rate varying between 1 s" 1 and 1000 s" 1 , with 5 points per decade.
- the viscosities for comparing the various formulations are then taken from the viscosity value corresponding to a shear rate of 8.6 s ⁇ 1 .
- Test No. 1 Formulation of a biocompatible product with an HA cross-linked matrix, without divalent zinc cation present in the matrix
- An HA formulation comprising an HA crosslinked phase is prepared.
- the final concentration of HA is 0.9% by weight relative to the total weight of the matrix.
- the crosslinked phase of HA is prepared as previously described.
- the biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
- the glass syringes are then subjected to heat treatment as previously described, by autoclaving with a sterilization plate for 1 minute at 131°C.
- the total duration of the heat treatment including the temperature rise, the plateau and the cooling is approximately 22 to 23 minutes.
- Test N*2 Formulation of a biocompatible product with an HA cross-linked matrix, with a divalent zinc cation present in the matrix
- An HA formulation comprising 90% crosslinked HA phase and 10% non-crosslinked (linear) phase based on HA is prepared.
- the HA concentration is 0.9% by weight relative to the total weight of the matrix.
- a divalent zinc cation is added by dispersion in the matrix.
- the crosslinked phase of HA is prepared as previously described in connection with test No. 1.
- NaHa sodium hyaluronate
- the cross-linked phase and the linear (non-cross-linked) phase are then mixed in a 9:1 ratio.
- a divalent zinc cation is added to the matrix by incorporating zinc gluconate into the solution (by means of a scatter).
- a mixture makes it possible to dissolve and homogenize the zinc salt in the linear phase.
- the biocompatible cross-linked matrix product obtained has a density of about 1, and is then transferred into 1 mL glass syringes.
- the glass syringes are then subjected to heat treatment as described above, by autoclaving with a sterilization plate for 1 minute at 131°C.
- the total duration of the heat treatment including heat-up, plateau and cool-down is approximately 22-23 minutes.
- Test No. 3 Formulation of a biocompatible product with a co-crosslinked matrix HA and CHITO, without divalent zinc cation present in the matrix
- a formulation of HA and of CHITO comprising 90% of HA-CHITO coreticulated phase is prepared.
- concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
- the crosslinked phase of HA-CHITO is prepared as follows.
- crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
- the biocompatible cross-linked matrix product obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes. [0101]
- the glass syringes are then subjected to heat treatment as previously described, by autoclaving with a sterilization plate for 1 minute at 131°C.
- the total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes.
- Test No. 4 Formulation of a biocompatible product with an oo-cross-linked HA and CHITO matrix, with a divalent zinc cation present in the matrix by adding zinc gluconate
- a formulation of HA and of CHITO comprising 90% co-crosslinked HA-CHITO phase and 10% non-crosslinked (linear) phase based on HA-CHITO is prepared.
- the concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
- the crosslinked phase of HA-CHITO is prepared as previously described in connection with test No. 3.
- a linear phase with HA and CHITO is prepared as previously described in connection with test No. 3, except that after complete dissolution of sodium hyaluronate (NaHa) and carboxymethyl chitosan, a divalent zinc cation is added to the matrix by incorporating zinc gluconate into the solution (by means of a dispersion).
- NaHa sodium hyaluronate
- carboxymethyl chitosan carboxymethyl chitosan
- crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
- the biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
- the glass syringes are then subjected to heat treatment as described above, by autoclaving with a sterilization tray for 1 minute at 131°C.
- the total duration of the heat treatment including the temperature rise, the plateau and the cooling is approximately 22 to 23 minutes.
- Test No. 5 Formulation of a biocompatible product with a co-crosslinked matrix HA and CHITO, with a divalent zinc cation present in the matrix by adding zinc chloride
- a formulation of HA and of CHITO comprising 90% co-crosslinked HA-CHITO phase and 10% non-crosslinked (linear) phase based on HA-CHITO is prepared.
- the concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
- the crosslinked phase of HA-CHITO is prepared as previously described in connection with test No. 4.
- a linear phase with HA and CHITO is prepared as previously described in connection with test No. 4, except that after complete dissolution of sodium hyaluronate (NaHa) and carboxymethyl chitosan, a divalent zinc cation is added to the matrix by incorporating zinc chloride (ZnCl 2 ) into the solution (by means of a dispersion).
- ZnCl 2 zinc chloride
- crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
- the biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
- the glass syringes are then subjected to heat treatment as described above, by autoclaving with a sterilization plate for 1 minute at 131°C.
- the total duration of the heat treatment including the temperature rise, the plateau and the cooling is approximately 22 to 23 minutes.
- Test No. 6 Formulation of a biocompatible product with a co-crosslinked matrix HA and CHITO, with a divalent zinc cation present in the matrix by adding zinc sulphate
- a formulation of HA and CHITO comprising 90% co-crosslinked HA-CHITO phase and 10% non-crosslinked (linear) phase based on HA-CHITO is prepared.
- the concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
- the crosslinked phase of HA-CHITO is prepared as previously described in connection with test No. 4.
- a linear phase with HA and CHITO is prepared as previously described in connection with test No. 4, except that after complete dissolution of sodium hyaluronate (NaHa) and carboxymethyl chitosan, a divalent zinc cation is added to the matrix by incorporating zinc sulphate (ZnSO 4 ) into the solution (by means of a dispersion).
- ZnSO 4 zinc sulphate
- crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
- the biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
- the glass syringes are then subjected to a heat treatment as described above, by passage through an autodave with a sterilization tray for a period of 1 minute at 131°C.
- the total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes.
- viscosities of formulations 1, 2a to 2c, 3, 4a, 4b, 5a to 5c and 6a to 6c were measured using a Discovery hybrid rheometer "DHR2" from the company TA Instruments as previously explained, and this before and after application of the previously explained heat treatment (sterilization with a plateau lasting 1 minute at a temperature of 131°C, total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes).
- DHR2 Discovery hybrid rheometer
- a fourth observation, based more particularly on formulations 4b, 5a to 5c, 6b and 6c, is that the addition of a divalent zinc cation in a coreticulated matrix of HA and of CHITO according to a concentration between approximately 0.005% and about 0.06% makes it possible to obtain a viscosity after heat treatment almost close to the viscosity before heat treatment (formulations 5a, 5b), or even greater than the viscosity before heat treatment (formulations 4b, 5c, 6b and 6c).
- the present invention which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, proves to be very valuable for the prevention and/or treatment of pathologies which can be improved or avoided by :
- the present invention which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, also proves to be very valuable for a method for treating osteoarthritis, or for repairing a cartilage defect, the composition being for example formulated for administration by injection into synovial fluid or for implantation into cartilage after mixing with blood, or for a method of treating dry eye.
- the present invention which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, also proves to be very valuable for use in a treatment method in therapy, in surgery, or cosmetics, including in particular treatment in rheumatology, ophthalmology, gynecology, aesthetic medicine, plastic surgery, internal surgery, orthopedic surgery, for the prevention of post-surgical tissue adhesions, in dermatology.
- the present invention which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, also proves to be very valuable for use in a therapeutic treatment of an eye syndrome. dryness, corneal damage or eye or joint inflammation.
- the present invention which makes it possible to obtain a high viscosity after heat treatment, or even higher than the viscosity before heat treatment, also proves to be very valuable for use in a therapeutic treatment during which said composition is applied by instillation. on the ocular surface to prevent or combat corneal damage or dry eye syndrome, in particular for the purpose of lubricating or regenerating the ocular surface.
- composition of ophthalmic drops comprising a biocompatible product with a co-crosslinked matrix of HA and of CHITO as described previously.
- Biocompatibility trials and tests were carried out by intracutaneous injections of doses of 0.2 mL on the backs of rabbits at separate sites. The sites were observed immediately after injection. Observations were made in terms of erythema and edema after 24h (1 day), 48h (2 days), 72h (3 days), 7 days and 14 days.
- - sample A a biocompatible product according to formulation 2a, the divalent zinc cation being added to the matrix by incorporating zinc gluconate according to a zinc gluconate concentration of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix 0.002%),
- - sample B a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of plant (fungal) origin,
- - sample C a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of animal origin,
- - sample D a product marketed under the PERFECTHA® DERM brand (batch number: 190625-2) from the company Sinclair France SAS,
- - sample F a solution of sodium chloride (physiological serum) at 9 g/L (ie 0.9% by weight by volume).
- Tests and ocular irritation tests were carried out (in adaptation of the ISO 10993 standard - part 10) by instillation of doses of 0.1 mL of samples to be tested into the lower conjunctival sac of the left eye of rabbits while a dose of 0.1 mL of a solution of sodium chloride (physiological serum) at 9 g/L (i.e. 0.9% by weight by volume) was instilled as a control in the lower conjunctival sac of the right eye of said rabbits. Observations were made in terms of ocular reactions after 1 h, 24 h (1 day), 48 h (2 days) and 72 h (3 days). Each sample was tested on two rabbits.
- - sample G a biocompatible product according to formulation 2a, the divalent zinc cation being added to the matrix by incorporating zinc gluconate according to a zinc gluconate concentration of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix 0.002%),
- - sample H a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of plant (fungal) origin,
- - sample I a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of animal origin.
- product with adaptive viscoelastic behavior is meant a product having:
- biocompatible products according to the present invention which were tested (after heat treatment) are:
- sample L (HYLO-FORTE® from the company Ursapharm Arzneistoff GmbH) shows a viscoelastic behavior that is clearly more adaptive, its viscosity remains low over the entire range of shear rates tested.
- formulations according to the present invention all have a viscosity which is high at low shear rate and which decreases fairly regularly (more or less quickly) down to a viscosity significantly lower at high shear rates.
- the formulations according to the invention thus have an adaptive viscoelastic behavior making them suitable for use in an ophthalmic drop composition, and the concentration of divalent zinc cation in the matrix and the rate of crosslinking of the matrix make it possible to adapt the viscosity to the desired use.
- the formulations according to the present invention are thus particularly interesting for a therapeutic treatment by instillation on the ocular surface to prevent or fight against a corneal lesion or a dry eye syndrome, in particular with the aim of lubricating or regenerating the ocular surface.
- the viscosity of the formulations according to the invention is markedly higher than the viscosity of the products available on the market.
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Abstract
The invention relates to a biocompatible product having a crosslinked matrix, in which a polysaccharide is co-crosslinked with chitosan, chitosan derivative, or chitosan salt, said matrix further comprising a divalent zinc cation.
Description
DESCRIPTION DESCRIPTION
TITRE DE L’INVENTION : PRODUIT BIOCOMPATIBLE A MATRICE COMPRENANT UN POLYSACCHARIDE ET DU CHITOSANE CO-RETICULES TITLE OF THE INVENTION: BIOCOMPATIBLE PRODUCT WITH A MATRIX COMPRISING A CO-CROSSTICULATED POLYSACCHARIDE AND CHITOSAN
DOMAINE TECHNIQUE DE L'INVENTION TECHNICAL FIELD OF THE INVENTION
[0001] La présente invention concerne le domaine des produits biocompatibles à visées cosmétique et/ou médicale, notamment chirurgicale. Elle concerne tout particulièrement un produit biocompatible à matrice comprenant un polysaccharide au moins en partie co-réticulé avec du chitosane, de préférence un dérivé de chitosane ou un sel de chitosane. The present invention relates to the field of biocompatible products for cosmetic and/or medical, in particular surgical, purposes. It relates most particularly to a biocompatible product with a matrix comprising a polysaccharide at least partly co-crosslinked with chitosan, preferably a chitosan derivative or a chitosan salt.
[0002] Depuis déjà un certain nombre d’années, on constate un intérêt croissant pour les produits permettant le comblement, le remplacement, l'augmentation de volume d'un tissu biologique et/ou le remplacement, la supplémentation d'un fluide biologique, aussi bien dans le domaine cosmétique que dans le domaine médical. [0002] For a number of years now, there has been a growing interest in products for filling, replacing, increasing the volume of a biological tissue and/or replacing or supplementing a biological fluid , both in the cosmetic field and in the medical field.
[0003] Ainsi, par exemple l'utilisation de produits permettant l'augmentation de volume d'un tissu biologique est particulièrement intéressante dans le domaine cosmétique, pour traiter les rides et ridules mais aussi pour redéfinir les contours du visage, du corps. [0004] Les produits d'augmentation de volume, de comblement, de remplacement d'un tissu biologique, ou de remplacement, de supplémentation d'un fluide biologique peuvent également être utiles dans le domaine médical. [0003] Thus, for example, the use of products allowing the volume increase of a biological tissue is particularly interesting in the cosmetics field, to treat wrinkles and fine lines but also to redefine the contours of the face, of the body. [0004] Products for increasing volume, for filling, for replacing a biological tissue, or for replacing or supplementing a biological fluid can also be useful in the medical field.
[0005] Par exemple, on connaît dans l’art antérieur, l'utilisation de produits destinés à supplémenter le liquide synovial chez des patients atteints de dégénérescence articulaire. De tels produits comprennent le plus souvent de l'acide hyaluronique. [0005] For example, in the prior art, the use of products intended to supplement the synovial fluid in patients suffering from joint degeneration is known. Such products most often include hyaluronic acid.
[0006] On connaît également des produits dits « viscoélastiques » qui sont employés lors de chirurgies ophtalmiques afin de remplacer ou supplémenter l'humeur aqueuse (lors de la chirurgie de la cataracte ou dans le cadre de chirurgie réfractive) ou l'humeur vitrée (dans le cas d'une vitrectomie), tels que décrits dans le document US 4,716,154. [0006] So-called "viscoelastic" products are also known which are used during ophthalmic surgeries in order to replace or supplement the aqueous humor (during cataract surgery or in the context of refractive surgery) or the vitreous humor ( in the case of a vitrectomy), as described in document US 4,716,154.
[0007] Les propriétés rhéologiques du produit ont une importance particulière. [0007] The rheological properties of the product are of particular importance.
[0008] Un certain nombre de produits biocompatibles, notamment des produits comprenant de l’acide hyaluronique réticulé ou un sel d’acide hyaluronique réticulé, ont permis de combler, remplacer, augmenter le volume d'un tissu biologique et/ou remplacer, supplémenter un fluide biologique. Toutefois, certains d’entre eux ne peuvent être utilisés efficacement ni dans le domaine cosmétique ni dans le
domaine médical du fait de leurs effets secondaires indésirables et/ou de leur faible efficacité. [0008] A certain number of biocompatible products, in particular products comprising cross-linked hyaluronic acid or a salt of cross-linked hyaluronic acid, have made it possible to fill, replace, increase the volume of a biological tissue and/or replace, supplement a biological fluid. However, some of them cannot be used effectively either in the cosmetic field or in the medical field because of their undesirable side effects and/or low efficacy.
[0009] L'efficacité de certains de ces produits pourrait être améliorée en leur procurant des propriétés rhéologiques plus élevées, et en limitant aussi les risques de dégradation de leurs propriétés rhéologiques. [0009] The effectiveness of some of these products could be improved by providing them with higher rheological properties, and also by limiting the risks of degradation of their rheological properties.
[0010] Il est en particulier utile et important, pour de nombreuses applications, que le produit présente une viscosité élevée, notamment à faible taux de cisaillement. [0010] It is particularly useful and important, for many applications, for the product to have a high viscosity, in particular at low shear rates.
[0011] Les produits à base d’acide hyaluronique réticulé ou de sel d'acide hyaluronique réticulé présentent une viscosité relativement satisfaisante après réticulation. [0012] Toutefois, la viscosité de ces produits a tendance à diminuer fortement après l’accomplissement d’un traitement thermique. Or, ces produits doivent être stérilisés avant leur utilisation chez un être humain ou animal, et cette stérilisation est généralement effectuée par un traitement thermique (par exemple au moyen d’un autoclave). [0013] Le document US 10,898,613 B2 décrit une composition hydrogel injectable biocompatible d’acide hyaluronique réticulée contenant de 0,05 mM à 4 mM de cation divalent zinc pour conférer une stabilité améliorée (évaluée par un paramètre de viscosité) après stérilisation par autoclave. [0011] Products based on cross-linked hyaluronic acid or cross-linked hyaluronic acid salt have a relatively satisfactory viscosity after cross-linking. [0012] However, the viscosity of these products tends to decrease sharply after the completion of a heat treatment. However, these products must be sterilized before their use in a human or animal, and this sterilization is generally carried out by heat treatment (for example by means of an autoclave). [0013] Document US 10,898,613 B2 describes a biocompatible injectable hydrogel composition of cross-linked hyaluronic acid containing from 0.05 mM to 4 mM of zinc divalent cation to confer improved stability (evaluated by a viscosity parameter) after sterilization by autoclave.
[0014] Le document FR 3 096260 A1 décrit une co-réticulation de carboxyméthyl chitosane avec du hyaluronane dans le but de combiner les propriétés hydratantes reconnues du hyaluronane aux propriétés de protection contre le stress oxydant du chitosane. [0014] Document FR 3 096260 A1 describes a co-crosslinking of carboxymethyl chitosan with hyaluronan with the aim of combining the recognized moisturizing properties of hyaluronan with the protective properties against oxidative stress of chitosan.
EXPOSE DE L’INVENTION [0015] Un problème proposé par la présente invention est de fournir un produit biocompatible permettant de mieux combler, remplacer, augmenter le volume d'un tissu biologique et/ou remplacer, supplémenter un fluide biologique. DESCRIPTION OF THE INVENTION [0015] A problem proposed by the present invention is to provide a biocompatible product making it possible to better fill, replace, increase the volume of a biological tissue and/or replace, supplement a biological fluid.
[0016] Simultanément, l'invention vise à fournir un tel produit présentant des propriétés rhéologiques améliorées, notamment en termes de viscosité après application d’un traitement thermique tel qu’une stérilisation par autoclave. Simultaneously, the invention aims to provide such a product having improved rheological properties, in particular in terms of viscosity after application of a heat treatment such as sterilization by autoclave.
[0017] Pour atteindre ces objets ainsi que d'autres, l'invention propose un produit biocompatible selon la revendication 1. To achieve these and other objects, the invention provides a biocompatible product according to claim 1.
[0018] Par « produit biocompatible » au sens de la présente invention, on entend désigner tout produit qui est bien toléré par un organisme vivant et qui ne provoque pas de réaction de rejet, de réaction toxique, de lésion ou d'effet nocif sur les fonctions biologiques de ce dernier.
[0019] Par « dérivé de chitosane », on entend désigner un chitosane substitué présentant une substitution des unités D-glucosamine et/ou N-acétyl-D- glucosamine, et dans lequel le groupe de substitution est lié de manière covalente. By "biocompatible product" within the meaning of the present invention, is meant any product which is well tolerated by a living organism and which does not cause a rejection reaction, a toxic reaction, a lesion or a harmful effect on its biological functions. [0019] The term "chitosan derivative" is intended to denote a substituted chitosan having a substitution of the D-glucosamine and/or N-acetyl-D-glucosamine units, and in which the substitution group is covalently bonded.
[0020] La demanderesse a constaté qu’une co-réticulation d’un polysaccharide (choisi dans le groupe comprenant l’acide hyaluronique, un sel d’acide hyaluronique, le sulfate de chondroïtine, les dérivés cellulosiques, et un mélange de ceux-ci) avec du chitosane, un dérivé de chitosane ou un sel de chitosane, qui mène à l’établissement dans la matrice de liaisons covalentes entre le polysaccharide et le chitosane, dérivé de chitosane ou sel de chitosane, permet d'augmenter très sensiblement la viscosité du produit par rapport au polysaccharide réticulé. [0020] The Applicant has found that a co-crosslinking of a polysaccharide (chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture of these ci) with chitosan, a chitosan derivative or a chitosan salt, which leads to the establishment in the matrix of covalent bonds between the polysaccharide and the chitosan, chitosan derivative or chitosan salt, makes it possible to very significantly increase the viscosity of the product relative to the cross-linked polysaccharide.
Toutefois, la demanderesse a aussi constaté que la viscosité dudit produit coréticulé demeurait fortement sujette à dégradation suite à un traitement thermique tel qu’un passage à l’autoclave. However, the Applicant has also observed that the viscosity of said coreticulated product remained highly subject to degradation following a heat treatment such as passage through an autoclave.
[0021] C’est dans ce cadre que la demanderesse a eu la surprise de constater que la co-réticulation d’un polysaccharide (choisi dans le groupe comprenant l’acide hyaluronique, un sel d’acide hyaluronique, le sulfate de chondroïtine, les dérivés cellulosiques, et un mélange de ceux-ci) avec du chitosane, un dérivé de chitosane ou un sel de chitosane, combinée avec la présence d’un cation zinc divalent, permet non seulement d’augmenter de façon très importante la viscosité du produit, mais permet en outre de limiter efficacement la diminution de cette viscosité après un traitement thermique tel qu’un passage à l’autoclave. Cette diminution moindre de la viscosité augure également d’une durabilité améliorée et d'une meilleure aptitude pour combler, remplacer, augmenter le volume d'un tissu biologique et/ou remplacer, supplémenter un fluide biologique. [0022] Selon une première possibilité, le cation zinc divalent peut être introduit par l’ajout d’un saccharide de zinc pour être réticulé dans la matrice. On entend par « réticulé dans la matrice », au sens de la présente invention, une liaison à au moins un des constituants de la matrice par au moins deux liaisons covalentes. [0021] It is in this context that the applicant was surprised to find that the co-crosslinking of a polysaccharide (chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture thereof) with chitosan, a chitosan derivative or a chitosan salt, combined with the presence of a divalent zinc cation, not only makes it possible to very significantly increase the viscosity of the product, but also makes it possible to effectively limit the reduction in this viscosity after a heat treatment such as passage through an autoclave. This lesser decrease in viscosity also augurs for improved durability and a better ability to fill, replace, increase the volume of a biological tissue and/or replace, supplement a biological fluid. According to a first possibility, the divalent zinc cation can be introduced by adding a zinc saccharide to be crosslinked in the matrix. The term “crosslinked in the matrix”, within the meaning of the present invention, is understood to mean a bond to at least one of the constituents of the matrix by at least two covalent bonds.
[0023] Selon une autre possibilité, le cation zinc divalent peut être introduit par l’ajout d’un saccharide de zinc pour être greffé dans la matrice. On entend par « greffé dans la matrice », au sens de la présente invention, une liaison à au moins un des constituants de la matrice par une liaison covalente. According to another possibility, the divalent zinc cation can be introduced by adding a zinc saccharide to be grafted into the matrix. The term “grafted into the matrix”, within the meaning of the present invention, means a bond to at least one of the constituents of the matrix by a covalent bond.
[0024] Selon encore une autre possibilité, le cation zinc divalent peut être de préférence dispersé dans la matrice. On entend par « dispersé dans la matrice » une absence de liaison covalente aux constituants de la matrice. Une dispersion dans la matrice du cation zinc divalent a procuré d'excellents résultats en termes de viscosité. Par ailleurs, le procédé de fabrication est plus simple qu’en cas d’ajout en
vue d’une réticulation ou d’une greffe, car le zinc (sous forme de sel de zinc ou sous forme d’un saccharide de zinc notamment) présente une solubilité relativement médiocre dans la gamme de pH nécessaire pour une réticulation ou une greffe. According to yet another possibility, the divalent zinc cation can preferably be dispersed in the matrix. The term "dispersed in the matrix" means an absence of covalent bond to the constituents of the matrix. A dispersion in the matrix of the divalent zinc cation provided excellent results in terms of viscosity. Moreover, the manufacturing process is simpler than in the case of addition in view of a crosslinking or a graft, because zinc (in the form of a zinc salt or in the form of a zinc saccharide in particular) has a relatively poor solubility in the pH range necessary for a crosslinking or a graft.
[0025] Avantageusement, pour une bonne augmentation de la viscosité, la concentration de cation zinc divalent dans la matrice peut être comprise entre[0025] Advantageously, for a good increase in viscosity, the concentration of divalent zinc cation in the matrix can be between
0,001 % et 1 % en poids par rapport au poids total de la matrice, et de préférence entre 0,01 % et 1 % en poids par rapport au poids total de la matrice. 0.001% and 1% by weight relative to the total weight of the matrix, and preferably between 0.01% and 1% by weight relative to the total weight of the matrix.
[0026] De préférence, afin de conserver une bonne transparence du produit pour les applications le nécessitant (notamment dans le domaine ophtalmologique ou pour des injections à proximité de la surface de la peau), la concentration de cation zinc divalent dans la matrice peut être inférieure ou égale à 0,1 % en poids par rapport au poids total de la matrice. Preferably, in order to maintain good transparency of the product for applications requiring it (in particular in the ophthalmological field or for injections close to the surface of the skin), the concentration of divalent zinc cation in the matrix can be less than or equal to 0.1% by weight relative to the total weight of the matrix.
[0027] Avantageusement, la concentration de cation zinc divalent dans la matrice peut être comprise entre 0,002 % et 0,06 % en poids par rapport au poids total de la matrice, et de préférence entre 0,01 % et 0,6 % en poids par rapport au poids total de la matrice. Avec une telle concentration, la demanderesse a constaté avec un grand étonnement mais aussi un grand intérêt que la viscosité du produit selon l’invention après traitement thermique (tel qu’un passage à l’autoclave) reste élevée, peut être voisine de sa viscosité avant traitement thermique, voire peut même être supérieure à sa viscosité avant traitement thermique. Advantageously, the concentration of divalent zinc cation in the matrix can be between 0.002% and 0.06% by weight relative to the total weight of the matrix, and preferably between 0.01% and 0.6% by weight. weight relative to the total weight of the matrix. With such a concentration, the applicant has observed with great astonishment but also great interest that the viscosity of the product according to the invention after heat treatment (such as passage through an autoclave) remains high, can be close to its viscosity before heat treatment, or even may even be greater than its viscosity before heat treatment.
[0028] De préférence, le cation zinc divalent peut être inclus dans la matrice par l’ajout d’un sel de zinc ou d’un saccharide de zinc, de préférence du gluconate de zinc, du chlorure de zinc ou du sulfate de zinc. Le gluconate de zinc favorise l’obtention d’un produit de bonne transparence, en particulier pour les applications le nécessitant (notamment dans le domaine ophtalmologique ou pour des injections à proximité de la surface de la peau). Le chlorure de zinc et le sulfate de zinc se sont révélés intéressants pour des applications en rhumatologie, en chirurgie orthopédique, ou pour le traitement d'une arthrose ou la réparation d'un défaut de cartilage. [0028] Preferably, the divalent zinc cation can be included in the matrix by the addition of a zinc salt or a zinc saccharide, preferably zinc gluconate, zinc chloride or zinc sulphate. . Zinc gluconate helps to obtain a product with good transparency, in particular for applications requiring it (notably in the ophthalmological field or for injections close to the surface of the skin). Zinc chloride and zinc sulphate have proved interesting for applications in rheumatology, in orthopedic surgery, or for the treatment of osteoarthritis or the repair of a cartilage defect.
[0029] Avantageusement, on peut prévoir que : - la concentration en polysaccharide choisi dans le groupe comprenant l’acide hyaluronique, un sel d’acide hyaluronique, le sulfate de chondroïtine, les dérivés cellulosiques, et un mélange de ceux-ci, est comprise entre 0,01 % et 3 % en poids par rapport au poids total de la matrice, et/ou [0029] Advantageously, it can be provided that: - the concentration of polysaccharide chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture thereof, is between 0.01% and 3% by weight relative to the total weight of the matrix, and/or
- la concentration en chitosane, en dérivé de chitosane, ou en sel de chitosane est comprise entre 0,01 % et 3 % en poids par rapport au poids total de la matrice. - the concentration of chitosan, chitosan derivative, or chitosan salt is between 0.01% and 3% by weight relative to the total weight of the matrix.
[0030] De préférence, le dérivé de chitosane peut être un carboxyalkyle chitosane. De bons résultats ont en particulier été obtenus avec le carboxyméthyle chitosane.
[0031] Par carboxya!ky!e chitosane, on entend désigner un chitosane présentant des unités glucosamine, des unités N-acétyl- glucosamine et des unités glucosamine substituées par un groupe carboxyalkyl. On parle ainsi de dérivé de chitosane ou de chitosane substitué. [0032] Avantageusement, le polysaccharide peut être l’acide hyaluronique ou un sel d’acide hyaluronique, et peut de préférence présenter un poids moléculaire compris entre 0,1 et 5 MDa. [0030] Preferably, the chitosan derivative can be a carboxyalkyl chitosan. Good results have in particular been obtained with carboxymethyl chitosan. By carboxya! ky! e chitosan is meant a chitosan having glucosamine units, N-acetyl-glucosamine units and glucosamine units substituted by a carboxyalkyl group. This is thus referred to as a chitosan derivative or a substituted chitosan. Advantageously, the polysaccharide can be hyaluronic acid or a salt of hyaluronic acid, and can preferably have a molecular weight of between 0.1 and 5 MDa.
[0033] Selon un autre aspect de la présente invention, il est proposé une composition cosmétique ou pharmaceutique comprenant un produit biocompatible tel que précédemment décrit. Cette composition cosmétique ou pharmaceutique peut se présenter sous la forme d’une solution viscoélastique ou d’un hydrogel. According to another aspect of the present invention, there is provided a cosmetic or pharmaceutical composition comprising a biocompatible product as previously described. This cosmetic or pharmaceutical composition can be in the form of a viscoelastic solution or a hydrogel.
[0034] Avantageusement, la composition cosmétique ou pharmaceutique peut comprendre un tampon physiologiquement acceptable, contenant de préférence des polyols (mannitol, sorbitol, glycérol) et/ou des phospholipides. [0035] De préférence, ladite composition peut être utilisée dans une méthode de traitement cosmétique ou de traitement thérapeutique, comprenant notamment l'application topique, l’implantation, l’instillation ou l'injection par voie sous-cutanée, intradermique, mucosale, oculaire, intraoculaire, ou intra-articulaire, de ladite composition. [0036] Avantageusement, ladite composition peut être utilisée pour la prévention et/ou le traitement de pathologies pouvant être améliorées ou évitées par : Advantageously, the cosmetic or pharmaceutical composition may comprise a physiologically acceptable buffer, preferably containing polyols (mannitol, sorbitol, glycerol) and/or phospholipids. Preferably, said composition can be used in a method of cosmetic treatment or therapeutic treatment, comprising in particular topical application, implantation, instillation or injection by subcutaneous, intradermal, mucosal, ocular, intraocular, or intra-articular, of said composition. Advantageously, said composition can be used for the prevention and/or treatment of pathologies which can be improved or avoided by:
- le comblement ou le remplacement d'un tissu biologique ; et/ou - the filling or replacement of a biological tissue; and or
- l'augmentation de volume dudit tissu biologique ; et/ou - the increase in volume of said biological tissue; and or
- la supplémentation ou le remplacement d'un fluide biologique. [0037] De préférence, ladite composition peut être utilisée pour une méthode de traitement d'une arthrose, ou de réparation d'un défaut de cartilage, la composition étant par exemple formulée pour une administration par injection dans le fluide synovial ou pour une implantation dans le cartilage après mélange avec le sang, ou pour une méthode de traitement de la sécheresse oculaire. [0038] Avantageusement, ladite composition peut être utilisée dans une méthode de traitement en thérapeutique, en chirurgie, ou cosmétique, incluant en particulier un traitement en rhumatologie, en ophtalmologie, en gynécologie, en médecine esthétique, en chirurgie plastique, en chirurgie interne, en chirurgie orthopédique, pour la prévention des adhérences tissulaires post-chirurgicales, en dermatologie. [0039] De façon plus particulièrement préférée, la composition peut être utilisée dans un traitement thérapeutique d’un syndrome de l’œil sec, d’une lésion de cornée ou d’une inflammation oculaire ou articulaire.
[0040] Avantageusement, ladite composition peut être utilisée dans un traitement thérapeutique lors duquel on applique ladite composition par instillation sur la surface oculaire pour prévenir ou lutter contre une lésion de cornée ou un syndrome de l’œil sec, en particulier dans le but de lubrifier ou régénérer la surface oculaire. - supplementation or replacement of a biological fluid. Preferably, said composition can be used for a method of treating osteoarthritis, or repairing a cartilage defect, the composition being for example formulated for administration by injection into the synovial fluid or for implantation in cartilage after mixing with blood, or for a method of treating dry eyes. Advantageously, said composition can be used in a therapeutic, surgical or cosmetic treatment method, including in particular a treatment in rheumatology, ophthalmology, gynecology, aesthetic medicine, plastic surgery, internal surgery, in orthopedic surgery, for the prevention of post-surgical tissue adhesions, in dermatology. [0039] More particularly preferably, the composition can be used in a therapeutic treatment of a dry eye syndrome, of a corneal lesion or of an ocular or articular inflammation. [0040] Advantageously, said composition can be used in a therapeutic treatment during which said composition is applied by instillation on the ocular surface to prevent or fight against a corneal lesion or a dry eye syndrome, in particular with the aim of lubricate or regenerate the ocular surface.
[0041] Selon un autre aspect de la présente invention, il est proposé une composition de gouttes ophtalmiques comprenant un produit biocompatible tel que précédemment décrit. According to another aspect of the present invention, there is provided an ophthalmic drop composition comprising a biocompatible product as previously described.
[0042] Selon un autre aspect de la présente invention, il est proposé un procédé de fabrication d’un produit biocompatible tel que précédemment décrit ou d’une composition telle que précédemment décrite, ledit procédé comprenant les étapes suivantes : a. dissoudre dans une même solution aqueuse : i. un polysaccharide choisi dans le groupe comprenant l’acide hyaluronique, un sel d’acide hyaluronique, le sulfate de chondroïtine, les dérivés cellulosiques, et un mélange de ceux-ci, de préférence de l’acide hyaluronique ou un sel d'acide hyaluronique, ii. du chitosane, de préférence un dérivé de chitosane, ou un sel de chitosane, b. ajouter dans ladite solution aqueuse un agent réticulant et provoquer une réticulation du mélange pour former une matrice, c. ajouter un cation divalent de zinc avant et/ou après l’étape b. According to another aspect of the present invention, there is provided a method for manufacturing a biocompatible product as described above or a composition as described above, said method comprising the following steps: a. dissolve in the same aqueous solution: i. a polysaccharide selected from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulosic derivatives, and a mixture thereof, preferably hyaluronic acid or a salt of hyaluronic acid , ii. chitosan, preferably a chitosan derivative, or a chitosan salt, b. adding a crosslinking agent to said aqueous solution and causing crosslinking of the mixture to form a matrix, c. add a divalent zinc cation before and/or after step b.
[0043] Il doit être noté que l’invention n’est pas limitée à une méthode de réticulation covalente particulière, mais on peut préférer une méthode utilisant une molécule chimique servant d'agent de réticulation, dit aussi agent réticulant, tel que l’éther diglycidylique de 1 ,4-butanediol (BDDE) ou le polyéthylène glycol diglycidyl éther (PEGDE) notamment. It should be noted that the invention is not limited to a particular covalent crosslinking method, but a method using a chemical molecule serving as crosslinking agent, also called crosslinking agent, such as 1,4-butanediol diglycidyl ether (BDDE) or polyethylene glycol diglycidyl ether (PEGDE) in particular.
[0044] Lorsque le cation divalent de zinc est ajouté avant l’étape b, cet ajout peut se faire sous la forme d’un saccharide de zinc, en vue d’une réticulation et/ou d’une greffe dans la matrice, ou peut se faire sous la forme d’un sel de zinc qui sera dispersé dans la matrice. When the divalent zinc cation is added before step b, this addition can be in the form of a zinc saccharide, with a view to crosslinking and/or grafting into the matrix, or can be in the form of a zinc salt which will be dispersed in the matrix.
[0045] Lorsque le cation divalent de zinc est ajouté après l’étape b, cet ajout se fait sous la forme de sel de zinc ou saccharide de zinc qui est dispersé dans la matrice. When the divalent zinc cation is added after step b, this addition takes place in the form of zinc salt or zinc saccharide which is dispersed in the matrix.
[0046] Les deux possibilités précédentes d’ajout de cation divalent de zinc peuvent être cumulées. The two previous possibilities for adding a divalent zinc cation can be combined.
[0047] Avantageusement, le pH du produit biocompatible ou de la composition peut être ajusté entre 6 et 8, de préférence à 7.
[0048] De préférence, le produit biocompatible ou la composition peut être soumis à un traitement thermique de stérilisation, de préférence un traitement thermique à une température comprise entre 120°C et 140°C pendant une durée comprise entre 1 et 20 minutes. Advantageously, the pH of the biocompatible product or of the composition can be adjusted between 6 and 8, preferably to 7. Preferably, the biocompatible product or the composition can be subjected to a heat treatment for sterilization, preferably a heat treatment at a temperature of between 120° C. and 140° C. for a period of between 1 and 20 minutes.
[0049] D'autres buts, caractéristiques et avantages de l'invention apparaîtront clairement à l'homme de l'art suite à la lecture de la description explicative qui fait référence à des exemples et modes de réalisation qui sont donnés seulement à titre d’illustration et qui ne sauraient en aucune façon limiter la portée des revendications. Other aims, characteristics and advantages of the invention will appear clearly to those skilled in the art following reading of the explanatory description which refers to examples and embodiments which are given only by way of illustration. illustration and which cannot in any way limit the scope of the claims.
[0050] Les exemples et modes de réalisation font partie intégrante de la présente invention et toute caractéristique apparaissant nouvelle par rapport à un état de la technique antérieure quelconque à partir de la description prise dans son ensemble, incluant les exemples et modes de réalisation, fait partie intégrante de l'invention dans sa fonction et dans sa généralité. [0050] The examples and embodiments form an integral part of the present invention and any feature appearing new with respect to any state of the prior art from the description taken as a whole, including the examples and embodiments, is integral part of the invention in its function and in its generality.
[0051] Ainsi, chaque exemple ou mode de réalisation a une portée générale. [0051] Thus, each example or embodiment has a general scope.
[0052] D'autre part, dans les exemples ou modes de réalisation, tous les pourcentages sont donnés en masse, sauf indication contraire, la température est exprimée en degré Celsius sauf indication contraire, et la pression est la pression atmosphérique, sauf indication contraire. On the other hand, in the examples or embodiments, all percentages are given by mass, unless otherwise indicated, the temperature is expressed in degrees Celsius unless otherwise indicated, and the pressure is atmospheric pressure, unless otherwise indicated. .
DESCRIPTION SOMMAIRE DES DESSINS BRIEF DESCRIPTION OF THE DRAWINGS
[0053] D'autres objets, caractéristiques et avantages de la présente invention ressortiront de la description suivante de modes de réalisation particuliers, faite en relation avec les figures jointes, parmi lesquelles : Other objects, characteristics and advantages of the present invention will emerge from the following description of particular embodiments, given in relation to the appended figures, among which:
[0054] [Fig.1 ] La figure 1 est un histogramme des viscosités de différentes formulations, mesurées avant et après traitement thermique ; et [0054] [Fig.1] Figure 1 is a histogram of the viscosities of different formulations, measured before and after heat treatment; and
[0055] [Fig.2] La figure 2 est un graphique illustrant l’évolution des viscosités de différentes formulations et de différents produits du marché en fonction du taux de cisaillement. [0055] [Fig.2] Figure 2 is a graph illustrating the evolution of the viscosities of different formulations and different products on the market as a function of the shear rate.
DESCRIPTION DES MODES DE REALISATION PREFERES DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0056] Matériaux ; [0056] Materials;
- hya!uronate de sodium (NaHa) issu de bio fermentation, - carboxyméthyle chitosane (CMCS) avec un degré d’acétylation inférieur à 10 %- sodium hya!uronate (NaHa) from bio-fermentation, - carboxymethyl chitosan (CMCS) with a degree of acetylation of less than 10%
(exprimé en nombre de moles d’unités N-acétyl -glucosamine par rapport au nombre de mole d'unités totales) et un degré de substitution de 80% (exprimé en nombre de
moles du substituant par rapport au nombre de moles d'unités totales), (expressed in number of moles of N-acetyl-glucosamine units relative to the number of moles of total units) and a degree of substitution of 80% (expressed in number of moles of the substituent relative to the number of moles of total units),
- éther diglycidylique de 1 ,4-butanediol (BDDE), - 1,4-butanediol diglycidyl ether (BDDE),
- polyéthylène glycol diglycidyl éther (PEGDE), - polyethylene glycol diglycidyl ether (PEGDE),
- gluconate de zinc (ZnGluc), - zinc gluconate (ZnGluc),
- chlorure de zinc (ZnCI2), - zinc chloride (ZnCl2),
- sulfate de zinc (ZnSO4), - zinc sulphate (ZnSO 4 ),
- chlorure de sodium (NaCI), - sodium chloride (NaCI),
- tampon physiologique, - physiological buffer,
- acide chlorhydrique (HCl), - hydrochloric acid (HCl),
- hydroxyde de sodium (NaOH), - sodium hydroxide (NaOH),
- membranes de dialyse. - dialysis membranes.
[0057] Préparation d’une solution tampon physiologique [0057] Preparation of a physiological buffer solution
[0058] Une solution tampon physiologique est préparée dans de l'eau déionisée pour atteindre un pH compris entre 6 et 8 et une osmolalité comprise entre 250 et 350 mOsm/L. A physiological buffer solution is prepared in deionized water to reach a pH of between 6 and 8 and an osmolality of between 250 and 350 mOsm/L.
[0059] Synthèse d'une ohase réticulée comprenant un polvsaccharide fô savoir de l’acide hyaluronique ou un sel d’acide hyaluronique) [0059] Synthesis of a cross-linked ohase comprising a polysaccharide (i.e. hyaluronic acid or a salt of hyaluronic acid)
[0060] Pour simplifier la compréhension du lecteur, l'acide hyaluronique ou un sel d'acide hyaluronique est désigné par « HA ». [0060] To simplify the reader's understanding, hyaluronic acid or a salt of hyaluronic acid is designated by “HA”.
La réticulation du HA est réalisée par dissolution du HA (par exemple d’hyaluronate de sodium (NaHa)) dans une solution aqueuse de soude à 0,25 mol/L jusqu’à solubilisation complète. On ajoute alors un agent réticulant (par exemple du BDDE ou du PEGDE) et on mélange pour homogénéiser. Le mélange est fermé hermétiquement et placé au bain-marie à 50°C pendant 3 heures pour induire une réaction de réticulation du HA. Des liaisons covalentes sont ainsi créées entre l’agent réticulant et le HA. Des ponts peuvent ainsi être formés entre deux chaînes de HA. Le gel est ensuite homogénéisé et neutralisé dans un récipient avec l’ajout d’une solution aqueuse d’acide chlorhydrique pour former une phase homogène et transparente. Une dialyse est alors effectuée pour éliminer l’agent réticulant résiduel et pour stabiliser le pH et l'osmolarité. The crosslinking of the HA is carried out by dissolving the HA (for example sodium hyaluronate (NaHa)) in an aqueous solution of sodium hydroxide at 0.25 mol/L until complete solubilization. A crosslinking agent (for example BDDE or PEGDE) is then added and the mixture is mixed to homogenize. The mixture is sealed and placed in a water bath at 50° C. for 3 hours to induce a crosslinking reaction of the HA. Covalent bonds are thus created between the crosslinking agent and the HA. Bridges can thus be formed between two HA chains. The gel is then homogenized and neutralized in a container with the addition of an aqueous solution of hydrochloric acid to form a homogeneous and transparent phase. Dialysis is then performed to remove residual cross-linking agent and to stabilize pH and osmolarity.
[0061] Synthèse d'une phase réticulée comprenant un polysaccharide (à savoir de l’acide hyaluronique ou un sel d'acide hyaluronique)avecdu chitosane. un dérivé de chitosane ou un sel de chitosane
[0062] Pour simplifier la compréhension du lecteur, l'acide hyaluronique ou un sel d’acide hyaluronique est désigné par « HA », tandis que du chitosane, un dérivé de chitosane ou un sel de chitosane est désigné par « CHITO ». Synthesis of a cross-linked phase comprising a polysaccharide (namely hyaluronic acid or a salt of hyaluronic acid) with chitosan. a chitosan derivative or a chitosan salt To simplify the reader's understanding, hyaluronic acid or a salt of hyaluronic acid is designated by “HA”, while chitosan, a chitosan derivative or a salt of chitosan is designated by “CHITO”.
[0063] La réticulation du HA avec du CHITO est réalisée par dissolution du HA (par exemple d’hyaluronate de sodium (NaHa)) et d'un « CHITO » (par exemple un carboxyalkyle chitosane) dans une solution aqueuse de soude à 0,25 mol/L jusqu'à solubilisation complète. On ajoute alors un agent réticulant (par exemple du BDDE ou du PEGDE) et on mélange pour homogénéiser. Le mélange est fermé hermétiquement et placé au bain-marie à 50°C pendant 3 heures pour induire une réaction de réticulation simultanée (ou co-réticulation) du HA et du CHITO. Par « réticulation simultanée » ou « co-réticulation », on signifie que des liaisons covalentes peuvent être créées entre l’agent réticulant et le HA mais également entre l'agent réticulant et le CHITO. Des ponts peuvent ainsi être formés entre deux chaînes de HA, entre deux chaînes de CHITO, ou entre une chaîne de HA et une chaîne de CHITO. Le gel est ensuite homogénéisé et neutralisé dans un récipient avec l’ajout d’une solution aqueuse d’acide chlorhydrique pour former une phase homogène et transparente. Une dialyse est alors effectuée pour éliminer l’agent réticulant résiduel et pour stabiliser le pH et l’osmolarité. The crosslinking of HA with CHITO is carried out by dissolving the HA (for example sodium hyaluronate (NaHa)) and a "CHITO" (for example a carboxyalkyl chitosan) in an aqueous solution of soda at 0 .25 mol/L until complete solubilization. A crosslinking agent (for example BDDE or PEGDE) is then added and the mixture is mixed to homogenize. The mixture is sealed and placed in a water bath at 50° C. for 3 hours to induce a simultaneous crosslinking reaction (or co-crosslinking) of the HA and of the CHITO. By “simultaneous crosslinking” or “co-crosslinking”, it is meant that covalent bonds can be created between the crosslinking agent and the HA but also between the crosslinking agent and the CHITO. Bridges can thus be formed between two chains of HA, between two chains of CHITO, or between a chain of HA and a chain of CHITO. The gel is then homogenized and neutralized in a container with the addition of an aqueous solution of hydrochloric acid to form a homogeneous and transparent phase. Dialysis is then performed to remove residual cross-linking agent and to stabilize pH and osmolarity.
[0064] Synthèse d'une Phase linéaire (non réticulée)d'un polvsaccharideïà savoir d'acide hyaluronique ou de sel d'acide hyalurizînc[0064] Synthesis of a linear (non-crosslinked) phase of a polysaccharide, namely hyaluronic acid or hyalurizinc acid salt
(et avec, le cas échéant du chitosane. un dérivé de chitosane ou un sel de chitosane) (and with, where appropriate, chitosan, a chitosan derivative or a chitosan salt)
[0065] Pour simplifier la compréhension du lecteur, l’acide hyaluronique ou un sel d’acide hyaluronique est désigné par « HA », tandis que du chitosane, un dérivé de chitosane ou un sel de chitosane est désigné par « CHITO ». To simplify the reader's understanding, hyaluronic acid or a salt of hyaluronic acid is designated by "HA", while chitosan, a derivative of chitosan or a salt of chitosan is designated by "CHITO".
[0066] Du HA, pris seul ou avec un CHITO, est dissout dans une solution tampon physiologique jusqu’à solubilisation complète pour former une solution viscoélastique transparente. Un cation divalent de zinc peut être ajouté par l’incorporation (par dispersion) dans la solution d’un sel de zinc ou d’un saccharide de zinc (en particulier du gluconate de zinc, du chlorure de zinc ou du sulfate de zinc). Un mélange permet de dissoudre et d’homogénéiser le sel de zinc dans la phase linéaire. [0066] HA, taken alone or with a CHITO, is dissolved in a physiological buffer solution until complete solubilization to form a transparent viscoelastic solution. A divalent cation of zinc can be added by incorporating (by dispersion) into the solution a zinc salt or a zinc saccharide (in particular zinc gluconate, zinc chloride or zinc sulphate) . A mixture dissolves and homogenizes the zinc salt in the linear phase.
[0067] Traitement thermique [0067] Heat treatment
[0068] Chaque formulation subit un traitement thermique correspondant à un cycle de stérilisation. Ce traitement thermique est effectué dans un autoclave de laboratoire
HMT 260 MB de la société HMC EUROPE. Le plateau de stérilisation d’une durée de 1 minute est réglé à une température de 131 °C. La durée totale du traitement thermique comprenant la montée en température, le plateau et le refroidissement est d'environ 22 à 23 minutes. Each formulation undergoes a heat treatment corresponding to a sterilization cycle. This heat treatment is carried out in a laboratory autoclave HMT 260 MB from HMC EUROPE. The 1-minute sterilization tray is set at a temperature of 131°C. The total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes.
[0069] Méthode de mesuré dé la vi
[0069] Method for measuring the vi
[0070] Les caractérisations rhéologiques sont réalisées à l'aide d’un rhéomètre hybride Discovery « DHR2 » de la société TA Instruments, équipé d’une géométrie cône- plan de 40 mm de diamètre et ayant un angle de 2 degrés, ainsi qu’une troncature de 55 microns. Le rhéomètre est aussi équipé d’un plateau Peltier afin de contrôler la température de l’échantillon lors de la mesure. The rheological characterizations are carried out using a Discovery "DHR2" hybrid rheometer from the company TA Instruments, equipped with a cone-plane geometry 40 mm in diameter and having an angle of 2 degrees, as well as a a truncation of 55 microns. The rheometer is also equipped with a Peltier plate in order to control the temperature of the sample during the measurement.
[0071] Lors d'une mesure, l’échantillon est placé sur le plateau inférieur et la géométrie est descendue jusqu’à atteindre le * trim gap » (105 μm). Le surplus de produit est éliminé à l’aide d’une spatule. Ensuite, la géométrie est descendue à 55 pm du plateau inférieur. During a measurement, the sample is placed on the lower plate and the geometry is lowered until it reaches the “trim gap” (105 μm). Excess product is removed with a spatula. Then the geometry went down to 55 µm from the lower plateau.
[0072] La méthode utilisée consiste en une rampe d’écoulement à 35°C en appliquant un taux de cisaillement variant entre 1 s"1 et 1000 s"1, avec 5 points par décade. The method used consists of a flow ramp at 35° C. by applying a shear rate varying between 1 s" 1 and 1000 s" 1 , with 5 points per decade.
[0073] Les viscosités pour comparer les différentes formulations sont ensuite tirées de la valeur de viscosité correspondant à un taux de cisaillement de 8,6 s-1. The viscosities for comparing the various formulations are then taken from the viscosity value corresponding to a shear rate of 8.6 s −1 .
[0074] Essai N°1 : Formulation d’un produit biocompatible à matrice réticulée HA, sans cation zinc divalent présent dans la matrice Test No. 1: Formulation of a biocompatible product with an HA cross-linked matrix, without divalent zinc cation present in the matrix
[0075] On prépare une formulation de HA comprenant une phase réticulée HA. La concentration finale en HA est de 0,9% en poids par rapport au poids total de la matrice. An HA formulation comprising an HA crosslinked phase is prepared. The final concentration of HA is 0.9% by weight relative to the total weight of the matrix.
[0076] La phase réticulée de HA est préparée comme précédemment décrit. The crosslinked phase of HA is prepared as previously described.
[0077] Tout d'abord, 1,12 g d’hyaluronate de sodium (NaHa) est pesé et dissout dans 8,7 g de solution aqueuse de soude à 0,25 mol/L. Après la solubilisation complète, l’agent réticulant est ajouté au goutte à goutte dans la solution. Un mélange est réalisé pour homogénéiser le milieu réactionnel et permettre une réticulation homogène. Ensuite, le récipient contenant le mélange est fermé hermétiquement et placé au bain-marie à 50°C pendant 3 heures. Le gel est ensuite stocké jusqu’au jour suivant entre 2°C et 8°C. First of all, 1.12 g of sodium hyaluronate (NaHa) is weighed and dissolved in 8.7 g of aqueous sodium hydroxide solution at 0.25 mol/L. After complete solubilization, the cross-linking agent is added drop by drop into the solution. A mixture is produced to homogenize the reaction medium and allow homogeneous crosslinking. Then, the container containing the mixture is hermetically sealed and placed in a water bath at 50° C. for 3 hours. The gel is then stored until the next day at 2°C to 8°C.
[0078] Le jour suivant, 9,58 g de gel est collecté et placé dans un homogénéiseur, dans lequel est ajouté 87,4 g d'acide chlorhydrique en solution aqueuse (HCl) concentré à 24 mmol/L. Le milieu est homogénéisé via un mélange cisaillant, ce qui conduit à un gonflement et une neutralisation rapide du pH. Le milieu ainsi
homogénéisé et neutralisé est collecté, et est ensuite transféré dans des membranes de dialyse fermées à l’aide de pinces et ces membranes sont placées dans une solution tampon pendant un minimum de 24h. The following day, 9.58 g of gel is collected and placed in a homogenizer, to which is added 87.4 g of hydrochloric acid in aqueous solution (HCl) concentrated at 24 mmol/L. The medium is homogenized via shear mixing, which leads to swelling and rapid pH neutralization. The middle as well homogenized and neutralized is collected, and is then transferred into closed dialysis membranes using forceps and these membranes are placed in a buffer solution for a minimum of 24 hours.
[0079] Le produit biocompatible à matrice réticulée ainsi obtenu a une densité d’environ 1 , et est ensuite transféré dans des seringues de 1 mL en verre. The biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
[0080] Les seringues en verre sont ensuite soumises à un traitement thermique tel que précédemment décrit, par passage à l'autoclave avec un plateau de stérilisation d'une durée de 1 minute à 131 °C. La durée totale du traitement thermique comprenant la montée en température, le plateau et le refroidissement est d’environ 22 à 23 minutes. [0080] The glass syringes are then subjected to heat treatment as previously described, by autoclaving with a sterilization plate for 1 minute at 131°C. The total duration of the heat treatment including the temperature rise, the plateau and the cooling is approximately 22 to 23 minutes.
[0081] On mesure la viscosité du produit biocompatible à matrice réticulée obtenu (formulation 1 ) comme décrit précédemment. The viscosity of the biocompatible product with a crosslinked matrix obtained (formulation 1) is measured as described above.
[0082] Essai N*2 : Formulation d'un produit biocompatible à matrice réticulée HA, avec un cation zinc divalent présent dans la matrice [0082] Test N*2: Formulation of a biocompatible product with an HA cross-linked matrix, with a divalent zinc cation present in the matrix
[0083] On prépare une formulation de HA comprenant 90% de phase réticulée HA et 10% de phase non réticulée (linéaire) à base de HA. La concentration en HA est de 0,9% en poids par rapport au poids total de la matrice. On ajoute un cation zinc divalent par dispersion dans la matrice. An HA formulation comprising 90% crosslinked HA phase and 10% non-crosslinked (linear) phase based on HA is prepared. The HA concentration is 0.9% by weight relative to the total weight of the matrix. A divalent zinc cation is added by dispersion in the matrix.
[0084] La phase réticulée de HA est préparée comme précédemment décrit en lien avec l'essai N°1. The crosslinked phase of HA is prepared as previously described in connection with test No. 1.
[0085] En parallèle, une phase linéaire est préparée comme précédemment décrit. In parallel, a linear phase is prepared as previously described.
[0086] 0,21 g d'hyaluronate de sodium (NaHa) est pesé, auquel on ajoute 20,0 g de solution tampon, et un mélange est réalisé. 0.21 g of sodium hyaluronate (NaHa) is weighed out, to which 20.0 g of buffer solution are added, and mixing is carried out.
[0087] La phase réticulée et la phase linéaire (non réticulée) sont ensuite mélangées en respectant un ratio 9 : 1. On ajoute un cation zinc divalent dans la matrice par l'incorporation dans la solution de gluconate de zinc (au moyen d’une dispersion). Un mélange permet de dissoudre et homogénéiser le sel de zinc dans la phase linéaire. The cross-linked phase and the linear (non-cross-linked) phase are then mixed in a 9:1 ratio. A divalent zinc cation is added to the matrix by incorporating zinc gluconate into the solution (by means of a scatter). A mixture makes it possible to dissolve and homogenize the zinc salt in the linear phase.
[0088] Plusieurs concentrations en cation zinc divalent sont effectuées, à savoir : 0,0022% (formulation 2a), 0,0072% (formulation 2b) et 0,0144% (formulation 2c) en poids par rapport au poids total de la matrice. Several concentrations of divalent zinc cation are carried out, namely: 0.0022% (formulation 2a), 0.0072% (formulation 2b) and 0.0144% (formulation 2c) by weight relative to the total weight of the matrix.
[0089] Le produit biocompatible à matrice réticulée obtenu a une densité d'environ 1 , et est ensuite transféré dans des seringues de 1 mL en verre. The biocompatible cross-linked matrix product obtained has a density of about 1, and is then transferred into 1 mL glass syringes.
[0090] Les seringues en verre sont ensuite soumises à un traitement thermique tel que précédemment décrit, par passage à l’autoclave avec un plateau de stérilisation d’une durée de 1 minute à 131 °C. La durée totale du traitement thermique
comprenant la montée en température, le plateau et le refroidissement est d’environ 22 à 23 minutes. [0090] The glass syringes are then subjected to heat treatment as described above, by autoclaving with a sterilization plate for 1 minute at 131°C. The total duration of the heat treatment including heat-up, plateau and cool-down is approximately 22-23 minutes.
[0091] On mesure la viscosité du produit biocompatible à matrice réticulée obtenu (formulations 2a, 2b et 2c) comme décrit précédemment. The viscosity of the biocompatible product with a crosslinked matrix obtained (formulations 2a, 2b and 2c) is measured as described previously.
[0092] Essai N°3 : Formulation d'un produit biocompatible à matrice co-réticulée HA et CHITO, sans cation zinc divalent présent dans la matrice Test No. 3: Formulation of a biocompatible product with a co-crosslinked matrix HA and CHITO, without divalent zinc cation present in the matrix
[0093] On prépare une formulation de HA et de CHITO comprenant 90% de phase coréticulée HA-CHITO. Les concentrations en HA et CHITO sont respectivement de 0,9% et 0,1% en poids par rapport au poids total de la matrice. A formulation of HA and of CHITO comprising 90% of HA-CHITO coreticulated phase is prepared. The concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
[0094] La phase réticulée de HA-CHITO est préparée comme suit. The crosslinked phase of HA-CHITO is prepared as follows.
[0095] Tout d’abord, 2,00 g d’hyaluronate de sodium (NaHa) est pesé. Ensuite on pèse 0,215 g de carboxyméthyle chitosane qu'on ajoute au hyaluronate de sodium. On dissout le mélange de carboxyméthyle chitosane et d’hyaluronate de sodium dans 20 g de solution aqueuse de soude à 0,25 mol/L. Après la solubilisation complète, l’agent réticulant est ajouté au goutte à goutte dans la solution. Un mélange est réalisé pour homogénéiser le milieu réactionnel et permettre une co-réticulation (ou réticulation simultanée) homogène. Ensuite, le récipient contenant le mélange est fermé hermétiquement et placé au bain-marie à 50°C pendant 3 heures. Le gel est ensuite stocké jusqu’au jour suivant entre 2°C et 8°C. First, 2.00 g of sodium hyaluronate (NaHa) is weighed. Then 0.215 g of carboxymethyl chitosan is weighed and added to the sodium hyaluronate. The mixture of carboxymethyl chitosan and sodium hyaluronate is dissolved in 20 g of aqueous sodium hydroxide solution at 0.25 mol/L. After complete solubilization, the cross-linking agent is added drop by drop into the solution. A mixture is produced to homogenize the reaction medium and allow homogeneous co-crosslinking (or simultaneous crosslinking). Then, the container containing the mixture is hermetically sealed and placed in a water bath at 50° C. for 3 hours. The gel is then stored until the next day at 2°C to 8°C.
[0096] Le jour suivant, 22,02 g de gel est collecté et placé dans un homogénéiseur, dans lequel est ajouté 175,4 g d’acide chlorhydrique en solution aqueuse (HCl) concentré à 28 mmol/L. Le milieu est homogénéisé via un mélange cisaillant, ce qui conduit à un gonflement et une neutralisation du pH rapide. Le milieu ainsi homogénéisé et neutralisé est collecté, et est ensuite transféré dans des membranes de dialyse fermées à l’aide de pinces et ces membranes sont placées dans une solution tampon pour un minimum de 24h. The following day, 22.02 g of gel is collected and placed in a homogenizer, to which 175.4 g of hydrochloric acid in aqueous solution (HCl) concentrated at 28 mmol/L is added. The medium is homogenized via shear mixing, which leads to swelling and rapid pH neutralization. The medium thus homogenized and neutralized is collected, and is then transferred into closed dialysis membranes using forceps and these membranes are placed in a buffer solution for a minimum of 24 hours.
[0097] En parallèle, une phase linéaire est préparée comme précédemment décrit, avec du HA et du CHITO. In parallel, a linear phase is prepared as previously described, with HA and CHITO.
[0098] 0,20 g d’hyaluronate de sodium (NaHa) et 22 mg de carboxyméthyle chitosane sont mélangés, auxquels on ajoute 20,0 g de solution tampon. Un mélange est réalisé. 0.20 g of sodium hyaluronate (NaHa) and 22 mg of carboxymethyl chitosan are mixed, to which 20.0 g of buffer solution are added. A mixture is made.
[0099] Les phases réticulée et linéaire (non réticulée) sont ensuite mélangées en respectant un ratio 9 : 1. The crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
[0100] Le produit biocompatible à matrice réticulée obtenu a une densité d’environ 1, et est ensuite transféré dans des seringues de 1 mL en verre.
[0101] Les seringues en verre sont ensuite soumises à un traitement thermique tel que précédemment décrit, par passage à l’autoclave avec un plateau de stérilisation d’une durée de 1 minute à 131 °C. La durée totale du traitement thermique comprenant la montée en température, le plateau et le refroidissement est d'environ 22 à 23 minutes. The biocompatible cross-linked matrix product obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes. [0101] The glass syringes are then subjected to heat treatment as previously described, by autoclaving with a sterilization plate for 1 minute at 131°C. The total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes.
[0102] On mesure la viscosité du produit biocompatible à matrice réticulée obtenu (formulation 3) comme décrit précédemment. The viscosity of the biocompatible product with a crosslinked matrix obtained (formulation 3) is measured as described previously.
[0103] Essai N°4 : Formulation d’un produit biocompatible à matrice oo-rétlculée HA et CHITO, avec un cation zinc divalent présent dans la matrice par ajout de gluconate de zinc [0103] Test No. 4: Formulation of a biocompatible product with an oo-cross-linked HA and CHITO matrix, with a divalent zinc cation present in the matrix by adding zinc gluconate
[0104] On prépare une formulation de HA et de CHITO comprenant 90% de phase coréticulée HA-CHITO et 10% de phase non réticulée (linéaire) à base de HA-CHITO. Les concentrations en HA et CHITO sont respectivement de 0,9% et 0,1% en poids par rapport au poids total de la matrice. A formulation of HA and of CHITO comprising 90% co-crosslinked HA-CHITO phase and 10% non-crosslinked (linear) phase based on HA-CHITO is prepared. The concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
[0105] La phase réticulée de HA-CHITO est préparée comme précédemment décrit en lien avec l'essai N°3. The crosslinked phase of HA-CHITO is prepared as previously described in connection with test No. 3.
[0106] En parallèle, une phase linéaire avec du HA et du CHITO est préparée comme précédemment décrit en lien avec l’essai N°3, à ceci près qu’après dissolution complète de l'hyaluronate de sodium (NaHa) et du carboxyméthyle chitosane, on ajoute un cation zinc divalent dans la matrice par l'incorporation dans la solution de gluconate de zinc (au moyen d’une dispersion). Un mélange permet de dissoudre et homogénéiser ledit sel de zinc dans la phase linéaire. In parallel, a linear phase with HA and CHITO is prepared as previously described in connection with test No. 3, except that after complete dissolution of sodium hyaluronate (NaHa) and carboxymethyl chitosan, a divalent zinc cation is added to the matrix by incorporating zinc gluconate into the solution (by means of a dispersion). A mixture makes it possible to dissolve and homogenize said zinc salt in the linear phase.
[0107] Plusieurs concentrations en cation zinc divalent sont effectuées, à savoir : 0,0072% (formulation 4a) et 0,0144% (formulation 4b) en poids par rapport au poids total de la matrice. Several concentrations of divalent zinc cation are carried out, namely: 0.0072% (formulation 4a) and 0.0144% (formulation 4b) by weight relative to the total weight of the matrix.
[0108] Les phases réticulée et linéaire (non réticulée) sont ensuite mélangées en respectant un ratio 9 : 1. The crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
[0109] Le produit biocompatible à matrice réticulée ainsi obtenu a une densité d’environ 1 , et est ensuite transféré dans des seringues de 1 mL en verre. The biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
[0110] Les seringues en verre sont ensuite soumises à un traitement thermique tel que précédemment décrit, par passage à l'autoclave avec un plateau de stérilisation d’une durée de 1 minute à 131 °C. La durée totale du traitement thermique comprenant la montée en température, le plateau et le refroidissement est d’environ 22 à 23 minutes. The glass syringes are then subjected to heat treatment as described above, by autoclaving with a sterilization tray for 1 minute at 131°C. The total duration of the heat treatment including the temperature rise, the plateau and the cooling is approximately 22 to 23 minutes.
[0111] On mesure la viscosité du produit biocompatible à matrice réticulée obtenu (formulations 4a et 4b) comme décrit précédemment.
[0112] Essai N°5 : Formulation d'un produit biocompatible à matrice co-réticulée HA et CHITO, avec un cation zinc divalent présent dans la matrice par ajout de chlorure de zinc The viscosity of the biocompatible product with a crosslinked matrix obtained (formulations 4a and 4b) is measured as described above. [0112] Test No. 5: Formulation of a biocompatible product with a co-crosslinked matrix HA and CHITO, with a divalent zinc cation present in the matrix by adding zinc chloride
[0113] On prépare une formulation de HA et de CHITO comprenant 90% de phase coréticulée HA-CHITO et 10% de phase non réticulée (linéaire) à base de HA-CHITO. Les concentrations en HA et CHITO sont respectivement de 0,9% et 0,1% en poids par rapport au poids total de la matrice. A formulation of HA and of CHITO comprising 90% co-crosslinked HA-CHITO phase and 10% non-crosslinked (linear) phase based on HA-CHITO is prepared. The concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
[0114] La phase réticulée de HA-CHITO est préparée comme précédemment décrit en lien avec l’essai N°4. The crosslinked phase of HA-CHITO is prepared as previously described in connection with test No. 4.
[0115] En parallèle, une phase linéaire avec du HA et du CHITO est préparée comme précédemment décrit en lien avec l’essai N°4, à ceci près qu’après dissolution complète de l’hyaluronate de sodium (NaHa) et du carboxyméthyle chitosane, on ajoute un cation zinc divalent dans la matrice par l’incorporation dans la solution de chlorure de zinc (ZnCI2) (au moyen d’une dispersion). Un mélange permet de dissoudre et homogénéiser ledit sel de zinc dans la phase linéaire. In parallel, a linear phase with HA and CHITO is prepared as previously described in connection with test No. 4, except that after complete dissolution of sodium hyaluronate (NaHa) and carboxymethyl chitosan, a divalent zinc cation is added to the matrix by incorporating zinc chloride (ZnCl 2 ) into the solution (by means of a dispersion). A mixture makes it possible to dissolve and homogenize said zinc salt in the linear phase.
[0116] Plusieurs concentrations en cation zinc divalent sont effectuées, à savoir : 0,0072% (formulation 5a), 0,0144% (formulation 5b) et 0,048% (formulation 5c) en poids par rapport au poids total de la matrice. Several concentrations of divalent zinc cation are carried out, namely: 0.0072% (formulation 5a), 0.0144% (formulation 5b) and 0.048% (formulation 5c) by weight relative to the total weight of the matrix.
[0117] Les phases réticulée et linéaire (non réticulée) sont ensuite mélangées en respectant un ratio 9 : 1. The crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
[0118] Le produit biocompatible à matrice réticulée ainsi obtenu a une densité d’environ 1 , et est ensuite transféré dans des seringues de 1 mL en verre. The biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
[0119] Les seringues en verre sont ensuite soumises à un traitement thermique tel que précédemment décrit, par passage à l’autoclave avec un plateau de stérilisation d’une durée de 1 minute à 131 °C. La durée totale du traitement thermique comprenant la montée en température, le plateau et le refroidissement est d’environ 22 à 23 minutes. The glass syringes are then subjected to heat treatment as described above, by autoclaving with a sterilization plate for 1 minute at 131°C. The total duration of the heat treatment including the temperature rise, the plateau and the cooling is approximately 22 to 23 minutes.
[0120] On mesure la viscosité du produit biocompatible à matrice réticulée obtenu (formulations 5a, 5b et 5c) comme décrit précédemment. The viscosity of the biocompatible product with a crosslinked matrix obtained (formulations 5a, 5b and 5c) is measured as described previously.
[0121] Essai N°6 : Formulation d’un produit biocompatible à matrice co-réticulée HA et CHITO, avec un cation zinc divalent présent dans la matrice par ajout de sulfate de zinc [0121] Test No. 6: Formulation of a biocompatible product with a co-crosslinked matrix HA and CHITO, with a divalent zinc cation present in the matrix by adding zinc sulphate
[0122] On prépare une formulation de HA et de CHITO comprenant 90% de phase co - réticulée HA-CHITO et 10% de phase non réticulée (linéaire) à base de HA-CHITO.
Les concentrations en HA est CHITO sont respectivement de 0,9% et 0,1% en poids par rapport au poids total de la matrice. A formulation of HA and CHITO comprising 90% co-crosslinked HA-CHITO phase and 10% non-crosslinked (linear) phase based on HA-CHITO is prepared. The concentrations of HA and CHITO are respectively 0.9% and 0.1% by weight relative to the total weight of the matrix.
[0123] La phase réticulée de HA-CHITO est préparée comme précédemment décrit en lien avec l'essai N°4. The crosslinked phase of HA-CHITO is prepared as previously described in connection with test No. 4.
[0124] En parallèle, une phase linéaire avec du HA et du CHITO est préparée comme précédemment décrit en lien avec l'essai N°4, à ceci près qu’après dissolution complète de l’hyaluronate de sodium (NaHa) et du carboxyméthyle chitosane, on ajoute un cation zinc divalent dans la matrice par l’incorporation dans la solution de sulfate de zinc (ZnSO4) (au moyen d’une dispersion). Un mélange permet de dissoudre et homogénéiser ledit sel de zinc dans la phase linéaire. In parallel, a linear phase with HA and CHITO is prepared as previously described in connection with test No. 4, except that after complete dissolution of sodium hyaluronate (NaHa) and carboxymethyl chitosan, a divalent zinc cation is added to the matrix by incorporating zinc sulphate (ZnSO 4 ) into the solution (by means of a dispersion). A mixture makes it possible to dissolve and homogenize said zinc salt in the linear phase.
[0125] Plusieurs concentrations en cation zinc divalent sont effectuées, à savoir : 0,0072% (formulation 6a), 0,0144% (formulation 6b) et 0,0360% (formulation 6c) en poids par rapport au poids total de la matrice. Several concentrations of divalent zinc cation are carried out, namely: 0.0072% (formulation 6a), 0.0144% (formulation 6b) and 0.0360% (formulation 6c) by weight relative to the total weight of the matrix.
[0126] Les phases réticulée et linéaire (non réticulée) sont ensuite mélangées en respectant un ratio 9 : 1. The crosslinked and linear (non-crosslinked) phases are then mixed, respecting a 9:1 ratio.
[0127] Le produit biocompatible à matrice réticulée ainsi obtenu a une densité d’environ 1 , et est ensuite transféré dans des seringues de 1 mL en verre. The biocompatible cross-linked matrix product thus obtained has a density of approximately 1, and is then transferred into 1 mL glass syringes.
[0128] Les seringues en verre sont ensuite soumises à un traitement thermique tel que précédemment décrit, par passage à l’autodave avec un plateau de stérilisation d’une durée de 1 minute à 131°C. La durée totale du traitement thermique comprenant la montée en température, le plateau et le refroidissement est d'environ 22 à 23 minutes. [0128] The glass syringes are then subjected to a heat treatment as described above, by passage through an autodave with a sterilization tray for a period of 1 minute at 131°C. The total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes.
[0129] On mesure la viscosité du produit biocompatible à matrice réticulée obtenu (formulations 6a, 6b et 6c) comme décrit précédemment. The viscosity of the biocompatible product with a crosslinked matrix obtained (formulations 6a, 6b and 6c) is measured as described previously.
[0130] Mesures de viscosités avant et après traitement thermique [0130] Viscosity measurements before and after heat treatment
[0131] On a mesuré les viscosités des formulations 1 , 2a à 2c, 3, 4a, 4b, 5a à 5c et 6a à 6c, à l'aide d’un rhéomètre hybride Discovery « DHR2 » de la société TA Instruments comme précédemment explicité, et ce avant et après application du traitement thermique précédemment explicité (stérilisation avec un plateau d’une durée de 1 minute à une température de 131 °C, durée totale du traitement thermique comprenant la montée en température, le plateau et le refroidissement est d’environ 22 à 23 minutes). The viscosities of formulations 1, 2a to 2c, 3, 4a, 4b, 5a to 5c and 6a to 6c were measured using a Discovery hybrid rheometer "DHR2" from the company TA Instruments as previously explained, and this before and after application of the previously explained heat treatment (sterilization with a plateau lasting 1 minute at a temperature of 131°C, total duration of the heat treatment including the rise in temperature, the plateau and the cooling is approximately 22 to 23 minutes).
[0132] [Tableau 1] Résultats en termes de viscosités avant et après traitement thermique
[0132] [Table 1] Results in terms of viscosities before and after heat treatment
[0133] Ces résultats sont repris sous forme graphique sur la figure 1 à l'aide d'un histogramme. En abscisse apparaissent les formulations testées, en ordonnée les viscosités mesurées (en cP). Les viscosités avant traitement thermique sont illustrées par des barres pleines tandis que les viscosités après traitement thermique sont illustrées par des barres hachurées.
[0134] Une première observation, basée sur les formulations 1 et 2a à 2c, est que si l’ajout d'un cation zinc divalent permet d’augmenter sensiblement la viscosité d’une matrice réticulée de HA, il demeure toujours une perte de viscosité importante après traitement thermique. Cette perte semble presque constante (sensiblement égale à 400 cP dans cet exemple) et indépendante de la concentration en cation zinc divalent. These results are shown in graphical form in FIG. 1 using a histogram. On the abscissa appear the formulations tested, on the ordinate the measured viscosities (in cP). The viscosities before heat treatment are illustrated by solid bars while the viscosities after heat treatment are illustrated by hatched bars. A first observation, based on formulations 1 and 2a to 2c, is that if the addition of a divalent zinc cation makes it possible to substantially increase the viscosity of a crosslinked matrix of HA, there always remains a loss of high viscosity after heat treatment. This loss seems almost constant (substantially equal to 400 cP in this example) and independent of the divalent zinc cation concentration.
[0135] Une deuxième observation, basée sur les formulations 1 et 3, est que la coréticulation du HA et du CHITO permet d’accroître très significativement la viscosité de la matrice avant et après traitement thermique. On note toutefois la persistance d’une chute importante (- 80%) de la viscosité après traitement thermique. A second observation, based on formulations 1 and 3, is that the co-crosslinking of HA and CHITO makes it possible to very significantly increase the viscosity of the matrix before and after heat treatment. However, the persistence of a significant drop (-80%) in viscosity after heat treatment is noted.
[0136] Une troisième observation, basée sur les formulations 4a, 4b, 5a à 5c et 6a à 6c, est que l’ajout d’un cation zinc divalent dans une matrice co-réticulée de HA et de CHITO selon une concentration relativement faible comprise entre 0,002 % et 0,06 % en poids par rapport au poids total de la matrice permet de conserver à la matrice, après traitement thermique, une viscosité plus élevée (au minimum deux fois plus élevée) que celle de la formulation 3 (matrice co-réticulée de HA et de CHITO dépourvue de cation zinc divalent). [0136] A third observation, based on formulations 4a, 4b, 5a to 5c and 6a to 6c, is that the addition of a divalent zinc cation in a co-crosslinked matrix of HA and CHITO in a relatively low concentration between 0.002% and 0.06% by weight relative to the total weight of the matrix allows the matrix to retain, after heat treatment, a higher viscosity (at least twice as high) than that of formulation 3 (matrix co-crosslinked HA and CHITO devoid of divalent zinc cation).
[0137] L’ajout d’un cation zinc divalent dans une matrice co-réticulée de HA et de CHITO selon une concentration comprise entre 0,001 % et 1 % permet ainsi d’obtenir simultanément une viscosité de la matrice bien plus élevée et une perte bien amoindrie de viscosité après traitement thermique. The addition of a divalent zinc cation in a co-crosslinked matrix of HA and CHITO according to a concentration of between 0.001% and 1% thus makes it possible to simultaneously obtain a much higher viscosity of the matrix and a loss much reduced in viscosity after heat treatment.
[0138] Une quatrième observation, basée plus particulièrement sur les formulations 4b, 5a à 5c, 6b et 6c, est que l’ajout d’un cation zinc divalent dans une matrice coréticulée de HA et de CHITO selon une concentration entre environ 0,005 % et environ 0,06 % permet d’obtenir une viscosité après traitement thermique quasiment voisine de la viscosité avant traitement thermique (formulations 5a, 5b), voire même supérieure à la viscosité avant traitement thermique (formulations 4b, 5c, 6b et 6c). A fourth observation, based more particularly on formulations 4b, 5a to 5c, 6b and 6c, is that the addition of a divalent zinc cation in a coreticulated matrix of HA and of CHITO according to a concentration between approximately 0.005% and about 0.06% makes it possible to obtain a viscosity after heat treatment almost close to the viscosity before heat treatment (formulations 5a, 5b), or even greater than the viscosity before heat treatment (formulations 4b, 5c, 6b and 6c).
[0139] Cette dernière observation est très surprenante : de façon classique le traitement thermique d’une matrice réticulée tend à dégrader la cohésion de ladite matrice et donc à faire baisser sa viscosité. Ce phénomène inattendu allant même jusqu’à une « inversion de viscosité » (signifiant que la viscosité de la matrice est plus élevée après traitement thermique qu’avant traitement thermique) s’avère donc particulièrement avantageux pour toutes les applications exigeant une stérilisation d’une composition comprenant le produit biocompatible, notamment pour une utilisation dans une méthode de traitement cosmétique ou de traitement thérapeutique, comprenant notamment l’application topique, l’implantation,
l’instillation ou l'injection par voie sous-cutanée, intradermique, mucosale, oculaire, intraoculalre, ou intra-articulalre, de ladite composition. This last observation is very surprising: conventionally, the heat treatment of a crosslinked matrix tends to degrade the cohesion of said matrix and therefore to lower its viscosity. This unexpected phenomenon, even going as far as "viscosity inversion" (meaning that the viscosity of the matrix is higher after heat treatment than before heat treatment) therefore proves to be particularly advantageous for all applications requiring sterilization of a composition comprising the biocompatible product, in particular for use in a method of cosmetic treatment or therapeutic treatment, comprising in particular topical application, implantation, instillation or injection by subcutaneous, intradermal, mucosal, ocular, intraocular, or intra-articulalre route, of said composition.
[0140] La présente invention, qui permet l’obtention d’une viscosité élevée après traitement thermique, voire supérieure à la viscosité avant traitement thermique, se révèle très appréciable pour la prévention et/ou le traitement de pathologies pouvant être améliorées ou évitées par : The present invention, which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, proves to be very valuable for the prevention and/or treatment of pathologies which can be improved or avoided by :
- le comblement ou le remplacement d'un tissu biologique ; et/ou - the filling or replacement of a biological tissue; and or
- l'augmentation de volume dudit tissu biologique ; et/ou - the increase in volume of said biological tissue; and or
- la supplémentation ou le remplacement d'un fluide biologique. - supplementation or replacement of a biological fluid.
[0141] La présente invention, qui permet l’obtention d'une viscosité élevée après traitement thermique, voire supérieure à la viscosité avant traitement thermique, se révèle également très appréciable pour une méthode de traitement d'une arthrose, ou de réparation d'un défaut de cartilage, la composition étant par exemple formulée pour une administration par injection dans le fluide synovial ou pour une implantation dans le cartilage après mélange avec le sang, ou pour une méthode de traitement de la sécheresse oculaire. The present invention, which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, also proves to be very valuable for a method for treating osteoarthritis, or for repairing a cartilage defect, the composition being for example formulated for administration by injection into synovial fluid or for implantation into cartilage after mixing with blood, or for a method of treating dry eye.
[0142] La présente invention, qui permet l’obtention d’une viscosité élevée après traitement thermique, voire supérieure à la viscosité avant traitement thermique, se révèle également très appréciable pour une utilisation dans une méthode de traitement en thérapeutique, en chirurgie, ou cosmétique, incluant en particulier un traitement en rhumatologie, en ophtalmologie, en gynécologie, en médecine esthétique, en chirurgie plastique, en chirurgie interne, en chirurgie orthopédique, pour la prévention des adhérences tissulaires post-chirurgicales, en dermatologie. The present invention, which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, also proves to be very valuable for use in a treatment method in therapy, in surgery, or cosmetics, including in particular treatment in rheumatology, ophthalmology, gynecology, aesthetic medicine, plastic surgery, internal surgery, orthopedic surgery, for the prevention of post-surgical tissue adhesions, in dermatology.
[0143] La présente invention, qui permet l’obtention d’une viscosité élevée après traitement thermique, voire supérieure à la viscosité avant traitement thermique, se révèle également très appréciable pour une utilisation dans un traitement thérapeutique d’un syndrome de l’œil sec, d’une lésion de cornée ou d’une inflammation oculaire ou articulaire. The present invention, which makes it possible to obtain a high viscosity after heat treatment, even higher than the viscosity before heat treatment, also proves to be very valuable for use in a therapeutic treatment of an eye syndrome. dryness, corneal damage or eye or joint inflammation.
[0144] La présente invention, qui permet l’obtention d’une viscosité élevée après traitement thermique, voire supérieure à la viscosité avant traitement thermique, se révèle également très appréciable pour une utilisation dans un traitement thérapeutique lors duquel on applique ladite composition par instillation sur la surface oculaire pour prévenir ou lutter contre une lésion de cornée ou un syndrome de l’œil sec, en particulier dans le but de lubrifier ou régénérer la surface oculaire. The present invention, which makes it possible to obtain a high viscosity after heat treatment, or even higher than the viscosity before heat treatment, also proves to be very valuable for use in a therapeutic treatment during which said composition is applied by instillation. on the ocular surface to prevent or combat corneal damage or dry eye syndrome, in particular for the purpose of lubricating or regenerating the ocular surface.
[0145] On peut en particulier élaborer une composition de gouttes ophtalmiques comprenant un produit biocompatible à matrice co-réticulée de HA et de CHITO tel que décrit précédemment.
[0146] ^sals et tests de bjocomoatibilité oar iniection intracutanée It is possible in particular to produce a composition of ophthalmic drops comprising a biocompatible product with a co-crosslinked matrix of HA and of CHITO as described previously. [0146] ^sals and bjocomoatibility tests for intracutaneous injection
[0147] Il a été procédé à des essais et tests de biocompatibilité (en adaptation de la norme ISO 10993 - partie 10) par injections intracutanées de doses de 0,2 mL sur le dos de lapins en des sites distincts. Les sites ont été observés immédiatement après Injection. Des observations ont été menées en termes d'érythème et d’œdème après 24h (1 jour), 48h (2 jours), 72h (3 jours), 7 jours et 14 jours. Biocompatibility trials and tests (adapted from ISO 10993—part 10) were carried out by intracutaneous injections of doses of 0.2 mL on the backs of rabbits at separate sites. The sites were observed immediately after injection. Observations were made in terms of erythema and edema after 24h (1 day), 48h (2 days), 72h (3 days), 7 days and 14 days.
[0148] Les produits suivants ont été testés : The following products were tested:
- échantillon A : un produit biocompatible selon la formulation 2a, le cation zinc divalent étant ajouté à la matrice par l'incorporation de gluconate de zinc selon une concentration en gluconate de zinc de 20 ppm (soit une concentration de cation zinc divalent dans la matrice de 0,002 %), - sample A: a biocompatible product according to formulation 2a, the divalent zinc cation being added to the matrix by incorporating zinc gluconate according to a zinc gluconate concentration of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix 0.002%),
- échantillon B : un produit biocompatible selon l'invention et ne différant des formulations 4a et 4b que par une concentration en gluconate de zinc de 20 ppm (soit une concentration de cation zinc divalent dans la matrice de 0,002 %), étant précisé que le carboxyméthyle chitosane est d’origine végétale (fongique),- sample B: a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of plant (fungal) origin,
- échantillon C : un produit biocompatible selon l'invention et ne différant des formulations 4a et 4b que par une concentration en gluconate de zinc de 20 ppm (soit une concentration de cation zinc divalent dans la matrice de 0,002 %), étant précisé que le carboxyméthyle chitosane est d’origine animale, - sample C: a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of animal origin,
- échantillon D : un produit commercialisé sous la marque PERFECTHA® DERM (numéro de lot : 190625-2) de la société Sinclair France SAS, - sample D: a product marketed under the PERFECTHA® DERM brand (batch number: 190625-2) from the company Sinclair France SAS,
- échantillon E : une solution tampon physiologique, - sample E: a physiological buffer solution,
- échantillon F : une solution de chlorure de de sodium (sérum physiologique) à 9 g/L (soit 0,9% en poids par volume). - sample F: a solution of sodium chloride (physiological serum) at 9 g/L (ie 0.9% by weight by volume).
[0149] [Tableau 2] Scores moyens d'irritation selon le système de notation de la norme ISO 10993-10
[0150] Les produits biocompatibles selon la présente Invention ont ainsi une biocompatibilité satisfaisante lors d’une injection intracutanée. [0149] [Table 2] Mean irritation scores according to the ISO 10993-10 standard scoring system The biocompatible products according to the present invention thus have satisfactory biocompatibility during an intracutaneous injection.
[0151] Essais et tests d'initation oculaire [0151] Tests and ocular initiation tests
[0152] Il a été procédé à des essais et tests d’irritation oculaire (en adaptation de la norme ISO 10993 - partie 10) par instillation de doses de 0,1 mL d’échantillons à tester dans le sac conjonctival inférieur de l’oeil gauche de lapins tandis qu’était instillée à titre de contrôle une dose de 0,1 mL d’une solution de chlorure de sodium (sérum physiologique) à 9 g/L (soit 0,9% en poids par volume) dans le sac conjonctival inférieur de l’œil droit desdits lapins. Des observations ont été menées en termes de réactions oculaires après 1 h, 24h (1 jour), 48h (2 jours) et 72h (3 jours). Chaque échantillon a été testé sur deux lapins. [0152] Tests and ocular irritation tests were carried out (in adaptation of the ISO 10993 standard - part 10) by instillation of doses of 0.1 mL of samples to be tested into the lower conjunctival sac of the left eye of rabbits while a dose of 0.1 mL of a solution of sodium chloride (physiological serum) at 9 g/L (i.e. 0.9% by weight by volume) was instilled as a control in the lower conjunctival sac of the right eye of said rabbits. Observations were made in terms of ocular reactions after 1 h, 24 h (1 day), 48 h (2 days) and 72 h (3 days). Each sample was tested on two rabbits.
[0153] Les produits suivants ont été testés : The following products were tested:
- échantillon G : un produit biocompatible selon la formulation 2a, le cation zinc divalent étant ajouté à la matrice par l’incorporation de gluconate de zinc selon une concentration en gluconate de zinc de 20 ppm (soit une concentration de cation zinc divalent dans la matrice de 0,002 %), - sample G: a biocompatible product according to formulation 2a, the divalent zinc cation being added to the matrix by incorporating zinc gluconate according to a zinc gluconate concentration of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix 0.002%),
- échantillon H : un produit biocompatible selon l’invention et ne différant des formulations 4a et 4b que par une concentration en gluconate de zinc de 20 ppm (soit une concentration de cation zinc divalent dans la matrice de 0,002 %), étant précisé que le carboxyméthyle chitosane est d’origine végétale (fongique),- sample H: a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of plant (fungal) origin,
- échantillon I : un produit biocompatible selon l’invention et ne différant des formulations 4a et 4b que par une concentration en gluconate de zinc de 20 ppm (soit une concentration de cation zinc divalent dans la matrice de 0,002 %), étant précisé que le carboxyméthyle chitosane est d’origine animale. - sample I: a biocompatible product according to the invention and differing from formulations 4a and 4b only by a concentration of zinc gluconate of 20 ppm (i.e. a concentration of divalent zinc cation in the matrix of 0.002%), it being specified that the carboxymethyl chitosan is of animal origin.
[0154;
[0159] L'innocuité des produits selon la présente invention a été évaluée pour une utilisation dans un traitement thérapeutique d’un syndrome de l'œil sec, d’une lésion de cornée ou d’une inflammation oculaire ou articulaire. Pour une telle utilisation, on a généralement recours à des produits viscoélastiques. Des produits à base d’acide hyaluronique, réticulé ou non, sont largement utilisés. [0154; [0159] The safety of the products according to the present invention has been evaluated for use in a therapeutic treatment of dry eye syndrome, corneal damage or ocular or joint inflammation. For such a use, recourse is generally had to viscoelastic products. Products based on hyaluronic acid, cross-linked or not, are widely used.
[0160] Pour une telle utilisation, une propriété majeure que doivent présenter les produits est le fait d’avoir un comportement viscoélastique adaptatif. Par produit à comportement viscoélastique adaptatif, on entend désigner un produit présentant :For such a use, a major property that the products must have is the fact of having an adaptive viscoelastic behavior. By product with adaptive viscoelastic behavior is meant a product having:
- une viscosité suffisamment élevée au repos (c’est-à-dire à un taux de cisaillement faible) pour avoir une bonne rémanence et assurer une protection satisfaisante de la cornée, et - a sufficiently high viscosity at rest (i.e. at a low shear rate) to have good persistence and ensure satisfactory protection of the cornea, and
- une viscosité qui décroît pendant les clignements d'yeux (c’est-à-dire à un taux de cisaillement élevé) pour améliorer le confort et une répartition satisfaisante du produit sur la surface oculaire. - a viscosity which decreases during eye blinks (i.e. at a high shear rate) to improve comfort and satisfactory distribution of the product on the ocular surface.
[0161] L’évaluation a été menée par comparaison en termes de viscosité avec des produits commercialement disponibles du marché, à savoir les produits : The evaluation was carried out by comparison in terms of viscosity with commercially available products on the market, namely the products:
- VisulXL® Gel de la société VISUfarma (échantillon J) ; - VisulXL® Gel from VISUfarma (sample J);
- OPTIVE FUSION® de la société ALLERGAN (échantillon K) ; - OPTIVE FUSION® from ALLERGAN (sample K);
- HYLO-FORTE® de la société Ursapharm Arzneimittel GmbH (échantillon L). - HYLO-FORTE® from Ursapharm Arzneimittel GmbH (sample L).
[0162] Les produits biocompatibles selon la présente invention qui ont été testés (après traitement thermique) sont : The biocompatible products according to the present invention which were tested (after heat treatment) are:
- la formulation 4a (échantillon M), - formulation 4a (sample M),
- la formulation 4b (échantillon N). - formulation 4b (sample N).
[0163] On a également testé la formulation 1 (échantillon O) et la formulation 3 (échantillon P). Formulation 1 (sample O) and formulation 3 (sample P) were also tested.
[0164] Les résultats sont illustrés sous forme graphique sur la figure 2. [0164] The results are illustrated in graphical form in Figure 2.
[0165] On observe tout d’abord que les échantillons J (VisulXL® Gel de la société VISUfarma), K (OPTIVE FUSION® de la société ALLERGAN) et Q (formulation 1) ont un comportement viscoélastique très peu adaptatif, avec une viscosité faible et sensiblement constante sur toute la plage de taux de cisaillement testée. It is observed first of all that samples J (VisulXL® Gel from the company VISUfarma), K (OPTIVE FUSION® from the company ALLERGAN) and Q (formulation 1) have a viscoelastic behavior that is very little adaptive, with a viscosity low and substantially constant over the entire shear rate range tested.
[0166] Si l’échantillon L (HYLO-FORTE® de la société Ursapharm Arzneimittel GmbH) montre un comportement viscoélastique nettement plus adaptatif, sa viscosité reste faible sur toute la plage de taux de cisaillement testée. Although sample L (HYLO-FORTE® from the company Ursapharm Arzneimittel GmbH) shows a viscoelastic behavior that is clearly more adaptive, its viscosity remains low over the entire range of shear rates tested.
[0167] On observe que les formulations selon la présente invention (échantillons M et N) ont toutes une viscosité qui est élevée à faible taux de cisaillement et qui décroît de façon assez régulière (de façon plus ou moins rapide) jusqu'à une viscosité nettement plus faible à haut taux de cisaillement. Les formulations selon l’invention
ont ainsi un comportement viscoélastique adaptatif les rendant aptes à une utilisation dans une composition de gouttes ophtalmiques, et la concentration de cation zinc divalent dans la matrice et le taux de réticulation de la matrice permettent d’adapter la viscosité à l’utilisation souhaitée. It is observed that the formulations according to the present invention (samples M and N) all have a viscosity which is high at low shear rate and which decreases fairly regularly (more or less quickly) down to a viscosity significantly lower at high shear rates. The formulations according to the invention thus have an adaptive viscoelastic behavior making them suitable for use in an ophthalmic drop composition, and the concentration of divalent zinc cation in the matrix and the rate of crosslinking of the matrix make it possible to adapt the viscosity to the desired use.
[0168] Les formulations selon la présente invention sont ainsi particulièrement intéressantes pour un traitement thérapeutique par instillation sur la surface oculaire pour prévenir ou lutter contre une lésion de cornée ou un syndrome de l'œil sec, en particulier dans le but de lubrifier ou régénérer la surface oculaire. [0168] The formulations according to the present invention are thus particularly interesting for a therapeutic treatment by instillation on the ocular surface to prevent or fight against a corneal lesion or a dry eye syndrome, in particular with the aim of lubricating or regenerating the ocular surface.
[0169] A faible taux de cisaillement, la viscosité des formulations selon l'invention (M et N) est nettement supérieure à la viscosité des produits disponibles sur le marché. At a low shear rate, the viscosity of the formulations according to the invention (M and N) is markedly higher than the viscosity of the products available on the market.
[0170] La présente invention n'est pas limitée aux modes de réalisation qui ont été explicitement décrits, mais elle en inclut les diverses variantes et généralisations contenues dans le domaine des revendications ci-après.
The present invention is not limited to the embodiments which have been explicitly described, but it includes the various variants and generalizations thereof contained in the field of the claims below.
Claims
[Revendication 1] Produit biocompatible à matrice comprenant : [Claim 1] Biocompatible matrix product comprising:
- un polysaccharide choisi dans le groupe comprenant l’acide hyaluronique, un sel d’acide hyaluronique, le sulfate de chondroïtine, les dérivés cellulosiques, et un mélange de ceux-ci, - a polysaccharide chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture thereof,
- un cation zinc divalent présent dans la matrice, caractérisé en ce que : - a divalent zinc cation present in the matrix, characterized in that:
- la matrice comprend du chitosane, de préférence un dérivé de chitosane ou un sel de chitosane, - the matrix comprises chitosan, preferably a chitosan derivative or a chitosan salt,
- dans ladite matrice, une partie au moins du polysaccharide est co-réticulée avec une partie au moins du chitosane, du dérivé de chitosane, ou du sel de chitosane. - in said matrix, at least part of the polysaccharide is co-crosslinked with at least part of the chitosan, the chitosan derivative, or the chitosan salt.
[Revendication 2] Produit biocompatible selon la revendication 1 , caractérisé en ce que la concentration de cation zinc divalent dans la matrice est comprise entre 0,001 % et 1 % en poids par rapport au poids total de la matrice, et de préférence entre 0,01 % et 1 % en poids par rapport au poids total de la matrice. [Claim 2] Biocompatible product according to claim 1, characterized in that the concentration of divalent zinc cation in the matrix is between 0.001% and 1% by weight relative to the total weight of the matrix, and preferably between 0.01 % and 1% by weight relative to the total weight of the matrix.
[Revendication 3] Produit biocompatible selon l’une des revendications 1 ou 2, caractérisé en ce que la concentration de cation zinc divalent dans la matrice est inférieure ou égale à 0,1 % en poids par rapport au poids total de la matrice. [Claim 3] Biocompatible product according to one of Claims 1 or 2, characterized in that the concentration of divalent zinc cation in the matrix is less than or equal to 0.1% by weight relative to the total weight of the matrix.
[Revendication 4] Produit biocompatible selon l'une quelconque des revendications 1 à 3, caractérisé en ce que la concentration de cation zinc divalent dans la matrice est comprise entre 0,002 % et 0,06 % en poids par rapport au poids total de la matrice. [Claim 4] Biocompatible product according to any one of Claims 1 to 3, characterized in that the concentration of divalent zinc cation in the matrix is between 0.002% and 0.06% by weight relative to the total weight of the matrix .
[Revendication 5] Produit biocompatible selon l’une quelconque des revendications 1 à 4, caractérisé en ce que le cation zinc divalent est Inclus dans la matrice par l'ajout d'un sel de zinc ou d’un saccharide de zinc, de préférence du gluconate de zinc, du chlorure de zinc ou du sulfate de zinc. [Claim 5] Biocompatible product according to any one of claims 1 to 4, characterized in that the divalent zinc cation is included in the matrix by the addition of a zinc salt or a zinc saccharide, preferably zinc gluconate, zinc chloride or zinc sulphate.
[Revendication 6] Produit biocompatible selon l’une quelconque des revendications 1 à 5, caractérisé en ce que : [Claim 6] Biocompatible product according to any one of Claims 1 to 5, characterized in that:
- la concentration en polysaccharide choisi dans le groupe comprenant l’acide hyaluronique, un sel d'acide hyaluronique, le sulfate de chondroïtine, les dérivés cellulosiques, et un mélange de ceux-ci, est comprise entre 0,01 % et 3 % en poids par rapport au poids total de la matrice, et/ou - the concentration of polysaccharide chosen from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulose derivatives, and a mixture thereof, is between 0.01% and 3% by weight relative to the total weight of the matrix, and/or
- la concentration en chitosane, en dérivé de chitosane, ou en sel de chitosane est comprise entre 0,01 % et 3 % en poids par rapport au poids total de la matrice.
- the concentration of chitosan, chitosan derivative, or chitosan salt is between 0.01% and 3% by weight relative to the total weight of the matrix.
[Revendication 7] Produit biocompatible selon l’une quelconque des revendications 1 à 6, caractérisé en ce que le dérivé de chitosane est un carboxyalkyle chitosane, de préférence un carboxyméthyle chitosane. [Claim 7] Biocompatible product according to any one of Claims 1 to 6, characterized in that the chitosan derivative is a carboxyalkyl chitosan, preferably a carboxymethyl chitosan.
[Revendication 8] Produit biocompatible selon l’une quelconque des revendications 1 à 7, caractérisé en ce que le polysaccharide est l'acide hyaluronique ou un sel d’acide hyaluronique, et a de préférence un poids moléculaire compris entre 0,1 et 5 MDa. [Claim 8] Biocompatible product according to any one of Claims 1 to 7, characterized in that the polysaccharide is hyaluronic acid or a salt of hyaluronic acid, and preferably has a molecular weight of between 0.1 and 5 MDa.
[Revendication 9] Composition cosmétique ou pharmaceutique comprenant un produit biocompatible selon l’une quelconque des revendications 1 à 8. [Claim 9] Cosmetic or pharmaceutical composition comprising a biocompatible product according to any one of claims 1 to 8.
[Revendication 10] Composition cosmétique ou pharmaceutique selon la revendication 9, comprenant un tampon physiologiquement acceptable, contenant de préférence des polyols et/ou des phospholipides. [Claim 10] Cosmetic or pharmaceutical composition according to claim 9, comprising a physiologically acceptable buffer, preferably containing polyols and/or phospholipids.
[Revendication 11] Composition selon l’une des revendications 9 ou 10, pour une utilisation dans une méthode de traitement cosmétique ou de traitement thérapeutique, comprenant notamment l'application topique, l’implantation, l’instillation ou l'injection par voie sous-cutanée, intradermique, mucosale, oculaire, intraoculaire, ou intra-articulaire, de ladite composition. [Claim 11] Composition according to one of Claims 9 or 10, for use in a method of cosmetic treatment or therapeutic treatment, comprising in particular topical application, implantation, instillation or injection by the subcutaneous route. -cutaneous, intradermal, mucosal, ocular, intraocular, or intra-articular, of said composition.
[Revendication 12] Composition pour l'utilisation selon la revendication 11, pour la prévention et/ou le traitement de pathologies pouvant être améliorées ou évitées par : [Claim 12] Composition for the use according to claim 11, for the prevention and/or treatment of pathologies which can be improved or avoided by:
- le comblement ou le remplacement d'un tissu biologique ; et/ou - the filling or replacement of a biological tissue; and or
- l'augmentation de volume dudit tissu biologique ; et/ou - the increase in volume of said biological tissue; and or
- la supplémentation ou le remplacement d'un fluide biologique. - supplementation or replacement of a biological fluid.
[Revendication 13] Composition pour l’utilisation selon l'une des revendications 11 ou 12, pour une utilisation dans une méthode de traitement d'une arthrose, ou de réparation d'un défaut de cartilage, la composition étant par exemple formulée pour une administration par injection dans le fluide synovial ou pour une implantation dans le cartilage après mélange avec le sang, ou pour une méthode de traitement de la sécheresse oculaire. [Claim 13] Composition for the use according to one of Claims 11 or 12, for use in a method for treating osteoarthritis, or for repairing a cartilage defect, the composition being for example formulated for a administration by injection into synovial fluid or for implantation into cartilage after mixing with blood, or for a method of treating dry eye.
[Revendication 14] Composition selon l'une des revendications 9 ou 10, pour une utilisation dans une méthode de traitement en thérapeutique, en chirurgie, ou cosmétique, incluant en particulier un traitement en rhumatologie, en ophtalmologie, en gynécologie, en médecine esthétique, en chirurgie plastique, en chirurgie interne, en chirurgie orthopédique, pour la prévention des adhérences tissulaires post-chirurgicales, en dermatologie.
[Claim 14] Composition according to one of Claims 9 or 10, for use in a therapeutic, surgical or cosmetic treatment method, including in particular a treatment in rheumatology, ophthalmology, gynecology, aesthetic medicine, in plastic surgery, in internal surgery, in orthopedic surgery, for the prevention of post-surgical tissue adhesions, in dermatology.
[Revendication 15] Composition selon l'une des revendications 9 ou 10, pour une utilisation dans un traitement thérapeutique d'un syndrome de l'œil sec, d’une lésion de cornée ou d’une inflammation oculaire ou articulaire. [Claim 15] Composition according to one of Claims 9 or 10, for use in a therapeutic treatment of dry eye syndrome, corneal damage or ocular or joint inflammation.
[Revendication 16] Composition selon l'une des revendications 9 ou 10, pour une utilisation dans un traitement thérapeutique lors duquel on applique ladite composition par instillation sur la surface oculaire pour prévenir ou lutter contre une lésion de cornée ou un syndrome de l’œil sec, en particulier dans le but de lubrifier ou régénérer la surface oculaire. [Claim 16] Composition according to one of Claims 9 or 10, for use in a therapeutic treatment during which the said composition is applied by instillation on the ocular surface to prevent or combat a corneal lesion or an eye syndrome dry, in particular for the purpose of lubricating or regenerating the ocular surface.
[Revendication 17] Composition de gouttes ophtalmiques comprenant un produit biocompatible selon l'une quelconque des revendications 1 à 8. [Claim 17] An eye drop composition comprising a biocompatible product according to any one of claims 1 to 8.
[Revendication 18] Procédé de fabrication d'un produit biocompatible selon l'une quelconque des revendications 1 à 8 ou d’une composition selon l'une quelconque des revendications 9 à 17, ledit procédé comprenant les étapes suivantes : a. dissoudre dans une même solution aqueuse : i. un polysaccharide choisi dans le groupe comprenant l'acide hyaluronique, un sel d’acide hyaluronique, le sulfate de chondroïtine, les dérivés cellulosiques, et un mélange de ceux-ci, de préférence de l’acide hyaluronique ou un sel d’acide hyaluronique, ii. du chitosane, de préférence un dérivé de chitosane, ou un sel de chitosane, b. ajouter dans ladite solution aqueuse un agent réticulant et provoquer une réticulation du mélange pour former une matrice, c. ajouter un cation divalent de zinc avant et/ou après l’étape b. [Claim 18] A method of making a biocompatible product according to any of claims 1 to 8 or a composition according to any of claims 9 to 17, said method comprising the following steps: a. dissolve in the same aqueous solution: i. a polysaccharide selected from the group comprising hyaluronic acid, a salt of hyaluronic acid, chondroitin sulphate, cellulosic derivatives, and a mixture thereof, preferably hyaluronic acid or a salt of hyaluronic acid , ii. chitosan, preferably a chitosan derivative, or a chitosan salt, b. adding a crosslinking agent to said aqueous solution and causing crosslinking of the mixture to form a matrix, c. add a divalent zinc cation before and/or after step b.
[Revendication 19] Procédé de fabrication selon la revendication 18, caractérisé en ce que le pH du produit biocompatible ou de la composition est ajusté entre 6 et 8, de préférence à 7. [Claim 19] Manufacturing process according to Claim 18, characterized in that the pH of the biocompatible product or of the composition is adjusted between 6 and 8, preferably to 7.
[Revendication 20] Procédé de fabrication selon l’une des revendications 18 ou 19, caractérisé en ce que le produit biocompatible ou la composition est soumis à un traitement thermique de stérilisation, de préférence à un traitement thermique à une température comprise entre 120°C et 140°C pendant une durée comprise entre 1 et 20 minutes.
[Claim 20] Manufacturing process according to one of Claims 18 or 19, characterized in that the biocompatible product or the composition is subjected to a heat treatment for sterilization, preferably to a heat treatment at a temperature of between 120°C and 140° C. for a period of between 1 and 20 minutes.
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PCT/IB2022/053637 WO2022229787A1 (en) | 2021-04-26 | 2022-04-19 | Biocompatible product having a matrix comprising a polysaccharide co-crosslinked with chitosan |
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FR2927255B1 (en) * | 2008-02-07 | 2011-08-12 | Keysan Consulting | BIOCOMPATIBLE INJECTABLE PRODUCTS WITH ZINC RELEASE AND / OR ZINC SACCHARIDE SALT AND USES THEREOF. |
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FR3074043B1 (en) * | 2017-11-28 | 2020-11-13 | Kiomed Pharma | ANIONIC CHARGED CHITOSAN |
FR3096260B1 (en) * | 2019-05-24 | 2022-05-27 | Kiomed Pharma | CHITOSAN AND ITS APPLICATIONS |
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