IL103118A - Tissue glue prepared by using cryoprecipitate - Google Patents
Tissue glue prepared by using cryoprecipitateInfo
- Publication number
- IL103118A IL103118A IL10311892A IL10311892A IL103118A IL 103118 A IL103118 A IL 103118A IL 10311892 A IL10311892 A IL 10311892A IL 10311892 A IL10311892 A IL 10311892A IL 103118 A IL103118 A IL 103118A
- Authority
- IL
- Israel
- Prior art keywords
- component
- tissue glue
- cryoprecipitate
- thrombin
- glue
- Prior art date
Links
- 239000003106 tissue adhesive Substances 0.000 title claims abstract description 38
- 229940012952 fibrinogen Drugs 0.000 claims abstract description 23
- 108010049003 Fibrinogen Proteins 0.000 claims abstract description 22
- 102000008946 Fibrinogen Human genes 0.000 claims abstract description 22
- 108010039627 Aprotinin Proteins 0.000 claims abstract description 19
- 229960004405 aprotinin Drugs 0.000 claims abstract description 18
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical group C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 claims abstract description 18
- 108091005804 Peptidases Proteins 0.000 claims abstract description 17
- 102000035195 Peptidases Human genes 0.000 claims abstract description 14
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims abstract description 10
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- 210000004369 blood Anatomy 0.000 claims abstract description 6
- 239000008280 blood Substances 0.000 claims abstract description 6
- 229920000642 polymer Polymers 0.000 claims abstract description 4
- 108090000190 Thrombin Proteins 0.000 claims description 39
- 229960004072 thrombin Drugs 0.000 claims description 39
- 239000003292 glue Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 9
- 108010071289 Factor XIII Proteins 0.000 claims description 7
- 241000700605 Viruses Species 0.000 claims description 7
- 229940012444 factor xiii Drugs 0.000 claims description 7
- 102000016359 Fibronectins Human genes 0.000 claims description 5
- 108010067306 Fibronectins Proteins 0.000 claims description 5
- 239000004365 Protease Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 241000282414 Homo sapiens Species 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 230000002779 inactivation Effects 0.000 claims description 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims 1
- 239000003998 snake venom Substances 0.000 abstract description 10
- 108090000790 Enzymes Proteins 0.000 abstract description 8
- 102000004190 Enzymes Human genes 0.000 abstract description 8
- 108010027612 Batroxobin Proteins 0.000 description 21
- 239000000243 solution Substances 0.000 description 17
- 210000002381 plasma Anatomy 0.000 description 13
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 12
- 239000001110 calcium chloride Substances 0.000 description 11
- 229910001628 calcium chloride Inorganic materials 0.000 description 11
- 235000011148 calcium chloride Nutrition 0.000 description 11
- 208000032843 Hemorrhage Diseases 0.000 description 10
- 208000034158 bleeding Diseases 0.000 description 10
- 230000000740 bleeding effect Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 108010080379 Fibrin Tissue Adhesive Proteins 0.000 description 7
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 108010073385 Fibrin Proteins 0.000 description 6
- 102000009123 Fibrin Human genes 0.000 description 6
- 229950003499 fibrin Drugs 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 241000283690 Bos taurus Species 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 206010052428 Wound Diseases 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 4
- 230000015271 coagulation Effects 0.000 description 4
- 238000005345 coagulation Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 208000031169 hemorrhagic disease Diseases 0.000 description 4
- 229960002897 heparin Drugs 0.000 description 4
- 229920000669 heparin Polymers 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 206010053567 Coagulopathies Diseases 0.000 description 3
- 108010054218 Factor VIII Proteins 0.000 description 3
- 102000001690 Factor VIII Human genes 0.000 description 3
- 208000009292 Hemophilia A Diseases 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 241000271897 Viperidae Species 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000035602 clotting Effects 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 239000003599 detergent Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229960000301 factor viii Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000023597 hemostasis Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 102100022641 Coagulation factor IX Human genes 0.000 description 2
- 102100026735 Coagulation factor VIII Human genes 0.000 description 2
- 201000003542 Factor VIII deficiency Diseases 0.000 description 2
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 2
- DEOKFPFLXFNAON-UHFFFAOYSA-N N-α-Benzoyl-DL-arginine 4-nitroanilide hydrochloride Chemical compound Cl.C=1C=C([N+]([O-])=O)C=CC=1NC(=O)C(CCCN=C(N)N)NC(=O)C1=CC=CC=C1 DEOKFPFLXFNAON-UHFFFAOYSA-N 0.000 description 2
- 208000002847 Surgical Wound Diseases 0.000 description 2
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 2
- 229940122388 Thrombin inhibitor Drugs 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- 230000002051 biphasic effect Effects 0.000 description 2
- 208000015294 blood coagulation disease Diseases 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000003593 chromogenic compound Substances 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000011026 diafiltration Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 208000009429 hemophilia B Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000012460 protein solution Substances 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000011146 sterile filtration Methods 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- 238000010257 thawing Methods 0.000 description 2
- 239000003868 thrombin inhibitor Substances 0.000 description 2
- 235000019263 trisodium citrate Nutrition 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 229940038773 trisodium citrate Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
- JWICNZAGYSIBAR-LEEGLKINSA-N (4s)-4-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-2-aminopropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]amino]-5-[[2-[[(2s)-3-carboxy-1-[[(2s)-1-[[1-[[(2s)-1-[[(2s)-4-carboxy-1-[[2-[[2-[[2-[[(2s)-1-[[(1s)-1-carboxy-4-(diaminomethylideneamino Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)C(CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)N)CC1=CC=CC=C1 JWICNZAGYSIBAR-LEEGLKINSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 101800000974 Fibrinopeptide A Proteins 0.000 description 1
- 102400000525 Fibrinopeptide A Human genes 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
- 206010020524 Hydronephrosis Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- 125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029148 Nephrolithiasis Diseases 0.000 description 1
- 229940122791 Plasmin inhibitor Drugs 0.000 description 1
- 102100038124 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 206010051077 Post procedural haemorrhage Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 239000005700 Putrescine Substances 0.000 description 1
- 206010038419 Renal colic Diseases 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000504 antifibrinolytic agent Substances 0.000 description 1
- 239000004019 antithrombin Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960002210 batroxobin Drugs 0.000 description 1
- 239000003364 biologic glue Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000003914 blood derivative Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical class NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000058 esterolytic effect Effects 0.000 description 1
- 239000000535 fibrinogen concentrate Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000004023 fresh frozen plasma Substances 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 229940106780 human fibrinogen Drugs 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000000244 kidney pelvis Anatomy 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 238000002616 plasmapheresis Methods 0.000 description 1
- 239000002806 plasmin inhibitor Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000012209 synthetic fiber Substances 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940108519 trasylol Drugs 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 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
- A61L24/0005—Ingredients of undetermined constitution or reaction products 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
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
- A61L2/0088—Liquid substances
-
- 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
- A61L24/10—Polypeptides; Proteins
- A61L24/106—Fibrin; Fibrinogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Surgery (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Thermotherapy And Cooling Therapy Devices (AREA)
- Materials For Medical Uses (AREA)
- Packages (AREA)
- Pyrane Compounds (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Adhesives Or Adhesive Processes (AREA)
- Peptides Or Proteins (AREA)
- Vehicle Body Suspensions (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
A tissue glue is described comprising a component A which comprises a cryoprecipitate of whole blood and high an amount of a protease inhibitor corresponding to 3,000 to 5,000 KIU/ml units of aprotinin, and a component B comprising a proteolytic enzyme being capable of cleaving specifically fibrinogen present in component A and causing the formation of a fibrine polymer. In another embodiment an improved tissue glue is described comprising a component A which comprises a cryoprecipitate of whole blood, and a component B comprising a proteolytic enzyme obtainable from snake venom which enzyme is capable of cleaving specifically fibrinogen present in component A and causing the formation of a fibrine polymer.
[CA2079077C]
Description
103118/3 Tissue glue prepared by using cryoprecipitate OMRIX BIOPHARMACEUTICALS SA.
C. 87215 "Improved tissue glue prepared by using cryoprecipitate" This invention relates to a tissue glue comprising two components A and B, a process for preparing the tissue glue, the use of a high amount of aprotinin and the use of a snake venom proteolytic enzyme for preparing a tissue glue.
Improvement of local hemostasis at the site of a surgical wound by application of plasma proteins is a well-known concept. Thus, fibrin patches for hemostasis in cerebral surgery have been used. Blood plasma and thrombin were used to produce a fibrin film over the surgical wound. In the last 20 years there are a lot of publications describing applications of "fibrin glue" or "fibrin adhesive" or "fibrin sealant" for most surgical disciplines. In the last 10 years commercial preparations of "glue" are used widely in Europe. The "glue" is composed of two components, whereas a mixture of these components produce a clot. The first component is a fibrinogen concentrate. This concentrate also contains fibronectin and factor XIII which are important for clot stabilization and strength. The second component is thrombin, an active enzyme that converts fibrinogen, the last component of the normal coagulation system into a fibrin clot. This process bypasses most of the steps of normal coagulation and mimicks its last phase. Some manufacturers add plasminogen which is an enzyme that will induce clot lysis after some time whereas others add aprotinin which is an inhibitor of proteases for preventing clot lysis.
Although, these products give satisfactory results in patients although with mild bleeding disorders, but patients suffering severe bleeding disorders such as hemophilia A or B, still have a very high risk of postoperative bleeding. Sometimes a delayed bleeding complications after an average of days from the surgery occur. Also patients who are treated with anticoagulation factors cannot be treated with the tissue glue of the prior art. Another severe disadvantage of the commercial concentrates are the high producing costs.
Wo 86/01814 discloses a method of preparing a cryoprecip-itated suspension containing fibrinogen and Factor VIII useful as a precursor in the preparation of a fibrin glue which involves (a) freezing fresh frozen plasma from a single donor such as a human or other animal which has been screened for blood transmitted diseases at about -80°C for at least about six hours; (b) raising the temperature of the frozen plasma, e.g. to between about 0°C and room temperature, so as to form a supernatant and cryoprecipitated suspension containing fibrinogen and Facot VIII; and (c) recovering the cryoprecipitated suspension. There is also disclosed a method of preparing a fribrin glue useful in surgical procedures which comprises: (a) preparing a cryoprecipitated suspension as described above; (b) applying a defined volume of the suspension to a desired site; and (c) applying a composition containing a sufficient amount of thrombin to the site so as to cause the fibrinogen in the suspension to be converted to the fibrin glue which then solidifies.
WO 86/01814 does not disclose the term concentrated cryoprecipitate and describes that aprotinin may optionally be added to the thrombin component, but makes no suggestion whatsoever that aprotinin could be added to the cryoprecipitate component. Moreover, none of the examples described in WO 86/01814 uses any aprotinin.
EP-A-0 341 007 discloses a surgical adhesive comprising, in an aqueous composition, patient autogenous plasma, collagen, thrombin, and optionally, an antifibrinolytic agent. The present adhesive is formed from the patient's plasma without the use of any added reagents for concen- - 2a - tration or isolation of the fibrinogen. Conveniently, the adhesive is formulated as a two-part composition which is mixed together just prior to use.
EP-A-0 253 198 descloses a one-component-tissue glue having an aqueous solution of fibrinogen, Factor VIII, a thrombin inhibitor, prothrombin factors, calcium ions and optionally a plasmin inhibitor. The tissue glue can be reconstituted from a lyophylized sample by adding water. The tissue glue may contain all active, substances in a pateurizated from in order to avoid hepatitis and HTLV III transference.
An object of the present inventic .i is to provide a tissue glue which is also suitable for patients with severe blood coagulation disorders like hemophilia A or B. A further object of the present invention is to provide a tissue glue which can also be used for patients which have already developed antibodies against bovine thrombin which is the active factor of the component B. Still another object of the present invention is to provide a tissue glue for patients who are treated with anticoagulation factors like heparin. Because of the risk of transferring viral diseases with the components of the tissue glue it must be ensured that fractions of the tissue glue are virus inactivated.
The tissue glue according to the invention comprises a component A which comprises a cryoprecipitate of whole blood and high an amount of a protease inhibitor corresponding to 3,000 to 5,000 KlU/ml units of aprotinin, preferably aprotinin, and a component B, comprising a proteolytic enzyme being capable of cleaving specifically fibrinogen present in component A and causing the formation of a fibrin polymer.
Commercially available cryoprecipitate can be used for preparation of the tissue glue of the invention. However, it can be advantageous to concentrate the cyroQrecipitate between a factor 2 and 5 , preferably factor 3.
The addition of a protease inhibitor in sufficient con- centration corresponding to an amount of 3,000 to 5,000 KlU/ml units of aprotinin to the cryoprecipitate makes the tissue glue of the invention suitable for use in patients with severe bleeding disorders. The preferred protease inhibitor is aprotinin, which is commerically available under the trademark Trasylol R or AntagosanR.
The cryoprecipitate. can be obtained frc.m the patient himself by donating an autologous blood unit prior to the operation. This approach revents the risk of transmissio of viral infections by .blood derivatives. However, in order to have a proper commercial product, the cryoprecipitate has to become virus-inactivated. A procedure for virus-inactivation is described in. 'PCT/EP 91/00503. The basic principle is treatment of the cryoprecipitate with special detergents and removing the detergent lateron from the cryoprecipitate.
The second component, component B, of the tissue glue of the present invention is prepared by a solution of a proteolytic enzyme being capable of cleaving specifically fibrinogen. Usually thrombin has been used which was isolated from plasma of human beings or mamals such as bovine. This thrombin can be delivered in a lyophilized form. The reconstitution of thrombin occurs with a 40 mmol solution of calcium chloride. The preferred concentration of thrombin is 50 to 200 u/ml .
For preparing a fast tissue glue the thrombin solution of roughly 100 u/ml of calcium chloride will be prepared. For preparing a slow glue for example by filing of "cavities, i. e. tooth extraction or sealing the cavity of transphenoided hypophisectomy the thrombin will be further dissolved to a concentration of 25 u/ml with the appropriate calcium chloride solution.
Another embodiment of the improved tissue glue of the invention comprises as component B a proteolytic enzyme which is isolated from snake venom. This embodiment is advantageous because also patients having developed antibodies against thrombin can be treated. Moreover, patients which are pretreated with heparin can be treated with the tissue glue according to the invention, because heparin does not influence the reaction of the snake venom enzyme. In a very preferred embodiment of the present invention there is used the snake venom enzyme batroxobin which can be isolated from the South American pit viper Bothrpos mouj eni. Preferably component B contains 0.5 to 10 u/ml of the respective proteolytic enzyme of snake venom.
Chemically batroxobin is a single chain glycopeptide with a molecular weight of approximately 36,000. Defibrase causes cleavage of a 16 Arg/17 Gly bound in fibrinogen which causes the release of fibrinopeptide A and the formation of monomeric fibrin I.
When aprotinin is used in the amounts of the invention, also the tissue glues comprising purified fibrinogen, fibronectin and factor XIII can be used as component A. The risk of after-bleeding is then dramatically reduced.
When proteolytic proteases from snake venom are used for the preparation of component B, also "conventional" com-, ponents A having fibrinogen, fibronectin and factor XIII can be used. The use of high amounts of aprotinin according to the invention is preferred. A very preferred embodiment is the combination of the component A of the invention derived from cryoprecipitate with or without high amounts of aprotinin and the component B of the invention having the proteolytic enzyme isolated from snake venom.
The process for preparing the fibrin glue of the invention comprises the steps of manufacturing component A com- - - prising the steps of preparing a cryosolution from cryo-precipitate, a virus inactivation, the removal of virucidal agent, the addition of the protease inhibitor and preparing a appropiate protease-solutibn.
Preferably a cryopaste is prethawed over night at 4 to 10 °C. The cryopaste is dissolved in a buffer containing sodiuitichlorid trisodiumcitrate and glycin and having a pH of 7.0 to 7.2 and than heated to 30 to 35 °C. The cryopaste should dissolve readily otherwise it is not suitable for the preparation. The dissolution can be speeded up by cutting the cryopaste in small pieces after thawing. After cooling the solution to almost room temperature and adjusting the pH to a value of 7.0 to 7.2 aluminiumhydroxid is added under stirring. The precipitate is centrifuged and discarded. Optionally a filtration step is carried out. Than calcium chloride is added up to the desired final concentration of calcium chloride.
For the virus inactivation the solution is heated up to 30 °C. Than the detergents are added. Other stirring for some time the solution is transferred into a virus free container and left at slightly elevated temperatures for several hours without stirring.
The virucidal agents are removed by adding an amount of ricine oil and gently stirring for several minutes. When the oil-/water-phases have been seperated the solution is cooled to room temperature. The aqueous layer is withdrawn in a virussafe container and the oillayer is discarded. The aqueous layer is clarified by filtration. The pH must be checked to be 7.0 to 7.2. Then the protein solution is pumped through a reversed phase column at ambient temperature. After having measured the protein content (in the range of 10 to 60 mg /ml the eluate is concentrated by diafiltration to a protein content of 60 to 100 mg/ml and dialysed against a buffer which is identical to the buffer mentioned above but having additionally a relatively high concentration of calcium chloride. Then the protease inhibitor is added. A sterile filtration is carried out and the sample is filled and deep frozen in suitable containers .
Component B is preferably a freeze dried protease. Particularly preferred is lyophilized thrombin or lyophilrzed fraction of the South American pip viper Bothrpos moujeni. The proteolyic enzyme is known under the tradename Repti- lase and is the enzyme batroxobin.
The proteolytic enzymes are dissolved in a calcium chloride buffer.
The application of the two components A and B is performed using a double syringe technique for example through a plastic connector. Upon mixing of the two components a clot will be formed. The application can occur via a canula or may be sprayed to a three lumen catheter. Each one of the two components is injected into a separate lumen and an air pressure source in the range of some atmospheres is connected to the third lumen in order to spray the mixture.
The tissue glue of the invention is advantageous because it can be used with patients having severe blood coagulation disorders and being still cheaper than the known jtissue glues. Patients with severe hemophilia can subsequently, for example undergo tooth extractions without preventive infusions of factor VIII concentrates with a success rate of over 80%. This means only about one fifth of the patients need infusions due to post extraction bleeding. Moreover, such patients who are pretreated with heparin can be treated with the tissue glue of the invention. Another advantage is that people who raised antibodies against thrombin the second component of the tissue glue can be treated with a tissue glue according to the invention wherein thrombin is substituted by a protease from snake venom especially Defibrase which is the serine protease batroxobin isolated from the venu of the South American pit viper Bothrpos moujeni.
The invention is further disclosed in the following examples which are non limiting.
Human fibrinogen (grade L) was from Kabi (Stockholm) , bovine thrombin from Merz-Dade. Chromogenic substrate N-a-benzoyl-DL-arginine-p-nitroanilide (BAPNA) and analytic grade reagents were from Sigma (St. Louis, MO) . Reagents and salts were diluted with 0.015 M Tris, 0.15 M NaCl, with pH 7.4. Fibrinogen was dialyzed in Tris buffer with concentration determined from Abs on using a con- 1% version factor of E 280 = 15.
Bovine thrombin was from commercial sources (Merz-Dade or Parke Davis) with activity rating by the manufacturer. Reptilase , a snake venom which only releases FPA, was from Pentapharm (Basel) . The proteolytic activity of Reptilase was normalized to that of thrombin by comparing their rates of proteolysis of a non-specific chromogenic substrate BAPNA (0.25 mM) at 37°C, in Tris/saline, pH 8.0, monitored at 405 nm for 15 minutes.
On the basis of their esterolytic activity, the unit activity of the reptilase was normalized to that of thrombin.
Fibrin glue was essentially generated by a dual syringe method with pure or cryoprecipitate fibrinogen substrate in one syringe, and reptilase (20 U/ml) or thrombin with CaCl_ (20 mM) in the other.
- - Clotting time (CT) was determined with a Research Model 300-R ACL Coagulation Analyzer (IL, Milan) . Viscoelasti-city (TEG) was determined on a 3-channel Heiliger Thrombo-elastograph at 37 °C. Breaking strength (BS) of glues (in grams) was determined by mixing the glue components between two pieces of coarse weaved, synthetic fiber (0.5 x 1 cm) , allowing the formation of gel totally interweaved between the two pieces of coarse mesh and after 2 hours at 24 °C the ensemble of mesh-glue-mesh pulled apart using an Accuforce Cadet Tensionometer (AMATEK, Mansfield & Greene, USA) .
Sterile cryoprecipitate (cryo) was prepared from frozen (-30 °C) human plasma which was thawed at 4°C and the supernatant plasma removed. Five such units were pooled to determine protein and fibrinogen concentrations was determined by the Buiret method before and after clotting the cryoprecipitate (diluted 1 : 5) with 2 U/mL thrombin. 3 Factor XIII was determined by measuring [ H] -putrescine incorporation into dimethylated casein after activation of the samples with 4 U/mL bovine thrombin, 10 min, 22 'C.
A notable feature of the CT-fibrinogen curve is that it is biphasic for a fixed level of thrombin or reptilase (i.e. 1 U/ml, figure 1A) and reaches a minimum in the 1 -8 mM fibrinogen range. This differs somewhat from the maximal turbidity (after 10 min) which peaks in the range 20 to 40 mM fibrinogen. A converse experiment shows the dependency of CT on either thrombin or reptilase levels. This curve shows a near linear inverse dependency of gelling rate at low enzyme levels (less than 2 U/mL) , which plateaus above at higher levels.
The development of viscoelasticity of pure fibrin is somewhat slower than its turbidity. Ca(II) is a major cofactor in gel reinforcement through factor Xllla-induced covalent interlocking of protein chains. Such gel crosslinking is a major source of mechanical strength of the gel, which plateaus after 20 min.
A note about the ability of reptilase to induce factor Xllla activity seems appropriate.
Protein Levels of pooled cryoprecipitate: Pooled cryo prepared from 5 units, gave the following mean values: Protein: 75 mg/mL Fibrinogen: 36 mg/mL Factor XIII: 4.10 U/mL Coagulation rates: The clotting time (CT) of cryo is linearly dependent on thrombin or reptilase levels. However, above 3 U/ml, increasing enzyme levels exert little effect on CT. For a fixed level of enzyme, serial dilution of cryo, gives a biphasic CT-curve equivalent to the fibrinogen-dependency noted in the pure fibrin system.
Viscoelasticity (TEG) and Breaking Strength (BS) of Cryo Glues .
The development of viscoelasticity of cryo glues was investigated with either thrombin or reptilase. This parameter takes much longer to develop than turbidity. However, cryo glues prepared with excess of CaCl2 and either thrombin or reptilase achieve equivalent TEG values in roughly the same time frame. It seems that after the initial onset of gelation, factor Xllla-induced cross-linking bolsters the gel fiber structure, so that the TEG values for both glues converge within 1 hour. Similarly with the final BS of both cryo glues formed with an excess of CaCl_. Both cryo glues break at 50 to 60g. These experi- ments indicate that the gel fibers within the glue become reinforced by factor Xllla-induced, covalent cross-linking.
Preparation of a cryo-solution. Com erically cryopaste is prethawed over night at 4 to 10 °C. One kilo of the cryo is dissolved in two liters of buffer A (120 mM/1 NaCl, 10 mM/1 trisodiumcitrate, 120 iriM/1 glycin and pK 7.0 to 7.2) and preheated to 30 to 35 "C. The cryopaste should dissolve readily otherwise it is not suitable for the preparation. In order to speed up the dissolution, cut the cryopaste in small pieces after thawing. Then the solution is cooled to 20°C to 22 'C and the pH is checked. Optionally it must be adjusted to pH 7.0 to 7.2 by adding diluted sodiumhydroxid or acidic acid. 100 ml aluminiumhydroxid is added and stirred for another 30 minutes. The precipitated is centrifuged and discarded. The supernatant is filtrated using a.l Mm filter. 0.1 M/l CaCl, is added to 2+ render a final concentration of Ca of 1 mM/1. Again the pK must be checked.
Virus inactivation.
The solution is heated up to 30" C. 1% w/v TNBP and 1% w/v Triton X 100 is added. The mixture is gently stirred for 1/2 hour. The solution is than transferred into a virus-free container and left at 30 'C for 3 1/2 hours without stirring.
Removal of Virucidal Agents. 150 ml Ricine oil is added to the mixture prepared as described above and stirred gently for 30 minutes. While waiting for the oil/water separation (30 to 45 minutes) the solution is cooled to 20°C. The aqueous layer is withdrawn into a virussafe container whereas the oillayer is discarded. The aqueous layer is clarified by filtration on 1 μπι/0.45 μιη filter cascade. The protein solution is than pumped through a reversed phase column (C-18-Column) at a rate of 3 liter/h at ambient temperature. The throughput is monitored by UV and collected until the absorbance has returned to 50%. The fraction contains roughly 40 mg/ml as measured in a protein assay.
The eluate is concentrated by diafiltration to a protein content of 70 to 80 mg/ml and dialyse against sufficient amount of a buffer B (same ingredients as buffer A but additionally 1 mM/1 calcium chloride) . Then 4 mio. KIU •aprotinin per liter solution is added. Afterwards a sterile filtration, carried out using a 0.45 μπι + 0.2 μτα. cascade. The solution is than filled and deep frozen in plastic bags, optionally lyophilized.
Preparation of a thrombin solution Lyophilized thrombin is dissolved in a solution of 40 mM/L calcium chloride. The amount of thrombin is 100 U/ml in the glue. For a fast working glue, for example for spraying of the glue to the area of the wound, a thrombin solution of 100 U/ml in calcium chloride will be sufficient. For a slow glue, for example filling of cavities during a tooth extraction or sealing the cavity of trans-phenoided hypophisectomy the .thrombin will be further dissolved to a final concentration of 25 U/ml by adding great amounts of CaCl2.
The preparation of reptilase is similar to that of thrombin. However, the amount of reptilase is roughly 2 U/ml .
Clinical case report The patient from the age of 21, MY (a 21 year old male) suffered from severe bleeding diathesis due to acquired inhibitor against thrombin. No background disease (i.e. tumor-, or autoimmune disease) could explain this problem. Laboratory test, confirmed by two outside laboratories indicated that MY had high levels of anti-thrombin IgG anitbody. In the last year he suffered repeated attacks of renal colic due to a large stone in his left kidney pelvis. Elective lithotripsy by ultrasound was planned. Based on the technique that IgG binds to protein-A affinity columns, the patient was placed on immunosuppressive therapy combined with extra-corporal immuno-adsorption. After 8 treatments, in which 60 L of the patient's plasma was processed through passage on the protein-A column, the inhibitor titer decreased by 98%. this was determined by measuring the thrombin time (TT) of normal pooled plasma, with pre- and post-affinity purified MJ plasma. Nevertheless, the TT as well as PT and APTT values were prolonged. At this time, the kidney stone moved to the urethra, causing complete blockage of the kidney accompanied by hydronephrosis. The patient received 10 more immuno-adsorption treatments (roughly 80 liter plasma) followed by intensive plasmapheresis (roughly 50 liter) and high doese immunoglobulin infusion (2 g/kg) . At this point, the thrombin-inhibitor level dereased to 0.5 %. PTT was decreased to 47" (vs. 85 - 90" pretreatment) and the TT was 35" (vs. 90" pre-treatment and 27" normal control) . It was decided to remove the stone by surgery, using biological adhesive (cryo glue) made up from cryo-precipitate and high levels (200 U/mL) of thrombin. With this mix, the cryo gelled immediately upon being sprayed. However, in the patient gelling did not occur and local hemostasis was achieved by suturing. At the end of surgery the wound looked "dry". Nevertheless, six hours later, the patient was bleeding from surgical drains. Immuno-absorption of 10 liter plasma was carried out, but with no effect on bleeding which actually increased.
The patient was re-operated to find the source of - - bleeding. Though no surgical bleeding was found. Diffuse bleeding was observed from the entire wound surface areas. This time, a mix of cryo and reptilase (2 U/mL; Defibrase) was sprayed onto the wound. The spray clotted immediately, the wound surface appeared turbid and bleeding stopped. The patient continued to receive daily immuno-adsorption therapy for another 5 days, with no bleeding. This demonstrates the advantage of using the snake proteasis as component B of the tissue glue of the invention. - 15 - 103118/4
Claims (9)
1. A tissue glue comprising a component A which comprises a concentrated cryoprecipitate of whole blood and a high amount of a protease inhibitor corresponding to 3,000 to 5,000 KlU/ml units of aprotinin, and a component B comprising a proteolytic enzyme being capable of cleaving specifically fibrinogen present in component A and causing the formation of a fibrine polymer .
2. The tissue glue of claim 1 wherein the protease inhibitor is aprotinin in amounts of 3,000 to 5,000 KlU/ml units .
3. The tissue glue of any one of the claims 1 and/or 2 wherein the proteolytic enzyme is thrombin derived from mammals or human beings.
4. The tissue glue of any one of the claims 1 to 3 wherein the cryoprecipitate is virus inactivated.
5. Process for manufacturing a fibrine glue according to claims 1 to 4 having the steps of manufacturing component A comprising the steps of preparing a concentrated cryo solution from cryoprecipitate, a virus inactivation, the removal of virucidal agents, addition of the protease inhibitor and preparing an appropriate solution of a suitable protease as component B. - 16 - 103118/4
6. The tissue glue according to Claim 1 comprising as component A fibrinogen, fibronectin and factor XIII and a protease inhibitor corresponding to an aprotinin amount of from 3,000 to 5,000 KlU/ml .
7. The tissue glue of Claim 6 wherein component B is a proteolytic enzyme according to Claims 4 and/or 5 or thrombin .
8. Use of a high amount of aprotinin of from 3,000 to 5,000 KlU/ml in combination with concentrated cryoprecipitate or a combination of fibrinogen, fibronectin and factor XIII for preparing a tissue glue, substantially as described in the specification.
9. Use of a concentrated cryoprecipitate for preparing a tissue glue of any one of the Claims 1 to 4, substantially as described in the specification. For the Applicants, NERS 87215-O-Claims-JP/be/l .11.1995
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PCT/EP1991/001850 WO1993005822A1 (en) | 1991-09-27 | 1991-09-27 | Tissue glue prepared by using cryoprecipitate |
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IL103118A0 IL103118A0 (en) | 1993-02-21 |
IL103118A true IL103118A (en) | 1996-11-14 |
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IL10311892A IL103118A (en) | 1991-09-27 | 1992-09-09 | Tissue glue prepared by using cryoprecipitate |
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JP (1) | JP2668762B2 (en) |
AT (1) | ATE200631T1 (en) |
AU (1) | AU648198B2 (en) |
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CA (1) | CA2079077C (en) |
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SK (1) | SK294292A3 (en) |
WO (1) | WO1993005822A1 (en) |
ZA (1) | ZA927360B (en) |
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JP2887329B2 (en) * | 1991-09-05 | 1999-04-26 | バクスター インターナショナル インク | Topical fibrinogen complex |
ITMI20021917A1 (en) * | 2002-09-10 | 2004-03-11 | New Dawn Consultores E Servicos L Da | ACTIVATOR FOR THE FORMATION OF PLASTIC GEL, PLASMA GEL POOR OF PLATES OR PLASMA GEL RICH IN PLATES. |
EP2011524A1 (en) | 2007-07-02 | 2009-01-07 | Omrix Biopharmaceuticals Ltd. | Fibrin glue with a visualization agent |
EP2034010A1 (en) | 2007-08-30 | 2009-03-11 | Omrix Biopharmaceuticals Ltd. | Compositions suitable for repair and/or treatment of injured spinal tissue |
US10039865B2 (en) | 2008-09-22 | 2018-08-07 | Omrix Biopharmaceuticals Ltd. | Implantable device comprising a substrate pre-coated with stabilized fibrin |
RU2556960C2 (en) | 2010-01-28 | 2015-07-20 | Омрикс Биофармасьютикалс Лтд. | Method of providing improved sealing by means of fibrin |
IL213864A0 (en) | 2011-06-30 | 2011-08-31 | Omrix Biopharmaceuticals Ltd | Method for removing a lytic enzyme from a heterogeneous mixture |
US10130346B2 (en) | 2012-07-24 | 2018-11-20 | Omrix Biopharmaceuticals Ltd. | Device and method for the application of a curable fluid composition to a bodily organ |
BR112015015703A2 (en) | 2012-12-30 | 2020-02-04 | Omrix Biopharmaceuticals Ltd | device and method for applying a curable fluid composition to a portion of an organ of the body |
USD754325S1 (en) | 2013-06-06 | 2016-04-19 | Omrix Biopharmaceuticals Ltd. | Device of a curable fluid composition to a bodily organ |
IL230151A0 (en) | 2013-12-24 | 2014-09-30 | Omrix Biopharmaceuticals Ltd | One component fibrin glue comprising a polymerization inhibitor |
IL230150A0 (en) | 2013-12-24 | 2014-09-30 | Omrix Biopharmaceuticals Ltd | One component fibrin glue comprising zymogens |
IL231230A0 (en) | 2014-02-27 | 2014-08-31 | Omrix Biopharmaceuticals Ltd | Fibrinogen formulation |
IL231792A0 (en) | 2014-03-27 | 2014-08-31 | Omrix Biopharmaceuticals Ltd | Device and method for preparing and administering one-component fibrin sealant |
IL234246A0 (en) | 2014-08-21 | 2014-11-30 | Omrix Biopharmaceuticals Ltd | Stabilized thrombin |
EP3258945B1 (en) | 2015-02-16 | 2020-10-07 | Nayacure Therapeutics Ltd. | Modified blood clots |
IL247821A0 (en) | 2016-09-14 | 2017-01-31 | Omrix Biopharmaceuticals Ltd | Sealant formulations and uses thereof |
IL249725A0 (en) | 2016-12-22 | 2017-03-30 | Omrix Biopharmaceuticals Ltd | Hemostatic composition comprising an anion exchanger and a calcium salt |
IL263679A (en) * | 2018-12-12 | 2019-03-31 | Omrix Biopharmaceuticals Ltd | Kits, methods, and compositions for preventing tissue adhesion |
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AT359652B (en) * | 1979-02-15 | 1980-11-25 | Immuno Ag | METHOD FOR PRODUCING A TISSUE ADHESIVE |
ATE20824T1 (en) * | 1981-06-25 | 1986-08-15 | Serapharm Gmbh & Co Kg | ENRICHED PLASMA DERIVES TO SUPPORT WOUND CLOSURE AND HEALING. |
US4627879A (en) * | 1984-09-07 | 1986-12-09 | The Trustees Of Columbia University In The City Of New York | Fibrin adhesive prepared as a concentrate from single donor fresh frozen plasma |
DE3622642A1 (en) * | 1986-07-05 | 1988-01-14 | Behringwerke Ag | ONE-COMPONENT TISSUE ADHESIVE AND METHOD FOR THE PRODUCTION THEREOF |
EP0341007B1 (en) * | 1988-05-02 | 1994-09-14 | Project Hear | Surgical adhesive material |
FR2650508A1 (en) * | 1989-08-01 | 1991-02-08 | Fondation Nale Transfusion San | PASTEURIZED ADHESIVE FOR JOINING HUMAN OR ANIMAL TISSUES |
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1991
- 1991-09-27 WO PCT/EP1991/001850 patent/WO1993005822A1/en active Application Filing
- 1991-09-27 SK SK2942-92A patent/SK294292A3/en unknown
- 1991-09-27 CZ CS922942A patent/CZ280540B6/en unknown
-
1992
- 1992-09-02 ES ES92114942T patent/ES2155437T3/en not_active Expired - Lifetime
- 1992-09-02 DE DE69231791T patent/DE69231791T2/en not_active Expired - Lifetime
- 1992-09-02 AT AT92114942T patent/ATE200631T1/en active
- 1992-09-09 IL IL10311892A patent/IL103118A/en not_active IP Right Cessation
- 1992-09-22 AU AU25288/92A patent/AU648198B2/en not_active Expired
- 1992-09-24 CA CA002079077A patent/CA2079077C/en not_active Expired - Fee Related
- 1992-09-25 FI FI924306A patent/FI924306A/en unknown
- 1992-09-25 BR BR929203763A patent/BR9203763A/en not_active Application Discontinuation
- 1992-09-25 NO NO19923737A patent/NO316155B1/en not_active IP Right Cessation
- 1992-09-25 ZA ZA927360A patent/ZA927360B/en unknown
- 1992-09-25 HU HU9203070A patent/HUT67051A/en unknown
- 1992-09-28 JP JP28112592A patent/JP2668762B2/en not_active Expired - Lifetime
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1995
- 1995-06-30 HU HU95P/P00739P patent/HU211631A9/en unknown
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FI924306A (en) | 1993-03-28 |
JPH05194263A (en) | 1993-08-03 |
JP2668762B2 (en) | 1997-10-27 |
ATE200631T1 (en) | 2001-05-15 |
AU2528892A (en) | 1993-04-01 |
NO923737D0 (en) | 1992-09-25 |
DE69231791D1 (en) | 2001-05-23 |
IL103118A0 (en) | 1993-02-21 |
ES2155437T3 (en) | 2001-05-16 |
HUT67051A (en) | 1995-01-30 |
CA2079077C (en) | 1999-11-30 |
SK294292A3 (en) | 1994-06-08 |
AU648198B2 (en) | 1994-04-14 |
WO1993005822A1 (en) | 1993-04-01 |
ZA927360B (en) | 1993-05-03 |
FI924306A0 (en) | 1992-09-25 |
HU9203070D0 (en) | 1992-12-28 |
BR9203763A (en) | 1993-04-20 |
CZ294292A3 (en) | 1994-02-16 |
CA2079077A1 (en) | 1993-03-28 |
NO316155B1 (en) | 2003-12-22 |
NO923737L (en) | 1993-03-29 |
DE69231791T2 (en) | 2001-11-22 |
HU211631A9 (en) | 1995-12-28 |
CZ280540B6 (en) | 1996-02-14 |
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