CN107185028A - Hemostatic anti-adhesion material and preparation method and application thereof - Google Patents
Hemostatic anti-adhesion material and preparation method and application thereof Download PDFInfo
- Publication number
- CN107185028A CN107185028A CN201710310654.8A CN201710310654A CN107185028A CN 107185028 A CN107185028 A CN 107185028A CN 201710310654 A CN201710310654 A CN 201710310654A CN 107185028 A CN107185028 A CN 107185028A
- Authority
- CN
- China
- Prior art keywords
- preventing material
- bleeding stopping
- adherence preventing
- pharmaceutical salts
- 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
- 239000000463 material Substances 0.000 title claims abstract description 89
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 230000002439 hemostatic effect Effects 0.000 title abstract description 12
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 32
- 239000005017 polysaccharide Substances 0.000 claims abstract description 32
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 30
- 238000004132 cross linking Methods 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 238000006467 substitution reaction Methods 0.000 claims abstract description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 15
- 230000000740 bleeding effect Effects 0.000 claims description 76
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 150000004676 glycans Chemical class 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000012190 activator Substances 0.000 claims description 16
- 239000000725 suspension Substances 0.000 claims description 16
- 150000001413 amino acids Chemical class 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- 108010039918 Polylysine Proteins 0.000 claims description 13
- 229920000656 polylysine Polymers 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 9
- 238000011938 amidation process Methods 0.000 claims description 8
- 230000023597 hemostasis Effects 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 229920003064 carboxyethyl cellulose Polymers 0.000 claims description 6
- 150000003384 small molecules Chemical class 0.000 claims description 5
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012567 medical material Substances 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- -1 carboxyl polysaccharide Chemical class 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 10
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 238000007112 amidation reaction Methods 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 83
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 66
- 208000032843 Hemorrhage Diseases 0.000 description 63
- 235000019441 ethanol Nutrition 0.000 description 61
- 239000001768 carboxy methyl cellulose Substances 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 238000000034 method Methods 0.000 description 38
- 239000011265 semifinished product Substances 0.000 description 35
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 30
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 30
- 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 29
- 230000003647 oxidation Effects 0.000 description 26
- 238000007254 oxidation reaction Methods 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- 239000002994 raw material Substances 0.000 description 19
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 16
- 230000008569 process Effects 0.000 description 16
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 15
- 208000027418 Wounds and injury Diseases 0.000 description 15
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 15
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 15
- 239000005708 Sodium hypochlorite Substances 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 13
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 13
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 13
- 229960000583 acetic acid Drugs 0.000 description 12
- 239000012362 glacial acetic acid Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 241000283973 Oryctolagus cuniculus Species 0.000 description 10
- 210000001015 abdomen Anatomy 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 8
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 238000006266 etherification reaction Methods 0.000 description 6
- 230000000025 haemostatic effect Effects 0.000 description 6
- 238000006386 neutralization reaction Methods 0.000 description 6
- 241000252983 Caecum Species 0.000 description 5
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical group ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 5
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 5
- 210000004534 cecum Anatomy 0.000 description 5
- 239000004744 fabric Substances 0.000 description 5
- 230000001954 sterilising effect Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 229920000742 Cotton Polymers 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000005238 degreasing Methods 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 229960005337 lysine hydrochloride Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 229940048086 sodium pyrophosphate Drugs 0.000 description 3
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- KWTQSFXGGICVPE-WCCKRBBISA-N Arginine hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCCN=C(N)N KWTQSFXGGICVPE-WCCKRBBISA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 108090000526 Papain Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
- 235000019834 papain Nutrition 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 1
- 241000219112 Cucumis Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001152 differential interference contrast microscopy Methods 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000005213 imbibition Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 108700005457 microfibrillar Proteins 0.000 description 1
- 150000007522 mineralic acids Chemical group 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000007666 subchronic toxicity Effects 0.000 description 1
- 231100000195 subchronic toxicity Toxicity 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229940035658 visco-gel Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/08—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
-
- 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
- A61L31/042—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- 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
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
-
- 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
- C08B15/05—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur
- C08B15/06—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur containing nitrogen, e.g. carbamates
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Materials Engineering (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention discloses a hemostatic anti-adhesion material and a preparation method and application thereof, wherein the hemostatic anti-adhesion material is prepared by carrying out amidation reaction on medicinal salt containing carboxyl polysaccharide and an amino acid compound, the polymerization degree of the medicinal salt containing carboxyl polysaccharide is 50-300, the carboxyl substitution degree is 0.4-1.0, the amino acid compound at least contains two amino groups, and the crosslinking degree of the hemostatic anti-adhesion material is 0.1-3.0%. The hemostatic anti-adhesion material prepared by the invention has excellent hemostatic effect, absorption effect, anti-adhesion effect and sticking property, strong adaptability, good biodegradability and good biological absorbability.
Description
Technical field
The present invention relates to wound care medical domain, more particularly it relates to a kind of bleeding stopping and adherence preventing material and its
Preparation method and application.
Background technology
Hemostatic material is a critical material of Clinical Processing wound, and conventional Absorbable hemostatic material has fiber egg at present
White glue, gelfoam, oxycellulose, microfibrillar collagen, chitosan and Sorbsan etc., hemostatic material have gelfoam,
Microcrystalline collagen and collagen etc..Many patent documents have been reported that to polysaccharide hemostatic material, such as United States Patent (USP) US6943154
B2 discloses a kind of method for manufacturing water insoluble biologically compatible composition, and in aqueous, polyanionic polysaccharide is such as
Carboxymethyl cellulose is mixed with nucleopilic reagent, modified compound, and fully reaction forms water insoluble biologically compatible composition, should
The problem of dissolving of composition for improved water-soluble polysaccharide is too fast, has prepared the polysaccharide of water-insoluble, for post-operation adhesion preventing, but
Composition haemostatic effect prepared by this method is poor, and applicating property is poor, in-convenience in use.United States Patent (USP) US6486285 B2 are disclosed
By the ester bond containing carboxylated polysaccharide with being reacted with least two alpha-amino compounds, it is reacted from derived from natural amino acid
And the water-swellable polymer gel prepared, and their foamed product, cross-linking products prepared by this method are water-swellable
Polymer gel, good biocompatibility, but adhesiveness, applicating property is poor, and haemostatic effect is bad.
The C of Chinese patent CN 100398159 disclose a kind of water-soluble ethers cellulose hemostatic material, and the hemostatic material takes
Dai Du is 0.4~0.9, and the degree of polymerization is 100~400, and with good haemostatic effect and assimilation effect, but molecular weight is larger
When, etherified cellulose is difficult to be completely exhausted out from vivo, shows as liver savings, produces subchronic toxicity；In addition, water-soluble ethers chemical fibre
The plain dissolution velocity of dimension is too fast, can be completely dissolved less than 24 hours, it is impossible to play physical barriers effect, and preventing adhesiving effect is poor.In
State patent CN 100369935C disclose the preparation method of carboxymethyl cellulose crosslinked amide derivative, carboxylic prepared by this method
Methylcellulose crosslinked amide derivative is water-insoluble, and degradation time is long, and applicating property is poor, and in aqueous prepared by crosslinking,
Accessory substance is more, low yield.
The content of the invention
Based on this, imitated the invention reside in the defect of prior art is overcome there is provided one kind with excellent haemostatic effect, absorption
Really, prevent being adhered the bleeding stopping and adherence preventing material of effect and applicating property, the bleeding stopping and adherence preventing material fabric remains fabric sofetening, suitable
Ying Xing, arbitrarily can cut out and fold, easy to use, strong adaptability, and with biological degradability and Bioabsorbable.
Its technical scheme is as follows：
A kind of bleeding stopping and adherence preventing material, the structural formula such as formula 1 of the bleeding stopping and adherence preventing material：
Wherein, R1、R2、R3、R4、R5For-OH or-OCH2COONa, and be asynchronously-OCH2COONa； R6For：
N=50~300, m=2~40.
The main chain of bleeding stopping and adherence preventing material of the present invention is cellulose, and side chain is amino-acid salt, the bleeding stopping and adherence preventing
Material can be degraded to carboxymethyl cellulose or carboxyethyl cellulose in the presence of enzyme in vivo and human body must amino acid, carboxymethyl
Cellulose, the control of the carboxyethyl cellulose degree of polymerization can be completely exhausted out from vivo at≤300 in 28 days, and amino acid can be with
It is absorbed by the body, it is safe.Bleeding stopping and adherence preventing material of the present invention has excellent haemostatic effect, assimilation effect, anti-stick
Connect effect and applicating property.
In one of the embodiments, n=100~250.
In one of the embodiments, the bleeding stopping and adherence preventing material is by the pharmaceutical salts containing carboxylated polysaccharide and amino acids
Compound is prepared through amidation process, and the pharmaceutical salts degree of polymerization containing carboxylated polysaccharide is 50~300, and carboxyl substitution value is
0.4~1.0, the amino acids at least containing two amino, the degree of cross linking of the bleeding stopping and adherence preventing material for 0.1~
3.0%.The present invention is by controlling the degree of polymerization and carboxyl substitution value of the pharmaceutical salts containing carboxylated polysaccharide to prepare the specific degree of cross linking
Bleeding stopping and adherence preventing material, it has excellent haemostatic effect, assimilation effect, anti-is adhered effect and applicating property.
In one of the embodiments, the carboxyl substitution value of the pharmaceutical salts containing carboxylated polysaccharide is 0.5~1.0.
In one of the embodiments, the degree of cross linking of the bleeding stopping and adherence preventing material is 0.1~2.0%.
In one of the embodiments, the pharmaceutical salts containing carboxylated polysaccharide for carboxymethyl cellulose pharmaceutical salts and/or
The pharmaceutical salts of carboxyethyl cellulose.
In one of the embodiments, the pharmaceutical salts containing carboxylated polysaccharide are sodium salt or sylvite containing carboxylated polysaccharide.
In one of the embodiments, the pharmaceutical salts containing carboxylated polysaccharide are sodium carboxymethylcellulose.
In one of the embodiments, the amino acids is arginine and its hydrochloride, lysine and its salt
One or more in hydrochlorate, polylysine and its hydrochloride.
The preparation method of the bleeding stopping and adherence preventing material, comprises the following steps：
S1, the preparation degree of polymerization 50~300, the pharmaceutical salts containing carboxylated polysaccharide of carboxyl substitution value 0.4~1.0；
S2, preparation mass/volume are than the pharmaceutical salts containing carboxylated polysaccharide for 0.5~40%-organic solvent suspension；
S3, addition activator or acid regulator and condensing agent into pharmaceutical salts-organic solvent suspension containing carboxylated polysaccharide,
Then it is 0.2~6.0% amino acids to add mass ratio, and 0.1~48h is reacted at 0~50 DEG C；
S4, wash unreacted small-molecule substance in product, after drying bleeding stopping and adherence preventing material.
In one of the embodiments, the organic solvent of the pharmaceutical salts-organic solvent suspension containing carboxylated polysaccharide is
Toluene, acetone, butanone, tetrahydrofuran, chloroform, dimethyl acetamide, dimethylformamide, dimethyl sulfoxide (DMSO), dichloromethane
At least one of alkane, chloroform, acetonitrile, pyridine.
In one of the embodiments, the activator is n-hydroxysuccinimide (NHS) or the nitrogen of 1- hydroxy benzos three
Azoles (HOBt).
In one of the embodiments, the consumption of the activator for bleeding stopping and adherence preventing material quality 0.1~
10.0%.
In one of the embodiments, the condensing agent is water-soluble carbodiimide class compound.Specifically, the water
Dissolubility carbodiimides can be 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, N, the rings of N'- bis-
Hexyl carbodiimide, N, N'- DICs.
In one of the embodiments, the consumption of the condensing agent for bleeding stopping and adherence preventing material quality 0.15%~
15%.
In one of the embodiments, the acid regulator is inorganic acid, such as hydrochloric acid, sulfuric acid.
In one of the embodiments, the acid regulator is the PH of control reaction system 4~6.
In one of the embodiments, the step S1 is：
1) oxidation processes：The degree of polymerization is mixed for 80~600 raw material gauze with sodium hypochlorite, water, reaction range is controlled
25~35 DEG C, 30~90min is reacted, the raw material gauze, sodium hypochlorite, the mass ratio of water are：Raw material gauze：Sodium hypochlorite：
Water=1：(1.0~3.0)：(5.0~15.0)；Adding hydrogen peroxide, sodium pyrophosphate and water, controlling reaction temperature is 90 DEG C~
100 DEG C of 30~90min of reaction obtain aoxidizing semi-finished product gauze, and raw material gauze, hydrogen peroxide, sodium pyrophosphate, the mass ratio of water are
Raw material gauze：Hydrogen peroxide：Sodium pyrophosphate：Water=1：(0.05~0.5)：(0.01~0.1)：(5.0~10.0)；
2) basification：Oxidation semi-finished product gauze is mixed with sodium hydroxide, water, alcohol, control range temperature 20~40
℃；30~90min of reaction time, oxidation semi-finished product gauze, sodium hydroxide, water, the mass ratio of alcohol are 1：(1.0~3.0)：
(4.0~6.0)：(5.0~8.0)；
3) etherification process：Monoxone, alcohol, water are added, 30~90min are reacted in stage heating, 35 DEG C~50 DEG C holdings,
30~90min is reacted at 60 DEG C~75 DEG C again, oxidation semi-finished product gauze, monoxone, alcohol, the mass ratio of water are：Oxidation half into
Product gauze：Monoxone：Alcohol：Water=1：(0.4~1.5)：(5.0~10.0)：(0.1~1.0)；
4) neutralisation treatment：Glacial acetic acid, alcohol, water is added to be neutralized, reaction temperature be 35 DEG C~45 DEG C react 30~
90min, oxidation semi-finished product gauze, glacial acetic acid, alcohol, the mass ratio of water are：1：(0.1~0.5)：(5.0~10.0)：(0.1
~1.0).
5) alcohol washes：With mass fraction for 83%~86% alcohol water blend in 37 DEG C~43 DEG C clean 10~
30min；
6) dry：Drying obtains sodium carboxymethylcellulose.
In one of the embodiments, the step S2 is：Pharmaceutical salts of the gained containing carboxymethyl polysaccharide are dissolved in organic molten
In agent acetone, mass/volume is prepared than pharmaceutical salts-organic solvent suspension containing carboxymethyl polysaccharide for 0.5~40%.
In one of the embodiments, quality/body of the pharmaceutical salts-organic solvent suspension containing carboxymethyl polysaccharide
Product is than being 10~30%.
In one of the embodiments, the step S3 is：Into pharmaceutical salts-organic solvent suspension of carboxymethyl polysaccharide
Condensing agent, activator, amino acids are added, controlling reaction temperature is 20~50 DEG C of progress amidation process, reaction 30
~240min, wherein, the condensing agent, activator, the mass ratio of the pharmaceutical salts of amino acids and carboxymethyl polysaccharide are：
The pharmaceutical salts of carboxymethyl polysaccharide：Condensing agent：Activator：Amino acids=1：(0.03~0.07)：(0.01~0.05)：
(0.002~0.06).
In one of the embodiments, 30 DEG C of the reaction temperature of the step S3, the reaction time is 60min.
In one of the embodiments, the step S4 is：Fall unreacted small-molecule substance in product with alcohol washes,
Bleeding stopping and adherence preventing material is obtained after drying.
Application of the bleeding stopping and adherence preventing material in medical material.The bleeding stopping and adherence preventing material can for braid or
Non-woven fabrics.
The beneficial effects of the present invention are：Bleeding stopping and adherence preventing material fabric prepared by the present invention remains fabric sofetening, suitable
Ying Xing, arbitrarily can cut out and fold, it is adaptable to different types of wound, easy to use；Hemostasis prepared by the present invention is prevented being adhered
Material is micro- cross-linked structure, and the degree of cross linking is relatively low, PhastGel after gauze imbibition, forms viscogel, blocks the surface of a wound, can be as
Hemostasis purposes, applicating property is good；Partial gel can retain 7~14 day time on wound, can isolate wound as physical barriers
Mouthful, prevent wound adhesion；Fabric prepared by the present invention has security, and biological degradability and Bioabsorbable, crosslinking
Gel digest in vivo must amino acid, carboxymethyl cellulose, carboxylic second for carboxymethyl cellulose, carboxyethyl cellulose and human body
It when base cellulosic degree of polymerization is not more than 300, can be completely exhausted out from vivo, amino acid can be absorbed by the body, protect in 28 days
The security of product is demonstrate,proved.
Brief description of the drawings
Fig. 1：The infrared spectrogram of bleeding stopping and adherence preventing material after embodiment 3 is crosslinked；
Embodiment
With reference to embodiment, the present invention will be described in detail.Following examples only express the embodiment party of the present invention
Formula, it describes more specific and detailed, but therefore can not be interpreted as the limitation to the scope of the claims of the present invention, as long as using etc.
The technical scheme obtained with the form of replacement or equivalent transformation, all should fall within the scope and spirit of the invention.
Following examples are adopted to be measured to the substitution value of carboxymethyl cellulose pharmaceutical salts with the following method：By standard
GB1904-2005 food additives sodium carboxymethylcelluloses method 5.5 is measured.
The degree of cross linking that following examples adopt with the following method to bleeding stopping and adherence preventing material is measured：
It is prepared by standard liquid：The lysine hydrochloride 0.1g by 80 DEG C of dry 2h is weighed, position very much is accurate to, added
After 20ml water fully dissolves, it is transferred in 100mL volumetric flasks, is settled to graduation mark, obtains 1000ppm stoste.It is respectively configured
0th, 30,60,90,120,150ppm standard liquid, respectively takes 4mL to add centrifuge tube, adds 2ml pH=6.0 acetate buffers, plus
Enter 2ml 20g/L ethanol solution of ninhydrin, cover lid, 99 DEG C of heating 15min cool down 10min, extinction is tested at 570nm
Degree, sets up standard curve.
Detect prepared by solution：The gauze 1.0g that prevents adhesion by 80 DEG C of dry 2h is weighed, position very much is accurate to, 50ml is added
Water, adds 2mL 1mol/L NaOH solution, seals lower 99 DEG C of degradeds 30min, adds 2mL 1mol/L's after room temperature cooling
HCL solution is neutralized to neutrality, is transferred in 100mL volumetric flasks, is settled to graduation mark.Take 2mL to add centrifuge tube, add 1ml pH
=6.0 acetate buffers, add 1ml 20g/L ethanol solution of ninhydrin, seal lower 99 DEG C of heating 15min, cool down 10min,
Take 1mL solution to be settled to 100mL, absorbance is tested at 570nm.
As a result calculate：Standard curve is substituted into according to obtained absorption values and obtains concentration, then calculates the degree of cross linking.
Embodiment 1
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
S1,1) oxidation processes：The degree of polymerization is mixed for 300~400 raw material gauze with sodium hypochlorite, water, control reaction
25~35 DEG C of scope, reacts 60min, the raw material gauze, sodium hypochlorite, the quality of water are respectively 1Kg, 1.4Kg, 9.0Kg；Plus
Enter 0.2L hydrogen peroxide, 0.05kg sodium pyrophosphates and 9.0Kg water, controlling reaction temperature is 90 DEG C~100 DEG C reaction 60min, is used
80 DEG C of drying of electric drying oven with forced convection, obtain aoxidizing semi-finished product gauze；
2) basification：Oxidation semi-finished product gauze is mixed with sodium hydroxide, water, alcohol, control range temperature 20~30
℃；30~90min of reaction time, oxidation semi-finished product gauze, sodium hydroxide, water, the mass ratio of alcohol are 1：2.0：5.0：6.8；
3) etherification process：Monoxone, alcohol, water are added, 60min are reacted in stage heating, 40 DEG C~50 DEG C holdings, then 65
DEG C~75 DEG C of reaction 60min, oxidation semi-finished product gauze, monoxone, alcohol, the mass ratio of water are：Aoxidize semi-finished product gauze：Chloroethene
Acid：Alcohol：Water=1：0.75：8.5：0.5；
4) neutralisation treatment：Add glacial acetic acid, alcohol, water to be neutralized, reaction temperature is 37 DEG C~43 DEG C reaction 60min,
Aoxidize semi-finished product gauze, glacial acetic acid, alcohol, mass ratio=1 of water：0.26：8.5：0.5.
5) alcohol washes：With mass fraction 20min is cleaned for 83%~86% alcohol water blend in 37 DEG C~43 DEG C；
6) dry：50 DEG C of drying obtain sodium carboxymethylcellulose.After measured, the carboxyl substitution of gained sodium carboxymethylcellulose
Spend for 0.73, the degree of polymerization is 220.
S2, gained sodium carboxymethylcellulose is dissolved in organic solvent-acetone, prepares mass/volume than the carboxylic first for 20%
Base sodium cellulosate-organic solvent suspension.
S3, addition condensing agent EDS, activator NHS, arginine salt into sodium carboxymethylcellulose-organic solvent suspension
Hydrochlorate, adds water and acetone, and controlling reaction temperature is 30 DEG C of progress amidation process, reacts 60min, wherein, the condensation
Agent, activator, the mass ratio of arginine monohydrochloride and sodium carboxymethylcellulose are：Sodium carboxymethylcellulose：Condensing agent：Activation
Agent：Arginine monohydrochloride=1：0.05：0.03：0.02.
S4, the mixed solution of addition second alcohol and water are washed, and concentration of alcohol is 83%~86%, in 35 DEG C~45 DEG C
Wash 20min and remove unreacted small-molecule substance, 50 DEG C of drying obtain bleeding stopping and adherence preventing material.After measured, the hemostasis is anti-
The degree of cross linking of adhering material is 0.83%.
Embodiment 2
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
S1, to prepare by the methods described of embodiment 1 substitution value be 0.73, and the degree of polymerization is 220 sodium carboxymethylcellulose.
S2, prepared by the methods described of embodiment 1 and prepare mass/volume than the sodium carboxymethylcellulose for 20%-organic molten
Agent suspension.
S3, addition condensing agent EDS, activator NHS, lysine salt into sodium carboxymethylcellulose-organic solvent suspension
Hydrochlorate, adds water and acetone, and controlling reaction temperature is 30 DEG C of progress amidation process, reacts 60min, wherein, the condensation
Agent, activator, the mass ratio of lysine hydrochloride and sodium carboxymethylcellulose are：Sodium carboxymethylcellulose：Condensing agent：Activation
Agent：Lysine hydrochloride=1：0.05：0.03：0.015.
S4, by the methods described washing and drying of embodiment 1, obtain bleeding stopping and adherence preventing material.After measured, the bleeding stopping and adherence preventing
The degree of cross linking of material is 0.67%.
Embodiment 3
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
S1, to prepare by the methods described of embodiment 1 substitution value be 0.73, and the degree of polymerization is 220 sodium carboxymethylcellulose.
S2, prepared by the methods described of embodiment 1 and prepare mass/volume than the sodium carboxymethylcellulose for 20%-organic molten
Agent suspension.
S3, addition condensing agent EDS, activator NHS, polylysine into sodium carboxymethylcellulose-organic solvent suspension
Hydrochloride (degree of polymerization m=25~35), adds water and acetone, and controlling reaction temperature is 30 DEG C of progress amidation process, reaction
60min, wherein, the condensing agent, activator, the mass ratio of polylysine hydrochloride and sodium carboxymethylcellulose are：Carboxymethyl
Sodium cellulosate：Condensing agent：Activator：Polylysine hydrochloride=1：0.05：0.03：0.04.
S4, by the methods described washing and drying of embodiment 1, obtain bleeding stopping and adherence preventing material.After measured, the bleeding stopping and adherence preventing
The degree of cross linking of material is 1.6%.
The infrared spectrogram of the bleeding stopping and adherence preventing material of raw material gauze and gained used in the present embodiment is shown in Fig. 1, can from Fig. 1
Know, compared with before crosslinking, the infrared spectrogram after crosslinking has newly increased 1589.06,1675.84cm-1Amido link characteristic peak,
Illustrate to have carried out amidation process, generate crosslinking.
Embodiment 4
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
S1,1) oxidation processes：The degree of polymerization is mixed for 300~400 raw material gauze with sodium hypochlorite, water, control reaction
25~35 DEG C of scope, reacts 60min, the raw material gauze, sodium hypochlorite, the quality of water are respectively 1Kg, 1.2Kg, 9.0Kg；Plus
Enter 0.2L hydrogen peroxide, 0.05kg sodium pyrophosphates and 9.0Kg water, controlling reaction temperature is 90 DEG C~100 DEG C reaction 60min, is used
80 DEG C of drying of electric drying oven with forced convection, obtain aoxidizing semi-finished product gauze；
2) basification：Oxidation semi-finished product gauze is mixed with sodium hydroxide, water, alcohol, control range temperature 20~30
℃；30~90min of reaction time, oxidation semi-finished product gauze, sodium hydroxide, water, the mass ratio of alcohol are 1：2.0：5.0：6.8；
3) etherification process：Monoxone, alcohol, water are added, 60min are reacted in stage heating, 40 DEG C~50 DEG C holdings, then 65
DEG C~75 DEG C of reaction 60min, oxidation semi-finished product gauze, monoxone, alcohol, the mass ratio of water are：Aoxidize semi-finished product gauze：Chloroethene
Acid：Alcohol：Water=1：0.45：8.5：0.5；
4) neutralisation treatment：Add glacial acetic acid, alcohol, water to be neutralized, reaction temperature is 37 DEG C~43 DEG C reaction 60min,
Aoxidize semi-finished product gauze, glacial acetic acid, alcohol, mass ratio=1 of water：0.3：8.5：0.5.
5) alcohol washes：With mass fraction 20min is cleaned for 83%~86% alcohol water blend in 37 DEG C~43 DEG C；
6) dry：50 DEG C of drying obtain sodium carboxymethylcellulose.After measured, the carboxyl substitution of gained sodium carboxymethylcellulose
Spend for 0.42, the degree of polymerization is 231.
By embodiment 3 step S2, S3, S4 methods described polylysine hydrochloride to the sodium carboxymethylcellulose prepared
It is modified, after measured, the degree of cross linking for obtaining bleeding stopping and adherence preventing material is 0.15%.
Embodiment 5
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
S1,1) oxidation processes：The degree of polymerization is mixed for 300~400 raw material gauze with sodium hypochlorite, water, control reaction
25~35 DEG C of scope, reacts 60min, the raw material gauze, sodium hypochlorite, the quality of water are respectively 1Kg, 1.5Kg, 9.0Kg；Plus
Enter 0.4L hydrogen peroxide, 0.08kg sodium pyrophosphates and 9.0Kg water, controlling reaction temperature is 90 DEG C~100 DEG C reaction 60min, is used
80 DEG C of drying of electric drying oven with forced convection, obtain aoxidizing semi-finished product gauze；
2) basification：Oxidation semi-finished product gauze is mixed with sodium hydroxide, water, alcohol, control range temperature 20~30
℃；30~90min of reaction time, oxidation semi-finished product gauze, sodium hydroxide, water, the mass ratio of alcohol are 1：2.8：5.0：6.8；
3) etherification process：Monoxone, alcohol, water are added, 60min are reacted in stage heating, 40 DEG C~50 DEG C holdings, then 65
DEG C~75 DEG C of reaction 60min, oxidation semi-finished product gauze, monoxone, alcohol, the mass ratio of water are：Aoxidize semi-finished product gauze：Chloroethene
Acid：Alcohol：Water=1：1.1：8.5：0.5；
4) neutralisation treatment：Add glacial acetic acid, alcohol, water to be neutralized, reaction temperature is 37 DEG C~43 DEG C reaction 60min,
Aoxidize semi-finished product gauze, glacial acetic acid, alcohol, mass ratio=1 of water：0.36：8.5：0.5.
5) alcohol washes：With mass fraction 20min is cleaned for 83%~86% alcohol water blend in 37 DEG C~43 DEG C；
6) dry：50 DEG C of drying obtain sodium carboxymethylcellulose.After measured, the carboxyl substitution of gained sodium carboxymethylcellulose
Spend for 0.95, the degree of polymerization is 208.
By embodiment 3 step S2, S3, S4 methods described polylysine hydrochloride to the sodium carboxymethylcellulose prepared
It is modified, after measured, the degree of cross linking for obtaining bleeding stopping and adherence preventing material is 2.8%.
Embodiment 6
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
S1,1) oxidation processes：The degree of polymerization is mixed for 300~400 raw material gauze with sodium hypochlorite, water, control reaction
25~35 DEG C of scope, reacts 60min, the raw material gauze, sodium hypochlorite, the quality of water are respectively 1Kg, 1.4Kg, 9.0Kg；Plus
Enter 0.2L hydrogen peroxide, 0.05kg sodium pyrophosphates and 9.0Kg water, controlling reaction temperature is 90 DEG C~100 DEG C reaction 60min, is used
80 DEG C of drying of electric drying oven with forced convection, obtain aoxidizing semi-finished product gauze；
2) basification：Oxidation semi-finished product gauze is mixed with sodium hydroxide, water, alcohol, control range temperature 20~30
℃；30~90min of reaction time, oxidation semi-finished product gauze, sodium hydroxide, water, the mass ratio of alcohol are 1：2.0：5.0：6.8；
3) etherification process：Monoxone, alcohol, water are added, 60min are reacted in stage heating, 40 DEG C~50 DEG C holdings, then 65
DEG C~75 DEG C of reaction 60min, oxidation semi-finished product gauze, monoxone, alcohol, the mass ratio of water are：Aoxidize semi-finished product gauze：Chloroethene
Acid：Alcohol：Water=1：0.66：8.5：0.5；
4) neutralisation treatment：Add glacial acetic acid, alcohol, water to be neutralized, reaction temperature is 37 DEG C~43 DEG C reaction 60min,
Aoxidize semi-finished product gauze, glacial acetic acid, alcohol, mass ratio=1 of water：0.3：8.5：0.5.
5) alcohol washes：With mass fraction 20min is cleaned for 83%~86% alcohol water blend in 37 DEG C~43 DEG C；
6) dry：50 DEG C of drying obtain sodium carboxymethylcellulose.After measured, the carboxyl substitution of gained sodium carboxymethylcellulose
Spend for 0.61, the degree of polymerization is 225.
By embodiment 3 step S2, S3, S4 methods described polylysine hydrochloride to the sodium carboxymethylcellulose prepared
It is modified, after measured, the degree of cross linking for obtaining bleeding stopping and adherence preventing material is 1.3%.
Embodiment 7
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
From the raw material gauze of the degree of polymerization 80~150, carboxymethyl cellulose is prepared according to the methods described of embodiment 3, through surveying
The substitution value for determining sodium carboxymethylcellulose is 0.75, and the degree of polymerization is 63, then prepares bleeding stopping and adherence preventing material by the methods described of embodiment 3
Material, after measured, the bleeding stopping and adherence preventing material degree of cross linking are 1.7%.
Embodiment 8
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
From the raw material gauze of the degree of polymerization 400~600, carboxymethyl cellulose is prepared according to the methods described of embodiment 3, through surveying
The substitution value for determining carboxymethyl cellulose is 0.68, and the degree of polymerization is 283, then prepares bleeding stopping and adherence preventing material by the methods described of embodiment 3
Material, after measured, the bleeding stopping and adherence preventing material degree of cross linking are 1.4%.
Embodiment 9
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
S1, embodiment 3 are similar, and difference is to substitute sodium hydroxide with potassium hydroxide, potassium carboxymethylcellulose is obtained, through surveying
Fixed, the carboxyl substitution value of gained potassium carboxymethylcellulose is 0.71, and the degree of polymerization is 224.
By embodiment 3 step S2, S3, S4 methods described polylysine hydrochloride to the potassium carboxymethylcellulose prepared
It is modified, after measured, the degree of cross linking for obtaining bleeding stopping and adherence preventing material is 1.7%.
Embodiment 10
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
The carboxyethyl cellulose that common commercially available substitution value is 0.5 is bought, by step S2, S3, S4 methods described of embodiment 3
Sodium hydroxyethlcellulose is modified with polylysine hydrochloride, after measured, the degree of cross linking for obtaining bleeding stopping and adherence preventing material is
0.92%.
Comparative example 1
A kind of bleeding stopping and adherence preventing material, its preparation process is as follows：
S1,1) oxidation processes：The degree of polymerization is mixed for 300~400 raw material gauze with sodium hypochlorite, water, control reaction
25~35 DEG C of scope, reacts 60min, the raw material gauze, sodium hypochlorite, the quality of water are respectively 1Kg, 1.4Kg, 9.0Kg；Plus
Enter 0.2L hydrogen peroxide, 0.05kg sodium pyrophosphates and 9.0Kg water, controlling reaction temperature is 90 DEG C~100 DEG C reaction 60min, is used
80 DEG C of drying of electric drying oven with forced convection, obtain aoxidizing semi-finished product gauze；
2) basification：Oxidation semi-finished product gauze is mixed with sodium hydroxide, water, alcohol, control range temperature 20~30
℃；30~90min of reaction time, oxidation semi-finished product gauze, sodium hydroxide, water, the mass ratio of alcohol are 1：2.8：5.0：6.8；
3) etherification process：Monoxone, alcohol, water are added, 60min are reacted in stage heating, 40 DEG C~50 DEG C holdings, then 65
DEG C~75 DEG C of reaction 60min, oxidation semi-finished product gauze, monoxone, alcohol, the mass ratio of water are：Aoxidize semi-finished product gauze：Chloroethene
Acid：Alcohol：Water=1：1.3：8.5：0.5；
4) neutralisation treatment：Add glacial acetic acid, alcohol, water to be neutralized, reaction temperature is 37 DEG C~43 DEG C reaction 60min,
Aoxidize semi-finished product gauze, glacial acetic acid, alcohol, mass ratio=1 of water：0.46：8.5：0.5.
5) alcohol washes：With mass fraction 20min is cleaned for 83%~86% alcohol water blend in 37 DEG C~43 DEG C；
6) dry：50 DEG C of drying obtain sodium carboxymethylcellulose.After measured, the carboxyl substitution of gained sodium carboxymethylcellulose
Spend for 1.1, the degree of polymerization is 196.
S2, gained sodium carboxymethylcellulose is dissolved in organic solvent-acetone, prepares mass/volume than the carboxylic first for 20%
Base sodium cellulosate-organic solvent suspension.
S3, addition condensing agent EDS, activator NHS, polylysine into sodium carboxymethylcellulose-organic solvent suspension
Hydrochloride, adds water and acetone, and controlling reaction temperature is 30 DEG C of progress amidation process, reacts 60min, wherein, the contracting
Mixture, activator, the mass ratio of polylysine hydrochloride and sodium carboxymethylcellulose are：Sodium carboxymethylcellulose：Condensing agent：It is living
Agent：Polylysine hydrochloride=1：0.08：0.05：0.06.
S4, the mixed solution of addition second alcohol and water are washed, and concentration of alcohol is 83%~86%, in 35 DEG C~45 DEG C
Wash 20min and remove unreacted small-molecule substance, 50 DEG C of drying obtain bleeding stopping and adherence preventing material.After measured, the hemostasis is anti-
The degree of cross linking of adhering material is 3.7%.
Comparative example 2
A kind of bleeding stopping and adherence preventing material, its preparation process is substantially the same manner as Example 3, and difference is, selected raw material
The gauze degree of polymerization is 650, and the degree of polymerization of the carboxymethyl cellulose prepared is 320, and substitution value is 0.39, the final degree of cross linking
0.8%.
Biocompatibility, biology are carried out to bleeding stopping and adherence preventing material prepared by embodiment 1~10, comparative example 1, comparative example 2
Degradability, anthemorrhagic performance, Bioabsorbable, it is anti-be adhered performance and tested, test result is shown in Table 2, and method of testing is as follows：
(1) biological degradability：Degradation time
By 121 DEG C of sterilization treatments of 250mL port grinding bottles and other glass apparatus high temperature, ultra violet lamp 30min before experiment
Processing.
The preparation of cushioning liquid：Tris 2.423g, cysteine 0.606g, EDTA 7.445g are weighed, 500mL is added
In volumetric flask, distilled water is added until graduation mark, is made into pH=8.0 cushioning liquid.By the buffering configured in limit room
Solution aperture is 0.45 μm filter membrane (EO sterilizings) filtration sterilization.
It is accurate to weigh papain 3.0g, 400mL cushioning liquid is added, 7.5mg/mL (6000U/mL) wood is made into
Melon albumen enzyme buffer solution, stirring is to being completely dissolved.
The gauze 0.1g that prevents adhesion of sterilized processing is weighed, is added in 250mL port grinding bottles, 100mL Papains are added
Encapsulation process after enzyme buffer solution, addition, prepares three samples respectively.It is molten that blank group only adds 100mL Papain enzyme buffers
Encapsulation process after liquid, addition, prepares 1 sample.
The port grinding bottle for carrying out mark is put into incubator, the sample degradable time is observed in 37 ± 1 DEG C of cultures.
(2) anthemorrhagic performance：Bleeding stopping period：
Rabbit is cleaned, pre-operative anxiety 24 hours, a preoperative evening prohibits water, uses 10% chloraldurate to rabbit in the preoperative
(4mL/kg) injects implementation anesthesia from auricular vein.The amount of taking fully degreasing cotton gauze is numbered and weighed before experiment, indicates every tablet quality.
Postanesthetic rabbit, which lies on the back, is fixed on surgical plate, preserved skin, sterilization, opening abdominal cavity, fully exposes liver.Ten are used by same patient
Cut a 1.0 × 1.0cm of cross recess, depth about 0.5cm cutting wound in word cutter right same position of liver in rabbit.
After Hemorrhage Model is set up, the free bleeding of wound 30 seconds are allowed, and blot with the degreasing cotton gauze weighed the blood of the surface of a wound
Liquid.After the free bleeding time reaches, the hemostasis of 2.0 × 2.0cm gauzes, light pressure 10 seconds are sticked to the bleeding surface of a wound immediately, and open simultaneously
Beginning is clocked, and the blood of outflow is drawn with the degreasing cotton gauze weighed, until blood stops flowing out, is now stopped timing, is recorded
Bleeding stopping period.Blank control group is without hemostasis operation.
(3) Bioabsorbable (soak time) and anti-it is adhered performance：
A, zoopery process：
Rabbit is cleaned, pre-operative anxiety 24 hours, a preoperative evening prohibits water, uses 10% chloraldurate to rabbit in the preoperative
(4mL/kg) injects implementation anesthesia from auricular vein.
Rabbit is lain on the back after anaesthetizing successfully and is fixed on surgical plate, cut off art area (before abdomen hit exactly) surrounding hair about 6cm ×
Visual area in 8cm sizes, sterilization abdomen, spreads aseptic hole-towel.Belly center longitudinal incision 4cm is removed, abdomen is entered successively.
Caecum, observation caecum and its surrounding organ situation are found, and records whether there is adhesion situation.Lift and be placed in sterile gauze
Upper about 5min, dries serous coat, gently scrapes caecum serous coat, until oozing of blood, then absolute ethyl alcohol is dripped on the surface of a wound, then with five tooth tweezers
Live in mesocecum artery about 2min, causes transient ischemia.Return receive caecum enter abdominal cavity it is in situ after with the corresponding abdomen of the clamp injury that stops blooding
Wall.
Make after adhesion model, blank control group is coated with the surface of a wound using 2mL physiological saline, test group is advised with 2cm × 2cm
The gauze that prevents adhesion of lattice, makes gauze that the whole surface of a wound is completely covered.After the completion of also receive caecum, recover its normal anatomical structures, note
Process adherence preventing material is also received without displacement, abdomen is closed.Every rabbit all controls the same time from the time for entering abdomen to pass abdomen, so that group
Knit the exposure aerial time equal.
B, soak time and adhesion situation are evaluated
Operation is finished, and animal puts attention insulation, and head is lain on one's side, and is kept respiratory tract smooth, is sent rabbit-hutch back to after reviving.
Animal situation is observed in postoperative 3 days, penicillin anti-inflammatory is during which used.Animal fasting 12h, sub-cage rearing, close observation.
Above-mentioned rabbit postoperative 3 days, 7 days, 14 days, 28 days, auricular vein injects anesthesia, and lower abdomen takes " u "-shaped otch to open abdomen, visually observed
Prevented adhesion the absorbing state and adhesion situation of gauze, and the situation of adhesion is recorded.The table of comparisons 1, to the adhesion feelings of rabbit
Condition is classified.
The adhesion grading evaluation criteria of table 1
The embodiment of table 2 and comparative example bleeding stopping and adherence preventing material performance test
| Detection project | Degradation time | Bleeding stopping period | Soak time | It is anti-to be adhered performance |
| Embodiment 1 | 4 days | 87 seconds | ﹤ 7 days | 3 points |
| Embodiment 2 | 3 days | 60 seconds | ﹤ 7 days | 3 points |
| Embodiment 3 | 9 days | 125 seconds | ﹤ 14 days | 4 points |
| Embodiment 4 | 8 days | 145 seconds | ﹤ 14 days | 4 points |
| Embodiment 5 | 14 days | 179 seconds | ﹤ 28 days | 4 points |
| Embodiment 6 | 7 days | 133 seconds | ﹤ 14 days | 4 points |
| Embodiment 7 | 7 days | 168 seconds | ﹤ 14 days | 4 points |
| Embodiment 8 | 8 days | 127 seconds | ﹤ 14 days | 4 points |
| Embodiment 9 | 9 days | 135 seconds | ﹤ 14 days | 4 points |
| Embodiment 10 | 5 days | 90 seconds | ﹤ 7 days | 4 points |
| Comparative example 1 | 28 days | Do not stop blooding | ＞ 28 days | 4 points |
| Comparative example 2 | 18 days | Do not stop blooding | ＞ 14 days | 4 points |
To verify the biocompatibility of bleeding stopping and adherence preventing material, cytotoxicity (ISO has also been carried out to bleeding stopping and adherence preventing material
10993-5:2009), acute toxicity (ISO 10993-11:2006), priming experiments (ISO 10993-10:2010) pierced with skin
Swash property test (ISO 10993-10:2010), test result shows that prepared bleeding stopping and adherence preventing material biocompatibility is good.
Each technical characteristic of embodiment described above can be combined arbitrarily, to make description succinct, not to above-mentioned reality
The all possible combination of each technical characteristic in example is applied all to be described, for the person of ordinary skill of the art,
On the premise of not departing from present inventive concept, various modifications and improvements can be made, these belong to protection scope of the present invention,
All it is considered to be the scope of this specification record.
Claims (10)
1. a kind of bleeding stopping and adherence preventing material, it is characterised in that the structural formula of the bleeding stopping and adherence preventing material such as formula 1：
Wherein, R1、R2、R3、R4、R5For-OH or-OCH2COONa, and be asynchronously-OCH2COONa；R6For：
N=50~300, m=2~40.
2. bleeding stopping and adherence preventing material according to claim 1, it is characterised in that n=100~250.
3. bleeding stopping and adherence preventing material according to claim 1, it is characterised in that the bleeding stopping and adherence preventing material is by more containing carboxyl
The pharmaceutical salts of sugar are prepared with amino acids through amidation process, and the pharmaceutical salts degree of polymerization containing carboxylated polysaccharide is
50~300, carboxyl substitution value is 0.4~1.0, and the amino acids is at least containing two amino, and the hemostasis is anti-sticking
Even the degree of cross linking of material is 0.1~3.0%.
4. bleeding stopping and adherence preventing material according to claim 3, it is characterised in that the carboxyl of the pharmaceutical salts containing carboxylated polysaccharide takes
Dai Du is 0.5~1.0.
5. bleeding stopping and adherence preventing material according to claim 3, it is characterised in that the degree of cross linking of the bleeding stopping and adherence preventing material is
0.1~2.0%.
6. bleeding stopping and adherence preventing material according to claim 1, it is characterised in that the pharmaceutical salts containing carboxylated polysaccharide are carboxylic first
In the pharmaceutical salts of base cellulose and/or the pharmaceutical salts of carboxyethyl cellulose.
7. bleeding stopping and adherence preventing material according to claim 6, it is characterised in that the pharmaceutical salts containing carboxylated polysaccharide are containing carboxylic
The sodium salt or sylvite of Quito sugar.
8. bleeding stopping and adherence preventing material according to claim 1, it is characterised in that the amino acids be arginine and
One or more in its hydrochloride, lysine and its hydrochloride, polylysine and its hydrochloride.
9. the preparation method of bleeding stopping and adherence preventing material described in claim 1-8 any claims, it is characterised in that including as follows
Step：
S1, the preparation degree of polymerization 50~300, the pharmaceutical salts containing carboxylated polysaccharide of carboxyl substitution value 0.4~1.0；
S2, preparation mass/volume are than the pharmaceutical salts containing carboxylated polysaccharide for 0.5~40%-organic solvent suspension；
S3, addition activator or acid regulator and condensing agent into pharmaceutical salts-organic solvent suspension containing carboxylated polysaccharide, then
Addition mass ratio is 0.2~6.0% amino acids, and 0.1~48h is reacted at 0~50 DEG C；
S4, wash unreacted small-molecule substance in product, after drying bleeding stopping and adherence preventing material.
10. application of the bleeding stopping and adherence preventing material in clinical medical material described in claim 1-8 any claims.
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| CN114272445A (en) * | 2021-12-06 | 2022-04-05 | 盐城工学院 | A kind of hemostatic and anti-adhesion material that can be used in vitro and in vivo and preparation method thereof |
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| US20130137850A1 (en) * | 2011-11-30 | 2013-05-30 | Jnc Corporation | Novel polymer and process for producing the same |
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| CN103384537A (en) * | 2010-11-23 | 2013-11-06 | 艾拉斯塔根私人有限公司 | Preparation and/or formulation of proteins cross-linked with polysaccharides |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114272445A (en) * | 2021-12-06 | 2022-04-05 | 盐城工学院 | A kind of hemostatic and anti-adhesion material that can be used in vitro and in vivo and preparation method thereof |
| CN114272445B (en) * | 2021-12-06 | 2023-02-03 | 盐城工学院 | Hemostatic anti-adhesion material for use in vitro and in vivo and preparation method thereof |
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