TR201906601A2 - - Google Patents
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- TR201906601A2 TR201906601A2 TR2019/06601A TR201906601A TR201906601A2 TR 201906601 A2 TR201906601 A2 TR 201906601A2 TR 2019/06601 A TR2019/06601 A TR 2019/06601A TR 201906601 A TR201906601 A TR 201906601A TR 201906601 A2 TR201906601 A2 TR 201906601A2
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- Turkey
- Prior art keywords
- chitosan
- mixture
- water
- biodegradable
- biocompatible
- Prior art date
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- 239000012528 membrane Substances 0.000 claims abstract description 57
- 229920001661 Chitosan Polymers 0.000 claims abstract description 47
- 239000000203 mixture Substances 0.000 claims abstract description 40
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims abstract description 29
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims abstract description 29
- 239000001768 carboxy methyl cellulose Substances 0.000 claims abstract description 19
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims abstract description 18
- 238000009472 formulation Methods 0.000 claims abstract description 12
- 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 abstract description 8
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 8
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 8
- 210000000056 organ Anatomy 0.000 claims abstract description 7
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 238000004132 cross linking Methods 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 8
- 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 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 6
- 239000004971 Cross linker Substances 0.000 claims description 5
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 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
- 239000002253 acid Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 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
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 238000004806 packaging method and process Methods 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
- 238000007598 dipping method Methods 0.000 claims 1
- 238000002844 melting Methods 0.000 claims 1
- 230000008018 melting Effects 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 230000004888 barrier function Effects 0.000 abstract description 12
- 125000003277 amino group Chemical group 0.000 abstract description 4
- 229920001282 polysaccharide Polymers 0.000 abstract description 4
- 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
- 210000004379 membrane Anatomy 0.000 description 38
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000013065 commercial product Substances 0.000 description 12
- 230000000844 anti-bacterial effect Effects 0.000 description 9
- 208000032843 Hemorrhage Diseases 0.000 description 8
- 238000001356 surgical procedure Methods 0.000 description 8
- 208000027418 Wounds and injury Diseases 0.000 description 7
- 230000000740 bleeding effect Effects 0.000 description 7
- 230000006378 damage Effects 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 206010016654 Fibrosis Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000004761 fibrosis Effects 0.000 description 4
- 208000014674 injury Diseases 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
- 206010052428 Wound Diseases 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 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
- 239000002609 medium Substances 0.000 description 3
- 150000004804 polysaccharides Chemical class 0.000 description 3
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
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- 230000001580 bacterial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000006150 trypticase soy agar Substances 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
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000252983 Caecum Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 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
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 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
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003187 abdominal 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
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 210000004534 cecum Anatomy 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
- -1 dimethylaminopropyl Chemical group 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012552 review Methods 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
- 238000004659 sterilization and disinfection Methods 0.000 description 1
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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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Materials Engineering (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Heart & Thoracic Surgery (AREA)
- Surgery (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Materials For Medical Uses (AREA)
Abstract
Bu buluş, cerrahi operasyon sonrası doku ve organ yapışmalarını önleme için kullanılan ve hiyaluronik asit/kitosan/karboksimetil selüloz içeren biyouyumlu, biyobozunur ve biyoemilebilir kanama durdurucu özelliğe sahip adezyon bariyer membranlar ile ilgilidir. Buluşun amacı farklı iyonik yüklü polisakkaritler olan pozitif yüklü kitosan ve negatif yüklü hiyaluronik asit ve karboksimetil selülozun tek bir formülasyon içerisinde karışımından dolayı oluşan topaklanmalar önüne geçilmesi amacıyla kitosan yapısındaki amin grubunun bir kısmının karboksilik aside dönüştürülmesiyle modifiye kitosan elde edilerek topaklanma sorununun çözülmesi ile üçlü kombinasyonun bir formül içerisinde kullanımının sağlanması ve adezyon bariyer membranların elde edilmesidir.The present invention relates to biocompatible, biodegradable and bioabsorbable adhesion barrier membranes containing hyaluronic acid / chitosan / carboxymethyl cellulose used to prevent post-surgical tissue and organ adhesions. The aim of the invention is a formula of a triple combination by obtaining modified chitosan by converting a part of the amine group in the chitosan structure to carboxylic acid in order to prevent clumping caused by the mixture of positively charged chitosan and negatively charged hyaluronic acid and carboxymethyl cellulose, which are different ionically charged polysaccharides, in a single formulation. It is to ensure its use and to obtain adhesion barrier membranes.
Description
TARIFNAME HIYALURONIK ASIT/KITOSAN/KARBOKSIMETIL SELÜLOZ IÇEREN BIYOUYUMLU, BIYOBOZUNUR VE BIYOEMILEBILIR BIR ADEZYON MEMBRAN VE ÜRETIM YÖNTEMI Teknik Alan Bu bulus, yaralanma veya cerrahi operasyon sonrasi anormal olarak olusan doku ve organ yapismalarini önleme için kullanilan ve hiyaluronik asit/kitosan/karboksimetil selüloz içeren biyouyumlu, biyobozunur ve biyoemilebilir adezyon membranlar ile ilgilidir. Önceki Teknik Adezyonlar özellikle karin içi bölgede gerçeklesen normalde birbirleri ile yapisik veya birlesik halde bulunmayan ve seröz zarla çevrili organlarin yaralanma veya cerrahi operasyonlar sonrasi aralarinda ve/veya komsu organlarla meydana gelen anormal yapismalar olarak tarif edilmektedir. DESCRIPTION CONTAINING HYYALURONIC ACID/CHITOSAN/CARBOXYMETHYL CELLULOSE A BIOCOMPATIBLE, BIODEGRADABLE AND BIOabsorbable ADHESION MEMBRANE AND PRODUCTION METHOD Technical Area Abnormally formed tissue after injury or surgery and hyaluronic acid used for preventing organ adhesions biocompatible, biodegradable and containing acid/chitosan/carboxymethyl cellulose relates to bioabsorbable adhesion membranes. Prior Art Adhesions, especially in the intra-abdominal region, are normally adherent to each other. or injury or injury to organs that are not united and surrounded by a serous membrane. occurring between and/or neighboring organs after surgical operations. described as abnormal adhesions.
Adezyonu azaltmak/önlemek için cerrahi teknigin gelistirilmesi, adezyon önleyici ilaçlarin kullanilmasi ve iyilesme sürecinde dokularin birbirinden ayrilmasi (adezyon bariyerleri) gibi teknikler kullanilmaktadir. Bunlardan yeni cerrahi teknikler ve önerilen ilaçlar adezyonu istenilen düzeyde önleyememistir. Adezyon bariyerlerinin kullanimi ise daha çok tercih edilmektedir. Improvement of surgical technique to reduce/prevent adhesion, anti-adhesion the use of drugs and the separation of tissues during the healing process (adhesion barriers) techniques are used. The new surgery Techniques and recommended drugs could not prevent the adhesion at the desired level. adhesion The use of barriers is more preferred.
Ideal bir adezyon bariyeri; biyouyumlu ve biyobozunur olmasinin yani sira, yara iyilesmesini etkilememeli, vücutta istenmeyen reaksiyonlar göstermemeli, vücut sivilari ve kan varliginda etkili olabilmeli ve kullanimi kolay olmalidir. Ayrica enfeksiyona ve iltihaplanmaya neden olmamali, antibakteriyel olmali, adezyon olusumunun baslangiç fazinda stabil kalarak ardindan metabolize olmali ve ekonomik olmalidir. An ideal adhesion barrier; Besides being biocompatible and biodegradable, the wound should not affect the healing, should not show undesirable reactions in the body, It should be effective in the presence of fluids and blood and should be easy to use. Moreover should not cause infection and inflammation, should be antibacterial, adhesion It must remain stable in the initial phase of its formation and then be metabolized and should be economical.
Teknigin bilinen durumunda yaygin alaraka yaralanma veya cerrahi operasyon sonrasinda anormal olarak gerçeklesen doku ve organ yapismalarinin önlenmesi amaciyla kullanilan membranlar elektrospinning yöntemi ile elde edilmektedir. In the state of the art, common injury or surgical operation Prevention of abnormal tissue and organ adhesions after Membranes used for this purpose are obtained by electrospinning method.
Elektrospinning metoduyla elde edilen membranlar düsük fiziksel dayanima sahip olmalarina bagli olarak, bu ürünlerin vücuda yerlestirilmesi sirasinda güçlükler yasanmaktadir. Elektrospinning yönteminin oldukça yavas ve kompleks bir metot olmasiyla birlikte saydam membran elde edilememesi diger bir dezavantajidir. Membranes obtained by electrospinning method have low physical strength. difficulties during insertion of these products into the body due to their is being made. Electrospinning method is a very slow and complex method. However, the inability to obtain a transparent membrane is another disadvantage.
Ayrica elde edilen membranlarin kalinliklari esit bir sekilde üretilememektedir. Üretim sonrasi elde edilecek olan membranlarin elektrospin cihazinin sarma tamburundan çikarilip çapraz baglama islemine tutulmasi sirasindaki aktarim islemleri de oldukça karisik ve güçtür. In addition, the thicknesses of the obtained membranes cannot be produced equally. Winding of the electrospin device of the membranes to be obtained after production transfer during removal from the drum and cross-linking operations are also quite complex and difficult.
Teflon membranlar yerlestirme zorluguna sahiptirler. Ayrica biyobozunur olmadiklari için vücut tarafindan yabanci cisim olarak algilanabilmektedir. Ayni zamanda fiksasyon için dikilmesi gerekmektedir. Bu dezavantajlar kullanimi kisitlamaktadir [1]. Teflon membranes are difficult to place. Also biodegradable Since they are not, they can be perceived as a foreign body by the body. Same need to be sutured for fixation at the same time. These disadvantages use restricts [1].
Biyobozunur olmayan membranlarin ikinci bir ameliyata ihtiyaç duyularak vücuttan çikarilmasi karsilasilan problemler arasinda yer almaktadir [2]. Ikinci ameliyata maruz kalan hastanin hayat konforu azalmakta ve maddi açidan zarar görmektedir. Non-biodegradable membranes needing a second surgery removal from the body is among the problems encountered [2]. Second The life comfort of the patient who is exposed to the surgery decreases and financial damage is caused. sees.
Okside rejenere selüloz membranlar hemostaz (kanama durdurmasi) tam yapilmadiginda ve periton sivisi varliginda etkisiz kalabilmektedirler [3]. Kötü biyouyumluluga sahip olmasi ve yapisindaki gözeneklerin boyutunun oldukça büyük olmasi sebebiyle kan proteinlerinin membrandan kolaylikla geçerek adezyon bariyer membrani deforme etmesi diger dezavantajidir Teknigin bilinen durumunda yer alan farkli bir uygulamadaki membranlar ise yapismalari etkili bir sekilde azaltmasina ragmen düsük mekanik özelliklerinden dolayi uygulama esnasinda yeniden pozisyonlandirmada güçlükler yasanabilmektedir [4]. Ayrica kirilgan ve çok yapiskan yapisi onun ameliyat sirasinda kullanimini sinirlamaktadir. Ayni zamanda bu membranlarin, bakteriyel karinzari iltihabi vakalarinda yapismayi artirdigi görülmüstür [5]. Oxidized regenerated cellulose membranes complete hemostasis (stop bleeding) They may be ineffective when not performed and in the presence of peritoneal fluid [3]. Bad It has biocompatibility and the size of the pores in its structure is quite large. Due to its large size, blood proteins can easily pass through the membrane. Another disadvantage is that it deforms the adhesion barrier membrane. Membranes in a different application in the state of the art are Despite its low mechanical properties, it effectively reduces adhesions. difficulties in repositioning during application due to can be experienced [4]. In addition, its fragile and very sticky structure makes it easy to operate. limits its use during At the same time, these membranes it has been found to increase adhesion in cases of carinzari inflammation [5].
Teknikte bilinen uygulamalardan CN102614551B sayili Çin patent basvurusu dokümaninda, biyoemilebilir adezyon membranlarin, sodyum karboksimetil selüloz, kondroitin sülfat ve sodyum hiyaluronat kullanilarak elde edilmesinden bahsedilmektedir. Plastiklestirici ajan olarak gliserin ve polietilen glikol kullanilmistir. Bu formülasyonun kalsiyum klorür ile çapraz baglanmasiyla adezyon membranlar elde edilmistir. Chinese patent application no. CN102614551B from applications known in the art In the document, bioabsorbable adhesion membranes, sodium carboxymethyl cellulose is obtained using chondroitin sulfate and sodium hyaluronate. is mentioned. Glycerin and polyethylene glycol as plasticizing agents used. By cross-linking this formulation with calcium chloride adhesion membranes were obtained.
Teknikte bilinen uygulamalardan U86693089 sayili Birlesik Devletler patent basvurusu dokümaninda ise, aljinik asit ve karboksimetil selülozun kalsiyum iyonlariyla çapraz bagli film olusturmasiyla elde edilmesinden bahsedilmektedir. United States patent number U86693089 from applications known in the art. In the application document, the calcium content of alginic acid and carboxymethyl cellulose It is mentioned that it is obtained by forming a cross-linked film with its ions.
Fakat, bu çalismalarda kalsiyum iyonlarinin degredasyonu sonucu çevre dokulara yayildigi gözlemlenmistir. Bu durum yarali dokularin hasarini daha da agirlastirmistir. basvurusu dokümanlarinda, adezyon membranlar karboksimetil selüloz ve polietilen oksitin çapraz baglanmasi sonucu elde edilmesinden bahsedilmektedir. However, in these studies, as a result of the degradation of calcium ions, spread has been observed. This situation further damages the injured tissues. aggravated. In the application documents, adhesion membranes are carboxymethyl cellulose and It is mentioned that it is obtained as a result of cross-linking of polyethylene oxide.
Polietilen oksitin biyobozunur olmamasi büyük bir dezavantajdir. Yalniz küçük molekül agirlikli polietilen oksit metabolize olabilir, ancak bu durumda hizli bir degredasyon meydana geleceginden, adezyon bariyer membran yeterli etkiyi gösterememektedir. A major disadvantage is that polyethylene oxide is not biodegradable. lonely little molecular weight polyethylene oxide may be metabolized, but in this case a rapid Since degradation will occur, the adhesion barrier membrane will not have sufficient effect. cannot show.
Teknikte bilinen durumunda yer alan diger referans dokümanlari; U85580923A, dokümanlardir. Other reference documents in the state known in the art; U85580923A, are documents.
Bulusun Kisa Açiklamasi Bulusun amaci farkli iyonik yüklü polisakkaritler olan pozitif yüklü kitosan ve negatif yüklü hiyaluronik asit ve karboksimetil selülozun tek bir formülasyon içerisinde karisimindan dolayi olusan topaklanmalar önüne geçilmesi amaciyla kitosan yapisindaki amin grubunun bir kisminin karboksilik aside dönüstürülmesiyle modifiye kitosan elde edilmesi ve topaklanma sorununun çözülmesidir. Brief Description of the Invention The object of the invention is the positively charged chitosan and polysaccharides with different ionic charges. A single formulation of negatively charged hyaluronic acid and carboxymethyl cellulose In order to prevent agglomerations due to the mixture in A part of the amine group in the chitosan structure is converted to carboxylic acid. obtaining modified chitosan by converting is solving.
Bulusun bir diger amaci, elde edilen adezyon bariyer membranin esnekliginin arttirilabilmesi ve düzenlenebilmesi amaciyla formülasyon içerisine plastiklestirici aj anlarin (USP gliserol veya Sorbitol) kullanilmasidir Bulusun bir diger amaci, adezyon olusumunu artiran serbest radikallerin formülasyondaki kitosamn yapisindaki amin gruplariyla reaksiyona girmesiyle kararli makromolekül radikalleri olusturarak adezyon olusumunu engellemesidir. Another object of the invention is to improve the flexibility of the obtained adhesion barrier membrane. plasticizer into the formulation so that it can be increased and regulated. using agents (USP glycerol or Sorbitol) Another object of the invention is to scavenge free radicals that increase adhesion formation. by reacting with the amine groups in the structure of chitosam in the formulation. It prevents adhesion formation by forming stable macromolecule radicals.
Ayrica doku olusumu sirasinda membranin fiziksel özelligini koruyarak istenmeyen doku olusumu boyunca yüzeyde kalmasini saglamasidir. It also preserves the physical properties of the membrane during tissue formation. It ensures that it remains on the surface throughout the formation of unwanted tissue.
Bulusun bir diger amaci, çok iyi bir kanama durdurucu olan kitosanin bu özelliginden faydalanip ameliyat sonrasinda gerçeklesen olagandisi kanamalarin engellenmesidir. Another object of the invention is the use of chitosan, which is a very good astringent. of the unusual bleeding that occurs after the operation by taking advantage of its is prevention.
Bulusun bir diger amaci, membranin saydam olarak elde edilmesi sayesinde ameliyat sirasinda doktorun görüs kolayliginin saglanmasidir. Another object of the invention is to obtain the membrane as transparent. It is to ensure the ease of vision of the doctor during the surgery.
Bulusun bir diger amaci, tamamiyla biyoemilebilir veya biyobozunur özellik sergileyen membranlar elde edilmesidir. Another object of the invention is that it is completely bioabsorbable or biodegradable. exhibiting membranes.
Bulusun Ayrintili Açiklamasi Bulus konusu biyouyumlu, biyobozunur ve biyoemilebilir adezyon mebranlar, ameliyat sonrasinda doku ve organ yapismalarinin engellenmesi amaciyla kullanilmakta olup, hiyaluronik asit, kitosan ve karboksimetil selüloz üçlü yapisinin sulu çözelti içerisinde çapraz baglayicilar ile çapraz baglanma islemi ile elde edilmektedir. Bulus kapsaminda membran bünyesinde kullanilan bu üçlü yapida yer alan kitosan, amin grubu içermesi sebebiyle pozitif yüklü bir dogal polisakkarittir; öte yandan hiyaluronik asit ve karboksimetil selüloz ise negatif yüklü dogal polisakkaritlerdir. Karsit yüklü bu malzemeler tek bir formülasyon içerisinde kullanildiginda elde edilen karisimda topaklanmalar gözlemlenmektedir. Bu sorunu çözmek için kitosanin yapisindaki amin gruplarinin bir kismi karboksilik aside dönüstürülerek modifiye kitosan elde edilmekte ve topaklanma sorunu çözülmektedir. Bu dogrultuda, kitosan alkalin ortamda kloroasetik asit ile reaksiyona sokularak suda çözülebilir bir forma çevrilmektedir. Detailed Description of the Invention The subject of the invention is biocompatible, biodegradable and bioabsorbable adhesion membranes, to prevent tissue and organ adhesions after surgery Hyaluronic acid, chitosan and carboxymethyl cellulose triplex are used. by the cross-linking process of its structure with cross-linkers in aqueous solution. is obtained. This triple used within the membrane within the scope of the invention Chitosan, which is in the structure, is a positively charged natural substance because it contains an amine group. is a polysaccharide; on the other hand, hyaluronic acid and carboxymethyl cellulose are negative. loaded natural polysaccharides. These karsite-loaded materials are used in a single formulation. lumps in the mixture obtained when used in is observed. To solve this problem, the amine in the structure of chitosan Some of the groups are converted to carboxylic acid to obtain modified chitosan. and the clumping problem is solved. Accordingly, chitosan alkaline It is formed into a water-soluble form by reacting with chloroacetic acid in the environment. is translated.
Bulus konusu membran; agirlikça %0,2-6 birim sodyum hiyaluronat, %0,05-3 birim modifiye kitosan, %0,02-2 birim karboksimetil selüloz, %0,05-5 birim plastiklestirici ajan (tercihen USP Gliserol veya Sorbitol) ve %90-99 birim deiyonize su içermektedir. The subject of the invention is the membrane; 0.2-6% unit sodium hyaluronate, 0.05-3% by weight unit modified chitosan, 0.02-2% unit carboxymethyl cellulose, 0.05-5% unit plasticizing agent (preferably USP Glycerol or Sorbitol) and 90-99% unit Contains deionized water.
Membran bünyesinde kullanilan modifiye ve suda çözülebilir özellikli kitosan hazirlanmasi yöntemi su adimlari içermektedir; - Bir reaksiyon balonu içerisine alinan kitosanin izopropil alkol içerisinde manyetik karistirici ile süspansiye edilmesi, - karisima sodyum hidroksit (NaOH) solüsyonundan eklenerek karistirma isleminin sürdürülmesi, - sonrasinda monokloroasetik asitin asamali olarak karisima eklenmesi, - olusturulan reaksiyon karisiminin karistirilmasi isleminin devam ettirilmesi, reaksiyon sona erdikten sonra karisimin hidroklorik asit (HCl) solüsyonu ile nötralize edilmesi, karisimin filtre edilmesi ve metanol ile çöktürme isleminin gerçeklestirilmesi, elde edilen çökmüs ürünün metanol/su karisimiyla yikanmasi, çökmüs ürünün vakum altinda kurutulmasi ile nihai ürün olan modifiye kitosanin toz halinde elde edilmesi. Modified and water-soluble chitosan used in the membrane The method of preparation includes water steps; - The chitosan taken into a reaction flask is in isopropyl alcohol. suspension with magnetic stirrer, - mixing by adding sodium hydroxide (NaOH) solution to the mixture continuation of the - followed by the gradual addition of monochloroacetic acid to the mixture, - continued mixing of the reaction mixture formed to be carried, hydrochloric acid (HCl) solution of the mixture after the reaction is over to be neutralized with filtration of the mixture and precipitation with methanol realization, washing the obtained precipitated product with methanol/water mixture, After drying the precipitated product under vacuum, the final product, the modified obtaining chitosan in powder form.
Yukarida açiklanan bu islem adimlari ile elde edilen modifiye kitosan üzerinden bulus konusu biyouyumlu, biyobozunur ve biyoemilebilir adezyon mebranlarin üretim yöntemi su adimlari içermektedir: sodyum hiyaluronat, modifiye kitosan, karboksimetil selüloz ve plastiklestirici ajanin (USP gliserolün) tartilarak sirasiyla deiyonize su içerisine alinmasi sonrasinda bir mekanik karistirici yardimiyla çözülmesi, karisimin selüloz membran filtre yardimiyla filtre edilmesi, elde edilen karisimin hava kabarciklari alindiktan sonra bir kaliba dökülerek formülasyondaki suyun oda sicakliginda vakum altinda uzaklasmasinin saglanmasi, suyun buharlasma ile ortamdan tümüyle uzaklastirilmasi sonucu adezyon membran film yapisinin elde edilmesi, filmlerin çapraz baglama islemine tabi tutulmasi amaciyla çapraz baglayicilarin etanol ile olusturulan solüsyon içerisine daldirilmasi, 24 saat sonunda filmlerin solüsyon içerisinden çikarilarak, film yüzeyinde kalan reaksiyona girmemis çapraz baglayicilarin uzaklastirilmasi amaciyla etanol ile yikanmasi, sonrasinda filmlerin oda sicakliginda vakum altinda kurutulmasi ile nihai ürün olan adezyon membranlarin elde edilmesi, nihai ürünün paketlenmesi ve sonrasinda sterilize edilmesi. Based on the modified chitosan obtained by these process steps described above. The subject of the invention is biocompatible, biodegradable and bioresorbable adhesion membranes. The production method includes the following steps: sodium hyaluronate, modified chitosan, carboxymethyl cellulose and Weighing the plasticizing agent (USP glycerol) into deionized water, respectively. Dissolving with the help of a mechanical mixer after being taken into it, filtering the mixture with the help of a cellulose membrane filter, After removing the air bubbles of the mixture obtained, it is poured into a mold. pouring the water in the formulation at room temperature under vacuum. ensuring its removal, Adhesion as a result of the complete removal of water from the environment by evaporation obtaining the membrane film structure, cross-linking of films immersing the binders in the solution formed with ethanol, At the end of 24 hours, the films are removed from the solution and on the film surface. to remove remaining unreacted cross-linkers. washing with ethanol After drying the films under vacuum at room temperature, the final Obtaining the product adhesion membranes, packaging and subsequent sterilization of the final product.
Suda Çözülebilir Kitosanin Hazirlanisi: oraninda kitosan izopropil alkol (IPA) içerisinde (tercihen 4 g kitosanin 100 m1 izopropil alkol (IPA) içerisinde) 1 saat boyunca manyetik karistirici yardimiyla süspansiye edildi. Senra karisima %60'11k alkalin solüsyonundan (tercihen sodyum hidroksit (NaOH)) alkol çözücüsüne oranla 1:1 veya 1:1,5 oraninda sonra alkol çözücüsüne oranla 2 kat oranda %60'11k monokloroasetik asit her 10 dakikada bir 5 es parça halinde karisima eklendi. Elde edilen son karisim 60-70 0C”de 8-10 saat boyunca karistirildi. Reaksiyon sona erdikten sonra asit solüsyonu (tercihen 4 M,11k hidroklorik asit (HC1)) ile nötralize edildi. Karisim en son filtre edildi ve metanol ile çöktürme islemi yapildi. Elde edilen çökmüs ürün 3 defa metanol/su karisimiyla yikandi ve vakum altinda kurutularak modifiye kitosan toz halinde elde edildi. Preparation of Water Soluble Chitosan: chitosan in isopropyl alcohol (IPA) (preferably 4 g chitosan 100 m1 in isopropyl alcohol (IPA) for 1 hour with the help of magnetic stirrer was suspended. Senra mix is made from a 60% alkaline solution (preferably sodium hydroxide (NaOH)) in 1:1 or 1:1.5 ratio to alcohol solvent then 60'11k% monochloroacetic acid every 10 times compared to alcohol solvent was added to the mixture in 5 equal parts every minute. The final mixture obtained is 60-70 It was stirred at 0C for 8-10 hours. After the reaction is over, the acid solution (preferably with 4M,11k hydrochloric acid (HC1)). Mixed latest filter and precipitation with methanol was done. Obtained precipitated product 3 times Modified chitosan powder was washed with methanol/water mixture and dried under vacuum. was obtained.
Sodyum hiyaluronat, modifiye kitosan, karboksimetil selüloz ve USP gliserol tartilarak sirasiyla deiyonize su içerisinde 200 rpm”de mekanik karistirici yardimiyla çözüldü. Karisim çözüldükten sonra 0.22 mikron membran filtre yardimiyla süzüldü. Elde edilen karisimin hava kabarciklari alindiktan sonra cam veya metal (paslanmaz çelik) kaliba dökülerek suyun oda sicakliginda vakum altinda uzaklasmasi saglandi. 24 saat sonra suyun ortamdan buharlasmasi sonucu adezyon membran filmler olustu. Olusan filmler çapraz baglanma reaksiyonunu gerçeklestirmek üzere BDDE veya EDC/NHS`nin etanol içerisindeki solüsyonuna daldirildi. Belirlenen süre içerisinde filmler çapraz baglayici solüsyonundan alinarak, etanol ile yikama islemi yapilip reaksiyona girmemis olan çapraz baglayicilar uzaklastirildi. Elde edilen nihai ürün oda sicakliginda vakum altinda kurutularak paketlendi ve sonrasinda sterilize edildi. Sodium hyaluronate, modified chitosan, carboxymethyl cellulose and USP glycerol mechanical stirrer at 200 rpm in deionized water, respectively. solved with your help. After the mixture is dissolved, a 0.22 micron membrane filter swept away with his help. After removing the air bubbles of the mixture obtained, the glass or by pouring into a metal (stainless steel) mold and vacuuming the water at room temperature. it was allowed to go away under it. As a result of evaporation of water from the environment after 24 hours adhesion membrane films were formed. The formed films have cross-linking reaction. solution of BDDE or EDC/NHS in ethanol to dipped. Within the specified time, the films are removed from the crosslinker solution. by taking the ethanol washed with unreacted cross binders removed. The final product obtained is at room temperature under vacuum. dried and packaged and then sterilized.
Hiyaluronik asit/Kitosan/Karboksimetil selüloz (HA/CHUCMC) numunesinin adezyon bariyer membran olarak kullanimini tespit etmek amaciyla yapilan adezyon olusumu testlerinde oldukça etkili bir performans sergilemistir. Bu amaçla, mevcuttaki bir ticari ürün ile adezyon olusumu karsilastirildiginda daha iyi performans gösterdigi tespit edilmistir. Asagidaki sonuçlar bu çalismadaki degerlendirmeleri göstermektedir. Hyaluronic acid/Chitosan/Carboxymethyl cellulose (HA/CHUCMC) sample to determine its use as an adhesion barrier membrane. It showed a very effective performance in adhesion formation tests. This For this purpose, when comparing adhesion formation with an existing commercial product, has been found to perform well. The following results are in this study shows the ratings.
Tablo 1. Adezyon Degerlendirme Dereceleri Degerlendirine Adezyon durumu Fibrozis dereceleri 0 Adezyon yok Fibrozis yok 1 . Minimal, Spontan ayrilabilen Gevsek 2 Traksiyonla ayrilabilen Orta derecede 3 Diseksiyonla ayrilabilen Florid, Yogun Tablo 2. Adezyon Degerlendirmelerinin Karsilastirilmasi Bulgular KO“tm' HA/CHI/CMC MeVCF'F-tal?' Numune Ticari Urun Adezyon Anesteziye alinan tavsanlarin önce karin bölgeleri tiras edilerek dezenfekte edildi. Table 1. Adhesion Evaluation Grades Evaluate Adhesion Status Fibrosis degrees 0 No adhesion No fibrosis one . minimal, Spontaneously Detachable Loose 2 Moderately detachable by traction 3 Dissectable Fluoride, Dense Table 2. Comparison of Adhesion Evaluations Results KO“tm' HA/CHI/CMC MeVCF'F-tal?' Sample Commercial Product adhesion The abdomen of the anesthetized rabbits was first disinfected by shaving.
Daha sonra abdominal bosluguna ulasilarak, sekum disari alindi ve yaklasik 4 cm251ik alanda noktasal kanamalar görülünceye kadar asindirildi. Olgular 3 gruba ayrildi. Birinci grup kontrol grubu olarak adlandirildi ve herhangi bir tedavi uygulanmadi. Ikinci grup ise 1. deney grubu olarak, ikinci grup ise 2. deney grubu olarak adlandirilarak asindirilan bölge HA/CHI/CMC ve mevcuttaki ticari ürün numuneleriyle örtüldü. Operasyon sonrasi tedavi bölgesi dikislerle kapatildi. On dört günlük sürenin ardindan karin bölgesi açilarak bölgenin makroskopik degerlendirmeleri Tablo l,deki derecelendirme kriterleri dikkate alinarak yapildi istatistiksel degerlendirmeler yapildi. Kontrol ve deney gruplarindan alinan sonuçlar Mann-Whitney U testi ile degerlendirildi. Degerlendirme sonuçlarina bakildiginda (Tablo 2), kontrol grubundaki olgularda farkli derecelerde adezyon olusumuna rastlanmistir. Deney gruplarinda ise adezyon olusumu neredeyse gözlemlenmedi. Fakat, HA/CHl/CMC numunesinin mevcuttaki ticari ürüne göre adezyon skorunun daha düsük oldugu, yani adezyon olusumunun daha az oldugu görüldü. Benzer bir sekilde fibrozisin olusumu HA/CHI/CMC numunesinde mevcuttaki ticari ürüne göre daha düsük oldugu saptandi. Yapilan incelemeler her iki numunenin de adezyon ve fibrozis olusumunu azalttigini, fakat HA/CHl/CMC numunesinin mevcuttaki ticari ürüne göre daha etkin oldugunu göstermistir. The abdominal cavity was then reached, the caecum was taken out and approximately 4 It was etched until punctate hemorrhages were seen in the cm251ik area. Cases were divided into 3 groups. Left. The first group was called the control group and did not receive any treatment. not implemented. The second group is the 1st experimental group, and the second group is the 2nd experimental group. the area of erosion called HA/CHI/CMC and the current commercial product covered with samples. After the operation, the treatment area was closed with sutures. Front After a four-day period, the abdominal region was opened and the macroscopic examination of the region was made. Evaluations were made taking into account the rating criteria in Table 1. statistical evaluations were made. from the control and experimental groups The results were evaluated with the Mann-Whitney U test. Evaluation results (Table 2), different degrees of adhesion in the subjects in the control group formation was found. In the experimental groups, adhesion formation was almost not observed. However, the HA/CHl/CMC sample compared to the current commercial product. that the adhesion score is lower, that is, the formation of adhesions is less seen. Similarly, the formation of fibrosis was observed in HA/CHI/CMC samples. It was determined that it was lower than the current commercial product. Every review made that both samples reduced the formation of adhesion and fibrosis, but HA/CHl/CMC showed that the sample was more effective than the current commercial product.
Formülasyonda bulunan kitosan ayni zamanda çok önemli bir hemostaz oldugu için elde edilen adezyon bariyer membran iyi bir kanama durdurucu özellige sahip olup. kan varliginda da etkisini korumaktadir. Mevcuttaki ticari ürün ile hemostatik özellikleri karsilastirildiginda daha hizli bir sekilde kanamayi durdurdugu Tablo 3”de gösterilmistir. Chitosan in the formulation is also a very important hemostasis. The adhesion barrier membrane obtained for is and It also maintains its effect in the presence of blood. with existing commercial product bleeding more rapidly when compared to its hemostatic properties. stopped is shown in Table 3.
Tablo 3. Hemostatik Özelliklerin Karsilastirilmasi Mevcuttaki Ticari Kanama Durma Kanama Durma Süresi (3) Süresi (3) l 129 190 2 138 181 3 132 206 ORTALAMA 1 33 192 Numunelerin hemostatik özellikleri tavsanlarin karacigerleri üzerinde test edilmistir. Karacigerlerin üzerinde esit büyüklükte yaralar açilip numuneler bu yaralar üzerine konuldu ve kanama durdurma süreleri kaydedildi. 3 farkli ölçümün sonucu degerlendirildiginde HA/CHI/CMC numunesi ortalama 133 snlde kanamayi durdururken. mevcuttaki ticari ürün numunesi 192 sn”de durdurmustur. HA/CHI/CMC numunesinin daha hizli hemostaz etki göstermesi, yapisindaki pozitif yüklü kitosan maddesinin kanda bulunan negatif yüklü trombositler ile koagülasyon olusturmasiyla açiklanabilmektedir. Kitosanin bu özelligi literatürde genisçe bahsedilmistir. Çok iyi bir antibakteriyel olan kitosan, ameliyat sirasinda olusabilecek olasi bakteriyel çogalmalara karsi etkili bir çözüm üretmistir. Mevcuttaki ticari ürün ile antibakteriyel özellikleri karsilastirildiginda daha etkin bir antibakteriyel özellik gösterdigi Tablo 4°te gösterilmistir. Table 3. Comparison of Hemostatic Properties Current Commercial Bleeding Stop Bleeding Stop Duration (3) Duration (3) l 129 190 2 138 181 3 132 206 AVERAGE 1 33 192 The hemostatic properties of the samples were tested on the livers of rabbits. has been made. Equal sized wounds were opened on the livers and the samples were taken from this was placed on the wounds and bleeding stopping times were recorded. 3 different When the result of the measurement is evaluated, the HA/CHI/CMC sample averages 133 while stopping bleeding instantly. current commercial product sample in 192 sec has stopped. HA/CHI/CMC sample showing a faster hemostasis effect, The positively charged chitosan substance in its structure is negatively charged in the blood. It can be explained by the formation of coagulation with platelets. This is chitosan feature has been widely mentioned in the literature. Chitosan, which is a very good antibacterial, is possible to occur during surgery. has produced an effective solution against bacterial proliferation. with existing commercial product a more effective antibacterial property when compared to its antibacterial properties. It is shown in Table 4 that it shows.
Tablo 4. Antibakteriyel Özelliklerin Karsilastirilmasi Mevcuttaki Ticari (Saat) E. coli E. coli 24 0 200 Ticari olarak satin alinan mevcuttaki ticari ürün ve HA/CHI/CMC üçlü kombinasyonuyla hazirlanan numuneler anti-bakteriyel teste tabi tutulmustur. 2x2 cm boyutlarinda kesilen numunelerin antibakteriyel etkinligi arastirilmistir. Table 4. Comparison of Antibacterial Properties Current Commercial (Hours) E. coli E. coli 24 0 200 Commercially available commercial product and HA/CHI/CMC triplex The samples prepared with the combination were subjected to anti-bacterial test. 2x2 The antibacterial activity of the samples cut in cm dimensions was investigated.
Deneyde gram negatif olarak Escherichra coli (Ecoli) ATCC 25922 kullanilmistir. Escherichra coli (Ecoli) as gram negative in experiment ATCC 25922 used.
Numunelerin E.coli üzerindeki antibakteriyel etkisini arastirmak amaciyla hazir steril besiyeri (Steril Tryptic soy agar (TSA) besiyeri) temin edilmistir. Yayma plaka yöntemi kullanilarak dilute spor solüsyonundan besiyerine inokulasyon yapilmistir. Petri kaplari 48 saat inkübasyona birakilmistir. Referans spor solüsyonu ile numunelerin bakteri büyümesi üzerine olumlu/olumsuz etkileri saatlerinde canli organizma sayim kontrolleri yapilmistir. Çalismalar LAF kabin altinda gerçeklestirilmistir. Prepared to investigate the antibacterial effect of samples on E.coli. sterile medium (Sterile Tryptic soy agar (TSA) medium) was provided. Spreading inoculation from dilute spore solution into medium using the plate method has been made. Petri dishes were incubated for 48 hours. Reference sport positive/negative effects on bacterial growth of samples with solution Live organism count checks were carried out at Studies LAF cabin carried out below.
Her iki üründe de 12. saatin sonunda belirgin derecede canli organizma sayisinda azalma meydana gelmistir. 24. saatte HA/CHI/CMC numunesinde koloni gözlenmezken mevcuttaki ticari ürün numunesinde az da olsa koloni mevcuttur. Significant number of viable organisms at the end of the 12th hour in both products decrease has occurred. Colony in HA/CHI/CMC sample at 24 hours While not observed, there are a few colonies in the current commercial product sample.
Her iki örnekte de 36 saatlik inkübasyon sonucunda E. coli kolonisine rastlanmamistir. Sonuçlar degerlendirildiginde HA/CHI/CMC numunesinin antibakteriyel özelliklerinin daha iyi oldugunu göstermektedir. In both samples, after 36 hours of incubation, E. coli colony was detected. not found. When the results are evaluated, the HA/CHI/CMC sample shows that its antibacterial properties are better.
Bulus kapsaminda elde edilen adezyon bariyer membranin esnekligi, formülasyonda bulunan ve membrana esneklik veren plastiklestirici ajanlar (USP glycerol veya Sorbitol) tarafindan kolaylikla ayarlanabilmektedir. Bu durum mevcuttaki ticari üründe karsilasilan kirilgan sert yapinin dezavantajlarini giderip ve kullanim avantaji saglamaktadir. Formülasyonda bulunan kitosan serbest radikalleri tutma özelligine sahip oldugu için doku olusumu sirasinda elde edilen membran özelligini koruyarak doku olusumu boyunca yüzeyde kalmasini saglamaktadir. The flexibility of the adhesion barrier membrane obtained within the scope of the invention, plasticizing agents (USP) in the formulation that give flexibility to the membrane It can be easily adjusted by glycerol or Sorbitol). This situation Eliminating the disadvantages of the brittle hard structure encountered in the current commercial product and provides the advantage of use. Chitosan free in the formulation Since it has the property of holding radicals, it is obtained during tissue formation. to remain on the surface during tissue formation by preserving its membrane feature. it provides.
Bulus konusu membran yapisi, ameliyat sirasinda doktorun görüs kolayligi saglamasi amaciyla saydam olmasi saglanmakta ve membran yapisinin vücuttan çikarilmasi amaciyla ikinci bir ameliyat uygulanmamasi amaciyla tamamiyla biyoemilebilir ve biyobozunur özellik gösteren bir ürün elde edilmesi saglanmaktadir. The membrane structure, which is the subject of the invention, facilitates the doctor's vision during the operation. It is provided to be transparent in order to ensure that the membrane structure is removed from the body. completely in order not to have a second operation to be removed. Obtaining a bioabsorbable and biodegradable product is provided.
Bulus kapsaminda olusturulan bu HA/CHl/CMC üçlü kombinasyonu ile adezyon bariyer membrani ticari olarak ilk kez üretilmektedir. Bu üçlü kombinasyon ayni formülasyon içerisinde herhangi bir topaklanma olmadan, yapilarinda bulunan hidroksil gruplari vasitasiyla ve l-etil-3-(3- dimetilaminopropil)karbodiimid/N-Hidroksisüksinimid (EDC/NHS) gibi çapraz baglayicilar ile çapraz baglama reaksiyonuna girebilmistir.Adhesion with this HA/CHl/CMC triple combination created within the scope of the invention The barrier membrane is commercially produced for the first time. This triple combination is the same without any agglomeration in the formulation, through hydroxyl groups and 1-ethyl-3-(3- such as dimethylaminopropyl)carbodiimide/N-Hydroxysuccinimide (EDC/NHS) It was able to enter into cross-linking reaction with binders.
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| PCT/TR2020/050358 WO2020226587A1 (en) | 2019-05-03 | 2020-04-30 | A biocompatible, biodegradable and bioresorbable adhesion membrane including hyaluronic acid / chitosan / carboxymethyl cellulose and production method |
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