EP3962546A1 - A biocompatible, biodegradable and bioresorbable adhesion membrane including hyaluronic acid / chitosan / carboxymethyl cellulose and production method - Google Patents
A biocompatible, biodegradable and bioresorbable adhesion membrane including hyaluronic acid / chitosan / carboxymethyl cellulose and production methodInfo
- Publication number
- EP3962546A1 EP3962546A1 EP20801738.4A EP20801738A EP3962546A1 EP 3962546 A1 EP3962546 A1 EP 3962546A1 EP 20801738 A EP20801738 A EP 20801738A EP 3962546 A1 EP3962546 A1 EP 3962546A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- chitosan
- mixture
- biodegradable
- biocompatible
- water
- 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
- 239000012528 membrane Substances 0.000 title claims abstract description 60
- 229920001661 Chitosan Polymers 0.000 title claims abstract description 50
- 229920002134 Carboxymethyl cellulose Polymers 0.000 title claims abstract description 30
- 235000010948 carboxy methyl cellulose Nutrition 0.000 title claims abstract description 30
- 239000001768 carboxy methyl cellulose Substances 0.000 title claims abstract description 20
- 239000008112 carboxymethyl-cellulose Substances 0.000 title claims abstract description 19
- 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 title claims abstract description 11
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 11
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 239000000203 mixture Substances 0.000 claims abstract description 42
- 238000009472 formulation Methods 0.000 claims abstract description 12
- 210000000056 organ Anatomy 0.000 claims abstract description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 239000004971 Cross linker Substances 0.000 claims description 9
- 238000004132 cross linking Methods 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 8
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 8
- 239000008367 deionised water Substances 0.000 claims description 7
- 229910021641 deionized water Inorganic materials 0.000 claims description 7
- 239000012467 final product Substances 0.000 claims description 7
- 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 claims description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 5
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 239000011521 glass Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 229910001220 stainless steel Inorganic materials 0.000 claims description 2
- 239000010935 stainless steel Substances 0.000 claims description 2
- 230000001954 sterilising effect Effects 0.000 claims description 2
- 239000003431 cross linking reagent Substances 0.000 claims 2
- HPILSDOMLLYBQF-UHFFFAOYSA-N 2-[1-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COC(CCC)OCC1CO1 HPILSDOMLLYBQF-UHFFFAOYSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 238000005303 weighing Methods 0.000 claims 1
- 230000004888 barrier function Effects 0.000 abstract description 15
- 238000005054 agglomeration Methods 0.000 abstract description 7
- 230000002776 aggregation Effects 0.000 abstract description 7
- 238000001356 surgical procedure Methods 0.000 abstract description 7
- 125000003277 amino group Chemical group 0.000 abstract description 6
- 229920001282 polysaccharide Polymers 0.000 abstract description 5
- 239000005017 polysaccharide Substances 0.000 abstract description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 3
- 150000004676 glycans Chemical class 0.000 abstract 1
- 230000001131 transforming effect Effects 0.000 abstract 1
- 210000004379 membrane Anatomy 0.000 description 40
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000013065 commercial product Substances 0.000 description 11
- 230000000844 anti-bacterial effect Effects 0.000 description 9
- 230000000740 bleeding effect Effects 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 230000006378 damage Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000009772 tissue formation Effects 0.000 description 4
- 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 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 230000003187 abdominal effect Effects 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000001523 electrospinning Methods 0.000 description 3
- 230000023597 hemostasis Effects 0.000 description 3
- 230000002439 hemostatic effect Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 150000004804 polysaccharides Chemical class 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 206010034650 Peritoneal adhesions Diseases 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000006150 trypticase soy agar Substances 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- 206010000050 Abdominal adhesions Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 229920000544 Gore-Tex Polymers 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940030225 antihemorrhagics Drugs 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229920000295 expanded polytetrafluoroethylene Polymers 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000007433 macroscopic evaluation Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002151 serous membrane Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
- C08L1/08—Cellulose derivatives
- C08L1/26—Cellulose ethers
- C08L1/28—Alkyl ethers
- C08L1/286—Alkyl ethers substituted with acid radicals, e.g. carboxymethyl cellulose [CMC]
-
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/041—Mixtures of macromolecular compounds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
- C08B15/005—Crosslinking of cellulose derivatives
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
Definitions
- BIOCOMPATIBLE, BIODEGRADABLE AND BIORESORBABLE ADHESION MEMBRANE INCLUDING HYALURONIC ACID / CHITOSAN / CARBOXYMETHYL CELLULOSE AND PRODUCTION
- the present invention relates to biocompatible, biodegradable and bioabsorbable adhesion membranes, containing hyaluronic acid / chitosan / carboxymethyl cellulose, that are used for the prevention of tissue and organ adhesions occurring abnormally after injury or surgical operation.
- Adhesions are described as abnormal adhesions occurring between and/or adjacent organs after injury or surgical operations that occur in the intra abdominal region, which are not normally adherent or combined with each other, and that are surrounded by serous membrane.
- adhesion barriers are used in the healing process to reduce / prevent adhesion.
- the new surgical techniques and recommended drugs could not prevent adhesion to the desired level.
- the use of adhesion barriers is more preferred.
- An ideal adhesion barrier in addition to being biocompatible and biodegradable, it should not affect wound healing and should not show undesirable reactions in the body, be effective in the presence of body fluids and blood, and be easy to use. In addition, it should not cause infection and inflammation, should be antibacterial, be stable in the initial phase of adhesion formation, then be metabolized and economical.
- the membranes used for preventing tissue and organ adhesions occurring abnormally after injury or surgical operation are obtained by the electro spinning method, taking the common state of the art. Due to the low physical strength of the membranes obtained by the electro spinning method, there are difficulties in placing these products on the body. Another disadvantage is that the electro spinning method is a very slow and complex method, also the transparent membrane cannot be obtained. In addition, the thickness of the membranes obtained cannot be produced equally. The transfer processes during the removal of the membranes to be obtained after production from the winding drum of the electrospin device and keeping them to the crosslinking process are also quite complicated and difficult.
- Teflon membranes have difficulty while placing. Also, since they are not biodegradable, they can be perceived by the body as a foreign body. It also needs to be planted for fixation. These disadvantages restrict use [1]
- Oxidized regenerated cellulose membranes can be ineffective when hemostasis (bleeding arrest) is not completely done and in the presence of peritoneal fluid [3].
- Another disadvantage is that the blood proteins easily pass through the membrane and deform the adhesion barrier membrane due to its poor biocompatibility and the size of the pores in its structure are quite large (US20120088832).
- membranes in a different application in the known state of the technique can effectively reduce adhesions, there may be difficulties in repositioning during application due to their low mechanical properties [4]. In addition, its brittle and very sticky structure limits its use during surgery. At the same time, these membranes have been shown to increase adhesion in cases of bacterial inflammation [5].
- bioabsorbable adhesion membranes are obtained using sodium carboxymethyl cellulose, chondroitin sulfate and sodium hyaluronate. Glycerin and polyethylene glycol were used as plasticizing agents. Adhesion membranes were obtained by crosslinking this formulation with calcium chloride.
- adhesion membranes are obtained by crosslinking carboxymethyl cellulose and polyethylene oxide. It is a big disadvantage that polyethylene oxide is not biodegradable. Only small molecular weight polyethylene oxide can be metabolised, but in this case, the fast adhesion will occur, so the adhesion barrier membrane is not effective.
- the aim of the invention is to obtain a modified chitosan and to solve the caking problem by converting a part of the amine group in the chitosan structure to prevent the agglomeration caused by the mixture of positively charged chitosan and negatively charged hyaluronic acid and carboxymethyl cellulose, which are different ionic charged polysaccharides, in a single formulation.
- Another object of the invention is to use plasticizing agents (USP glycerol or Sorbitol) in the formulation in order to increase and regulate the flexibility of the adhesion barrier membrane obtained.
- plasticizing agents USP glycerol or Sorbitol
- Another object of the invention is to prevent the formation of stable macromolecule radicals by reacting free radicals that increase adhesion formation with amine groups in the form of chitosan in the formulation. In addition, it protects the physical properties of the membrane during tissue formation and ensures that it stays on the surface throughout the undesired tissue formation.
- Another aim of the invention is to prevent this unusual bleeding after surgery by making use of this feature of chitosan, which is a very good hemostatic agent.
- Another aim of the invention is to provide easy visibility of the doctor during the operation by obtaining the membrane transparently.
- Another object of the invention is to obtain membranes that are completely bioresorbable or biodegradable.
- Biocompatible, biodegradable and bioabsorbable adhesion membranes of the present invention are used to prevent tissue and organ adhesions after surgery, hyaluronic acid, chitosan and carboxymethyl cellulose are obtained by crosslinking with cross-linkers in the aqueous solution of the triple structure.
- Chitosan in this triple structure used within the membrane within the scope of the invention is a positively charged natural polysaccharide because it contains an amine group; on the other hand, hyaluronic acid and carboxymethyl cellulose are negatively charged natural polysaccharides.
- chitosan is transformed into a water-soluble form by reacting with chloroacetic acid in alkaline medium.
- the membrane of the invention 0.2-6% by weight sodium hyaluronate, 0.05-3% by weight modified chitosan, 0.02-2% by carboxymethyl cellulose, 0.05-5% by plasticizing agent (preferably USP Glycerol or Sorbitol) and 90-99% by deionized water.
- plasticizing agent preferably USP Glycerol or Sorbitol
- the method of preparing a modified and water soluble chitosan used within the membrane includes the following steps;
- the production method of biocompatible, biodegradable and bioabsorbable adhesion membranes according to the invention of the modified chitosan obtained by these process steps described above includes the following steps:
- the mixture is poured into a mold and the water in the formulation is removed under vacuum at room temperature,
- the adhesion membrane film structure is obtained by completely removing the water from the environment by evaporation
- the films are removed from the solution and washed with ethanol in order to remove unreacted crosslinkers remaining on the surface of the film,
- chitosan at a ratio of 3-6% with respect to the alcohol solvent was suspended in a 1000 ml reaction flask in isopropyl alcohol (IPA) (preferably 4 g chitosan in 100 ml isopropyl alcohol (IPA)) for 1 hour with a magnetic stirrer.
- IPA isopropyl alcohol
- IPA isopropyl alcohol
- the obtained final mixture was stirred at 60-70 °C for 8-10 hours. After the reaction ended, it was neutralized with an acid solution (preferably 4 M hydrochloric acid (HC1)). Finally, the mixture was filtered and precipitated with methanol. The resulting precipitated product was washed 3 times with a methanol / water mixture and dried under vacuum to obtain modified chitosan powder.
- an acid solution preferably 4 M hydrochloric acid (HC1)
- Sodium hyaluronate, modified chitosan, carboxymethyl cellulose and USP glycerol were weighed and dissolved in deionized water at 200 rpm with a mechanical mixer, respectively. After the mixture was dissolved, it was filtered with a 0.22 micron membrane filter. After taking the air bubbles of the mixture obtained, it was poured into a glass or metal (stainless steel) mold and the water was removed under vacuum at room temperature.
- adhesion membrane films were formed.
- the resulting films were immersed in the solution of BDDE or EDC / NHS in ethanol to perform the crosslinking reaction.
- the films were removed from the crosslinker solution within the specified time, and the unreacted (residual) crosslinkers were removed by washing with ethanol.
- the final product obtained was dried under vacuum at room temperature and then sterilized.
- Hyaluronic acid / Chitosan / Carboxymethyl cellulose (HA / CHI / CMC) showed a very effective performance in adhesion formation tests to determine the use of adhesion barrier membrane. For this purpose, it has been found that it performs better when compared with an existing commercial product adhesion formation. The results below show the evaluations in this study. Table 1. Adhesion Evaluation Degrees
- the cases were divided into 3 groups.
- the first group was called the control group and no treatment was applied.
- the second group was named as the 1st experimental group and the second group as the 2nd experimental group, and the abraded area was covered with HA / CHI / CMC and existing commercial product samples. After the operation, the treatment area was closed with stitches.
- the formation of fibrosis was found to be lower in the HA / CHI / CMC sample than in the current commercial product. Studies have shown that both samples reduce adhesion and fibrosis formation, but the HA / CHI / CMC sample is more effective than the current commercial product. Since the chitosan in the formulation is also a very important hemostasis, the adhesion barrier membrane obtained has a good anti-bleeding feature and maintains its effect in the presence of blood. It is shown in Table 3 that it stops bleeding more quickly when the current commercial product and hemostatic properties are compared.
- the hemostatic properties of the samples were tested on the livers of rabbits. Wounds of equal size were opened on the liver, the samples were placed on these wounds and bleeding stop times were recorded. When the results of 3 different measurements are evaluated, the HA / CHI / CMC sample stopped bleeding in an average of 133 seconds, while the current commercial product sample stopped in 192 seconds.
- the faster hemostasis effect of the HA / CHI / CMC sample can be explained by the fact that the positively charged chitosan substance in its structure forms coagulation with negatively charged thrombocytes in the blood. This feature of chitosan has been widely mentioned in the literature.
- Chitosan which is a very good antibacterial, has produced an effective solution against possible bacterial growths that may occur during surgery. It is shown in Table 4 that when compared with the current commercial product and antibacterial properties, it shows a more effective antibacterial property.
- Samples prepared with the commercially available commercial product and HA / CHI / CMC triple combination were subjected to anti-bacterial testing.
- the antibacterial effectiveness of the samples cut in 2 x 2 cm dimensions were investigated.
- Escherichra coli (E.coli) ATCC 25922 was used as the gram negative in the experiment.
- TSA Tryptic soy agar
- Inoculation was made from dilute spore solution to the medium using the spreading plate method. Petri dishes were left incubated for 48 hours. The positive / negative effects of samples on bacterial growth were investigated with reference spore solution. Incubation temperature is 37 °C. Live organism count controls were performed at 6, 12, 24, 36 and 48 hours of the study. Work was carried out under the LAF cabin.
- the membrane structure of the invention is provided to be transparent in order to provide ease of vision for the doctor during the operation and it is ensured that a completely bioabsorbable and biodegradable product is obtained in order not to perform a second operation in order to remove the membrane structure from the body.
- the adhesion barrier membrane is commercially produced for the first time.
- This triple combination were able to undergo crosslinking reactions using cross-linkers such as 1,4-Butanediol diglycidyl ether (BDDE) and l-ethyl-3-(3- dimethylaminopropyl) carbodiimide / N-Hydroxysuccinimide (EDC / NHS),via hydroxyl groups in their structure without any agglomeration in the same formulation.
- cross-linkers such as 1,4-Butanediol diglycidyl ether (BDDE) and l-ethyl-3-(3- dimethylaminopropyl) carbodiimide / N-Hydroxysuccinimide (EDC / NHS),via hydroxyl groups in their structure without any agglomeration in the same formulation.
- Bakkum J.B.M.Z. Trimbos Effects of five different barrier materials on postsurgical adhesion formation in the rat, Human Reproduction, Volume
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Abstract
The present invention relates to biocompatible, biodegradable and bioabsorbable anti-bleeding adhesion barrier membranes that are used to prevent tissue and organ adhesions after surgery and contain hyaluronic acid / chitosan / carboxymethyl cellulose. The aim of the invention is to solve the agglomeration problem by converting a part of the amine group in the chitosan structure to carboxylic acid by transforming a part of the amine group in the chitosan structure into carboxylic acid in order to prevent agglomeration due to the mixture of positively charged chitosan and negatively charged hyaluronic acid and carboxymethyl cellulose, which are different ionic charged polysaccharides. Also, the aim of this invention is the use of triple combination in the same formulation without agglomeration and to provide adhesion barrier membranes.
Description
A BIOCOMPATIBLE, BIODEGRADABLE AND BIORESORBABLE ADHESION MEMBRANE INCLUDING HYALURONIC ACID / CHITOSAN / CARBOXYMETHYL CELLULOSE AND PRODUCTION
METHOD
Technical Field The present invention relates to biocompatible, biodegradable and bioabsorbable adhesion membranes, containing hyaluronic acid / chitosan / carboxymethyl cellulose, that are used for the prevention of tissue and organ adhesions occurring abnormally after injury or surgical operation. Prior Art
Adhesions are described as abnormal adhesions occurring between and/or adjacent organs after injury or surgical operations that occur in the intra abdominal region, which are not normally adherent or combined with each other, and that are surrounded by serous membrane.
Techniques such as the development of the surgical technique, the use of adhesion-inhibiting drugs and the separation of tissues (adhesion barriers) are used in the healing process to reduce / prevent adhesion. The new surgical techniques and recommended drugs could not prevent adhesion to the desired level. The use of adhesion barriers is more preferred.
An ideal adhesion barrier; in addition to being biocompatible and biodegradable, it should not affect wound healing and should not show undesirable reactions in the body, be effective in the presence of body fluids and blood, and be easy to use. In addition, it should not cause infection and inflammation, should be
antibacterial, be stable in the initial phase of adhesion formation, then be metabolized and economical.
The membranes used for preventing tissue and organ adhesions occurring abnormally after injury or surgical operation are obtained by the electro spinning method, taking the common state of the art. Due to the low physical strength of the membranes obtained by the electro spinning method, there are difficulties in placing these products on the body. Another disadvantage is that the electro spinning method is a very slow and complex method, also the transparent membrane cannot be obtained. In addition, the thickness of the membranes obtained cannot be produced equally. The transfer processes during the removal of the membranes to be obtained after production from the winding drum of the electrospin device and keeping them to the crosslinking process are also quite complicated and difficult.
Teflon membranes have difficulty while placing. Also, since they are not biodegradable, they can be perceived by the body as a foreign body. It also needs to be planted for fixation. These disadvantages restrict use [1]
Removal of non-biodegradable membranes from the body with the need for a second operation is among the problems encountered [2]. The patient's life comfort decreases and he / she suffers financially.
Oxidized regenerated cellulose membranes can be ineffective when hemostasis (bleeding arrest) is not completely done and in the presence of peritoneal fluid [3]. Another disadvantage is that the blood proteins easily pass through the membrane and deform the adhesion barrier membrane due to its poor biocompatibility and the size of the pores in its structure are quite large (US20120088832).
Although membranes in a different application in the known state of the technique can effectively reduce adhesions, there may be difficulties in repositioning during
application due to their low mechanical properties [4]. In addition, its brittle and very sticky structure limits its use during surgery. At the same time, these membranes have been shown to increase adhesion in cases of bacterial inflammation [5].
In the Chinese patent application document CN102614551B, one of the applications known in the art, it is mentioned that bioabsorbable adhesion membranes are obtained using sodium carboxymethyl cellulose, chondroitin sulfate and sodium hyaluronate. Glycerin and polyethylene glycol were used as plasticizing agents. Adhesion membranes were obtained by crosslinking this formulation with calcium chloride.
Among the applications known in the art, in the United States patent application document No. US6693089, alginate solutions; In the patent application document no. US20120088832, it is mentioned that alginic acid and carboxymethyl cellulose are obtained by forming cross-linked films with calcium ions. However, it was observed in these studies that calcium ions spread to surrounding tissues as a result of degredation. This situation has aggravated the damage of injured tissues.
In the patent application documents US20120088832 and US20080254091, which are known in the art, it is mentioned that adhesion membranes are obtained by crosslinking carboxymethyl cellulose and polyethylene oxide. It is a big disadvantage that polyethylene oxide is not biodegradable. Only small molecular weight polyethylene oxide can be metabolised, but in this case, the fast adhesion will occur, so the adhesion barrier membrane is not effective.
Other reference documents in the state of the art; Documents numbered US5580923A, US5914182A, W02007029913A1, CN102614551B,
EP0732110A1.
Brief Description of the Invention
The aim of the invention is to obtain a modified chitosan and to solve the caking problem by converting a part of the amine group in the chitosan structure to prevent the agglomeration caused by the mixture of positively charged chitosan and negatively charged hyaluronic acid and carboxymethyl cellulose, which are different ionic charged polysaccharides, in a single formulation.
Another object of the invention is to use plasticizing agents (USP glycerol or Sorbitol) in the formulation in order to increase and regulate the flexibility of the adhesion barrier membrane obtained.
Another object of the invention is to prevent the formation of stable macromolecule radicals by reacting free radicals that increase adhesion formation with amine groups in the form of chitosan in the formulation. In addition, it protects the physical properties of the membrane during tissue formation and ensures that it stays on the surface throughout the undesired tissue formation.
Another aim of the invention is to prevent this unusual bleeding after surgery by making use of this feature of chitosan, which is a very good hemostatic agent.
Another aim of the invention is to provide easy visibility of the doctor during the operation by obtaining the membrane transparently.
Another object of the invention is to obtain membranes that are completely bioresorbable or biodegradable.
Detailed Description of the Invention
Biocompatible, biodegradable and bioabsorbable adhesion membranes of the present invention are used to prevent tissue and organ adhesions after surgery, hyaluronic acid, chitosan and carboxymethyl cellulose are obtained by crosslinking with cross-linkers in the aqueous solution of the triple structure.
Chitosan in this triple structure used within the membrane within the scope of the invention is a positively charged natural polysaccharide because it contains an amine group; on the other hand, hyaluronic acid and carboxymethyl cellulose are negatively charged natural polysaccharides.
When these counter-loaded materials are used in a single formulation, agglomeration is observed in the mixture obtained. To solve this problem, some of the amine groups in the structure of chitosan are converted to carboxylic acid to obtain modified chitosan and the problem of agglomeration is solved. Accordingly, chitosan is transformed into a water-soluble form by reacting with chloroacetic acid in alkaline medium.
The membrane of the invention; 0.2-6% by weight sodium hyaluronate, 0.05-3% by weight modified chitosan, 0.02-2% by carboxymethyl cellulose, 0.05-5% by plasticizing agent (preferably USP Glycerol or Sorbitol) and 90-99% by deionized water.
The method of preparing a modified and water soluble chitosan used within the membrane includes the following steps;
- Suspension of chitosan taken in a reaction flask with magnetic stirrer in isopropyl alcohol
- Stirring is continued by adding sodium hydroxide (NaOH) solution to the mixture.
- gradually adding monochloroacetic acid to the mixture
- continuing the mixing of the reaction mixture formed
- neutralizing the mixture with hydrochloric acid (HC1) solution after the reaction is over
- filtering the mixture and precipitating with methanol
- washing the obtained precipitated product with a methanol / water mixture - drying of the precipitated product under vacuum to obtain modified chitosan, which is the final product.
The production method of biocompatible, biodegradable and bioabsorbable adhesion membranes according to the invention of the modified chitosan obtained by these process steps described above includes the following steps:
- Sodium hyaluronate, modified chitosan, carboxymethyl cellulose and plasticizing agent (USP glycerol) are weighed and dissolved by means of a mechanical mixer after being taken into deionized water,
- Filtering the mixture with the help of cellulose membrane filter,
- After the air bubbles are removed, the mixture is poured into a mold and the water in the formulation is removed under vacuum at room temperature,
- The adhesion membrane film structure is obtained by completely removing the water from the environment by evaporation,
- Immersing the film structure in the solution formed with ethanol and crosslinkers in order to crosslink the films,
- After 24 hours, the films are removed from the solution and washed with ethanol in order to remove unreacted crosslinkers remaining on the surface of the film,
- Then, drying the films under vacuum at room temperature to obtain adhesion membranes, which is the final product,
- Packaging the final product and then sterilizing it.
Preparation of Water Soluble Chitosan:
Firstly, chitosan at a ratio of 3-6% with respect to the alcohol solvent was suspended in a 1000 ml reaction flask in isopropyl alcohol (IPA) (preferably 4 g chitosan in 100 ml isopropyl alcohol (IPA)) for 1 hour with a magnetic stirrer.
Then, it was added to the mixture from a 60% alkaline solution (preferably sodium hydroxide (NaOH)) in proportion to the alcohol solvent at a ratio of 1: 1 or 1: 1.5 (preferably 150 ml) and stirred at 80-100 °C for 3-5 hours.
Then, a 2-fold ratio of 60% monochloroacetic acid was added to the alcohol solvent in 5 parts in a mixture every 10 minutes.
The obtained final mixture was stirred at 60-70 °C for 8-10 hours. After the reaction ended, it was neutralized with an acid solution (preferably 4 M hydrochloric acid (HC1)). Finally, the mixture was filtered and precipitated with methanol. The resulting precipitated product was washed 3 times with a methanol / water mixture and dried under vacuum to obtain modified chitosan powder.
Sodium hyaluronate, modified chitosan, carboxymethyl cellulose and USP glycerol were weighed and dissolved in deionized water at 200 rpm with a mechanical mixer, respectively. After the mixture was dissolved, it was filtered with a 0.22 micron membrane filter. After taking the air bubbles of the mixture obtained, it was poured into a glass or metal (stainless steel) mold and the water was removed under vacuum at room temperature.
After 24 hours, as a result of evaporation of water from the environment, adhesion membrane films were formed. The resulting films were immersed in the solution of BDDE or EDC / NHS in ethanol to perform the crosslinking reaction. The films were removed from the crosslinker solution within the specified time, and the unreacted (residual) crosslinkers were removed by washing with ethanol. The
final product obtained was dried under vacuum at room temperature and then sterilized.
Hyaluronic acid / Chitosan / Carboxymethyl cellulose (HA / CHI / CMC) showed a very effective performance in adhesion formation tests to determine the use of adhesion barrier membrane. For this purpose, it has been found that it performs better when compared with an existing commercial product adhesion formation. The results below show the evaluations in this study. Table 1. Adhesion Evaluation Degrees
Table 2. Comparison of Adhesion Evaluations
The abdominal areas of the rabbits taken under anesthesia were shaved then, disinfected. Later, the abdominal cavity was reached, the secum was taken out and abraded until spot bleeding was observed in an area of approximately 4 cm2.
The cases were divided into 3 groups. The first group was called the control group and no treatment was applied. The second group was named as the 1st experimental group and the second group as the 2nd experimental group, and the
abraded area was covered with HA / CHI / CMC and existing commercial product samples. After the operation, the treatment area was closed with stitches.
After a period of fourteen days, the abdominal region was opened and the macroscopic evaluations of the region were made taking into account the grading criteria in Table 1 [6]. Statistical evaluations were made with the Statistical Package for the Social Sciences (Windows) package program. Results from the control and experimental groups were evaluated with the Mann-Whitney U test. Considering the evaluation results (Table 2), different degrees of adhesion formation were found in the cases in the control group. In the experimental groups, adhesion formation was almost not observed. However, it was observed that the HA / CHI / CMC sample had a lower adhesion score than the current commercial product, ie less adhesion formation. Similarly, the formation of fibrosis was found to be lower in the HA / CHI / CMC sample than in the current commercial product. Studies have shown that both samples reduce adhesion and fibrosis formation, but the HA / CHI / CMC sample is more effective than the current commercial product. Since the chitosan in the formulation is also a very important hemostasis, the adhesion barrier membrane obtained has a good anti-bleeding feature and maintains its effect in the presence of blood. It is shown in Table 3 that it stops bleeding more quickly when the current commercial product and hemostatic properties are compared.
Table 3. Comparison of Hemostatic Properties
The hemostatic properties of the samples were tested on the livers of rabbits. Wounds of equal size were opened on the liver, the samples were placed on these wounds and bleeding stop times were recorded. When the results of 3 different measurements are evaluated, the HA / CHI / CMC sample stopped bleeding in an average of 133 seconds, while the current commercial product sample stopped in 192 seconds. The faster hemostasis effect of the HA / CHI / CMC sample can be explained by the fact that the positively charged chitosan substance in its structure forms coagulation with negatively charged thrombocytes in the blood. This feature of chitosan has been widely mentioned in the literature.
Chitosan, which is a very good antibacterial, has produced an effective solution against possible bacterial growths that may occur during surgery. It is shown in Table 4 that when compared with the current commercial product and antibacterial properties, it shows a more effective antibacterial property.
Table 4. Comparison of Antibacterial Properties
Samples prepared with the commercially available commercial product and HA / CHI / CMC triple combination were subjected to anti-bacterial testing. The antibacterial effectiveness of the samples cut in 2 x 2 cm dimensions were investigated. Escherichra coli (E.coli) ATCC 25922 was used as the gram negative in the experiment.
Ready to use sterile media (Sterile Tryptic soy agar (TSA) medium) was provided to investigate the antibacterial effect of the samples on E.coli. Inoculation was made from dilute spore solution to the medium using the spreading plate method. Petri dishes were left incubated for 48 hours. The positive / negative effects of samples on bacterial growth were investigated with reference spore solution. Incubation temperature is 37 °C. Live organism count controls were performed at 6, 12, 24, 36 and 48 hours of the study. Work was carried out under the LAF cabin.
There was a significant decrease in the number of living organisms in both products at the end of the 12th hour. At the 24th hour, no colonies were observed in the HA / CHI / CMC sample, but a small amount of colony was present in the current commercial product sample. In both samples, E. coli colony was not found after 36 hours incubation. When the results are evaluated, it shows that the antibacterial properties of HA / CHI / CMC sample are better. The flexibility of the adhesion barrier membrane obtained within the scope of the invention can be easily adjusted by plasticizing agents (USP glycerol or Sorbitol) contained in the formulation and giving the membrane flexibility. This situation eliminates the disadvantages of the brittle hard structure encountered in the current commercial product and provides the advantage of use. Since chitosan in the formulation has the capability of holding free radicals, it preserves the
membrane feature obtained during tissue formation and keeps it on the surface throughout the tissue formation.
The membrane structure of the invention is provided to be transparent in order to provide ease of vision for the doctor during the operation and it is ensured that a completely bioabsorbable and biodegradable product is obtained in order not to perform a second operation in order to remove the membrane structure from the body. With this HA / CHI / CMC triple combination created within the scope of the invention, the adhesion barrier membrane is commercially produced for the first time. This triple combination were able to undergo crosslinking reactions using cross-linkers such as 1,4-Butanediol diglycidyl ether (BDDE) and l-ethyl-3-(3- dimethylaminopropyl) carbodiimide / N-Hydroxysuccinimide (EDC / NHS),via hydroxyl groups in their structure without any agglomeration in the same formulation.
REFERENCES
[1].The Myomectomy Adhesion Multicenter Study Group, An expanded polytetrafluoroethylene barrier (Gore-Tex* Surgical Membrane ) reduces post-myomectomy adhesion formation, Fertility and Sterility, 63, (1995) 3,
491-493.
[2]. B.W.J. Hellebrekers G.C.M. Trimbos-Kemper C.A. van Blitterswijk E.A.
Bakkum J.B.M.Z. Trimbos, Effects of five different barrier materials on postsurgical adhesion formation in the rat, Human Reproduction, Volume
15, Issue 6, 1 June 2000, Pages 1358-1363.
[3]. S. Safak, E. Karaca, R.G. Ozalp, Cerrahi Adezyonun Onlenmesi igin Yeni Bir Yaklasim: Nanolifli Cerrahi Adezyon Bariyerleri, Tekstil ve Miihendis, 24: 106, 111-123.
[4]. Chialin Sheu, K. T. Shalumon, Chih-Hao Chen, Chang-Yi Kuo, Yi Teng
Fong and Jyh-Ping Chen, Dual crosslinked hyaluronic acid nanofibrous membranes for prolonged prevention of post-surgical peritoneal adhesion, J. Mater. Chem. B, 2016, 4, 6680-6693.
[5]. Chang, Jung-Jhih, Lee, Yen-Hsien, Wu, Meng-Hsiu, Yang, Ming-Chien,
Chien, Chiang-Ting, Electrospun anti-adhesion barrier made of chitosan alginate for reducing peritoneal adhesions, Carbohydrate Polymers, 88 (2012), 1304- 1312.
[6].D.M. Evans, K. McAree, D.P. Guyton, N. Hawkins, K. Stakleff, Dose dependency and wound healing aspects of the use of tissue plasminogen activator in the prevention of intra-abdominal adhesions, Am J Surg 1993; 165: 229-232
Claims
1. Biocompatible, biodegradable and bioabsorbable adhesion membranes obtained by crosslinking hyaluronic acid, chitosan and carboxymethyl cellulose triple structure in aqueous solution with cross-linkers.
2. Biocompatible, biodegradable and bioabsorbable adhesion membranes according to Claim 1, comprising 0.2-6% by weight of sodium hyaluronate, 0.05-3% by weight of modified chitosan, 0.02-2% by weight of carboxymethyl cellulose, 0.05-5% by weight of plasticizing agent and 90-99% by weight of deionized water.
3. Biocompatible, biodegradable and bioabsorbable adhesion membranes according to Claim 2, comprising USP Glycerol as a plasticizing agent.
4. Biocompatible, biodegradable and bioabsorbable adhesion membranes according to Claim 2, comprising sorbitol as a plasticizing agent.
5. Biocompatible, biodegradable and bioabsorbable adhesion membranes according to any one of the preceding claims, used to prevent tissue and organ adhesions after surgical operation.
6. Method of preparing modified and water soluble chitosan according to claim 2; comprising the steps of
- suspending chitosan taken in a reaction flask with magnetic stirrer in isopropyl alcohol,
- adding sodium hydroxide (NaOH) solution to the mixture while stirring,
- gradually adding monochloroacetic acid to the mixture,
- continuing to stir the reaction mixture formed,
- neutralizing the mixture with hydrochloric acid (HC1) solution after the reaction has ended,
- filtering the mixture and precipitating with methanol,
- washing the resulting precipitated product with methanol / water mixture, - drying the precipitated product under vacuum to obtain modified chitosan, the final product, in powder form.
7. The method of preparing modified and water-soluble chitosan according to Claim 6, wherein 4 g chitosan is suspended in 100 ml of isopropyl alcohol (IPA), at a ratio of 3 to 6% with respect to the alcohol solvent, for 1 hour in a 1000 ml reaction flask.
8. The method of preparing modified and water-soluble chitosan according to Claim 6, wherein 60% alkaline solution is added to the mixture at a ratio of 1: 1 or 1: 1.5 with respect to the alcohol solvent, and stirred at 80-100°C for 3-5 hours.
9. The method of preparing a modified and water-soluble chitosan according to Claim 6, wherein 60% monochloroacetic acid is added at a ratio of two times the amount of alcohol solvent to the mixture in 5 equal parts once in every 10 minutes.
10. The method of preparing modified and water-soluble chitosan according to claim 6, wherein the reaction mixture is stirred at 60-70°C for 8-10 hours.
11. The method of preparing modified and water-soluble chitosan according to claim 6, wherein the mixture is neutralized with the acid solution after the reaction has ended
12. The method of preparing modified and water soluble chitosan according to claim 6, characterized in that the precipitated product is washed 3 times with methanol / water mixture.
13. Production method of biocompatible, biodegradable and bioabsorbable adhesion membranes according to any one of the preceding claims, comprising the steps of
- weighing sodium hyaluronate, modified chitosan, carboxymethyl cellulose and plasticizing agent and introducing and dissolving them respectively in deionized water with a mechanical stirrer,
- filtering the mixture with the help of a cellulose membrane filter,
- pouring the resulting mixture into a glass or metal (stainless steel) mold after the air bubbles are removed and ensuring that the water in the formulation is removed under vacuum at room temperature,
- the adhesion membrane film structure upon complete removal of the water from the medium by evaporation,
- immersing the films in the solution formed with crosslinkers and ethanol in order to crosslink the films,
- removing the films from the solution at the end of 24 hours, and washing them with ethanol in order to remove unreacted crosslinkers remaining on the surface of the film,
- then, drying the films under vacuum at room temperature to obtain adhesion membranes as the final product,
- packaging and then sterilizing the final product.
14. The production method of biocompatible, biodegradable and bioabsorbable adhesion membranes according to Claim 13, wherein sodium hyaluronate, modified chitosan, carboxymethyl cellulose and plasticizing agent are dissolved in deionized water with the help of a mechanical stirrer at 200 rpm.
15. The production method of biocompatible, biodegradable and bioabsorbable adhesion membranes according to claim 13, wherein the mixture of sodium hyaluronate, modified chitosan, carboxymethyl cellulose and plasticizing agent is filtered with a 0.22 micron membrane filter after dissolution in deionized water.
16. The production method of biocompatible, biodegradable and bioabsorbable adhesion membranes according to claim 13, wherein the mixture in the mold is kept under vacuum for 24 hours in order to remove the water therein.
17. The production method of biocompatible, biodegradable and bioabsorbable adhesion membranes according to claim 13, wherein 1,4- Butanediol diglycidyl ether (BDDE) is used as a cross-linking agent to perform a crosslinking reaction on the films.
18. The production method of biocompatible, biodegradable and bioabsorbable adhesion membranes according to Claim 13, wherein 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide / N-Hydroxysuccinimide (EDC / NHS) is used as a cross-linking agent to perform a crosslinking reaction on the films.
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| CN112826975B (en) * | 2021-01-29 | 2022-04-15 | 欣乐加生物科技温州有限公司 | Medical chitosan rapid hemostatic dressing and preparation method thereof |
| JP2024506405A (en) * | 2021-02-16 | 2024-02-13 | コーネル ユニヴァーシティー | Polysaccharide-glycerin penetration resistant compositions and surgical barriers made therefrom |
| CN112813007A (en) * | 2021-02-23 | 2021-05-18 | 江苏科技大学 | Method for repairing biological material film by biological template method |
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| KR100252704B1 (en) * | 1998-02-16 | 2000-04-15 | 김갑종 | Method of making n,o-carboxy methyl chitosan with high purity crystallization and a method of controlling a molecular weight of water-soluble chitosan |
| CN1220528C (en) * | 2003-08-19 | 2005-09-28 | 大连永兴医用材料有限公司 | Carboxymethyl chitosan / carboxymethyl cellulose operative antiblocking film and method for making the same |
| KR100588614B1 (en) * | 2003-11-10 | 2006-06-13 | 주식회사 바이오레인 | Anti-adhesion agent with gas bubble |
| CN106975098B (en) * | 2017-04-13 | 2020-07-07 | 赛克赛斯生物科技股份有限公司 | Composite polysaccharide hemostatic composition and preparation method and application thereof |
| KR101923734B1 (en) * | 2017-04-13 | 2018-11-29 | 영남대학교 산학협력단 | A crosslinked film for adhesion prevention |
| CN107417801B (en) * | 2017-06-20 | 2020-11-24 | 中国人民解放军东部战区总医院 | Injectable hydrogel and preparation method and application thereof |
-
2019
- 2019-05-03 TR TR2019/06601A patent/TR201906601A2/tr unknown
-
2020
- 2020-04-30 WO PCT/TR2020/050358 patent/WO2020226587A1/en unknown
- 2020-04-30 EP EP20801738.4A patent/EP3962546A4/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| TR201906601A2 (en) | 2020-11-23 |
| EP3962546A4 (en) | 2023-01-04 |
| WO2020226587A1 (en) | 2020-11-12 |
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