DK157977B - PROCEDURE FOR MANUFACTURING A TEXTILE SUBSTANCE - Google Patents
PROCEDURE FOR MANUFACTURING A TEXTILE SUBSTANCE Download PDFInfo
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- DK157977B DK157977B DK300682A DK300682A DK157977B DK 157977 B DK157977 B DK 157977B DK 300682 A DK300682 A DK 300682A DK 300682 A DK300682 A DK 300682A DK 157977 B DK157977 B DK 157977B
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- Prior art keywords
- fibrinogen
- factor xiii
- antibiotic
- preparation
- added
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- 238000000034 method Methods 0.000 title claims description 20
- 238000004519 manufacturing process Methods 0.000 title description 2
- 239000000126 substance Substances 0.000 title 1
- 239000004753 textile Substances 0.000 title 1
- 108010049003 Fibrinogen Proteins 0.000 claims description 32
- 102000008946 Fibrinogen Human genes 0.000 claims description 32
- 229940012952 fibrinogen Drugs 0.000 claims description 32
- 108010071289 Factor XIII Proteins 0.000 claims description 31
- 229940012444 factor xiii Drugs 0.000 claims description 30
- 239000003106 tissue adhesive Substances 0.000 claims description 23
- 230000003115 biocidal effect Effects 0.000 claims description 20
- 239000003242 anti bacterial agent Substances 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 9
- 229940122791 Plasmin inhibitor Drugs 0.000 claims description 7
- 239000007853 buffer solution Substances 0.000 claims description 7
- 239000002806 plasmin inhibitor Substances 0.000 claims description 7
- 102000010752 Plasminogen Inactivators Human genes 0.000 claims description 6
- 108010077971 Plasminogen Inactivators Proteins 0.000 claims description 6
- 239000002797 plasminogen activator inhibitor Substances 0.000 claims description 6
- 108090000190 Thrombin Proteins 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 210000002381 plasma Anatomy 0.000 claims description 5
- 229960004072 thrombin Drugs 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 4
- 108010039627 Aprotinin Proteins 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 229960004405 aprotinin Drugs 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound 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 description 3
- 239000002753 trypsin inhibitor Substances 0.000 claims description 3
- 239000004098 Tetracycline Substances 0.000 claims description 2
- 229940126575 aminoglycoside Drugs 0.000 claims description 2
- 235000021120 animal protein Nutrition 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 229960002180 tetracycline Drugs 0.000 claims description 2
- 229930101283 tetracycline Natural products 0.000 claims description 2
- 235000019364 tetracycline Nutrition 0.000 claims description 2
- 150000003522 tetracyclines Chemical class 0.000 claims description 2
- 238000010257 thawing Methods 0.000 claims description 2
- 150000003952 β-lactams Chemical class 0.000 claims description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims 1
- 238000010790 dilution Methods 0.000 claims 1
- 239000012895 dilution Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 11
- 229930182566 Gentamicin Natural products 0.000 description 10
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 10
- 230000001070 adhesive effect Effects 0.000 description 6
- 238000004132 cross linking Methods 0.000 description 6
- 239000000853 adhesive Substances 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229940075469 tissue adhesives Drugs 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 206010052428 Wound Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 235000011148 calcium chloride Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229930193140 Neomycin Natural products 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 229960002518 gentamicin Drugs 0.000 description 2
- 229960002449 glycine Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229960004927 neomycin Drugs 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 2
- 229960000401 tranexamic acid Drugs 0.000 description 2
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- 206010000369 Accident Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 108010080379 Fibrin Tissue Adhesive Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 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 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- 108010001014 Plasminogen Activators Proteins 0.000 description 1
- 102000001938 Plasminogen Activators Human genes 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 102000003801 alpha-2-Antiplasmin Human genes 0.000 description 1
- 108090000183 alpha-2-Antiplasmin Proteins 0.000 description 1
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 description 1
- 229960003623 azlocillin Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940127126 plasminogen activator Drugs 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- FRGKKTITADJNOE-UHFFFAOYSA-N sulfanyloxyethane Chemical compound CCOS FRGKKTITADJNOE-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 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
- A61L24/10—Polypeptides; Proteins
- A61L24/106—Fibrin; Fibrinogen
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Surgery (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Materials For Medical Uses (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
Description
DK 157977 BDK 157977 B
iin
Opfindelsen angår en fremgangsmåde til fremstilling af et vævsklæbestof på basis af humane eller animalske proteiner og med et indhold af faktor XIII, fibrinogen og et antibiotikum valgt blandt aminoglycosid, betalactam, polypeptid og tetracyklin.The invention relates to a process for the preparation of a tissue adhesive based on human or animal proteins and containing a factor of XIII, fibrinogen and an antibiotic selected from aminoglycoside, beta-lactam, polypeptide and tetracycline.
55
Fremgangsmåder til fremstilling af et vævsklæbestof med et indhold af fibrinogen og faktor XIII er allerede kendt fra AT-patentskrifterne 359.652 og 359.653, ved hvilke bestemte koncentrationsforhold mellem faktor XIII og fibrinogen 10 og eventuelt albumin indstilles,og præparaterne dybfryses eller lyofiliseres. Disse præparater havde i det væsentlige tilfredsstillende egenskaber, nemlig en høj belastningsevne af klæbningerne og en god resorberbarhed. Det er dog ønskeligt at forbedre disse præparater med hensyn til en 15 antimikrobiel virkning.Methods for preparing a tissue adhesive containing fibrinogen and factor XIII are already known from the AT Patents 359,652 and 359,653, at which certain concentration ratios of factor XIII to fibrinogen 10 and optionally albumin are adjusted and the compositions are deep-frozen or lyophilized. These compositions had essentially satisfactory properties, namely a high load-bearing capacity of the adhesives and a good resorbability. However, it is desirable to improve these compositions for an antimicrobial effect.
Det blev ganske vist allerede i US patentskrift nr. 2.533.004 og af Fel linger og andre i tidsskriftet "Der Tuberkulosearzt" (6/11, 1952) foreslået, at sætte antibiotika til fibrino= 20 genopløsninger og anvende disse som sårklæbestof, men disse opløsninger, der først fremstilles ved sygesengen, resulterer ikke i tilstrækkelig holdbarhed og belastningsevne af det deraf dannede fibrinkoagulat.Admittedly, in U.S. Patent No. 2,533,004 and by Fel linger and others in the journal "Der Tuberculosearzt" (6/11, 1952), it was suggested that antibiotics be used for fibrino = 20 remedies and use them as wound adhesives, but these solutions first prepared by the hospital bed do not result in sufficient durability and load capacity of the resulting fibrin coagulate.
25 Det er endvidere kendt fra et arbejde af Bosch et al,25 It is further known from a work by Bosch et al.
Archiv fur Orthopådische und Unfall-Chirurgie, bind 90 (1977), side 63 til 75, i forbindelse med knogletransplantater at anvende et fibrinklæbesystem til udfyldelse af knogledefekter, hvorved fibrinet dannes direkte på det 30 valgte sted i knoglehulrummet ved tilsætning af thrombin til en fibrinogenopløsning. Efter behov tilsattes også i handelen gående kombinationspræparater af neomycin i pulverform.Archiv fur Orthopådische und Unfall-Chirurgie, Vol. 90 (1977), pages 63 to 75, in connection with bone grafts, to use a fibrin adhesive system for filling bone defects, whereby the fibrin is formed directly at the selected site in the bone cavity by the addition of thrombin to a fibrinogen solution. . As needed, commercially available powder formulations of neomycin were also added.
35 Endeligt blev det ifølge PCT-ansøgning WO 81/00516 foreslået at fremstille en fibrinogen-anti biot ikumgel, hvorved en til fremstilling ved sygesengen bestemt blanding af kryopræcipi tat 2Finally, according to PCT application WO 81/00516, it was proposed to prepare a fibrinogen-anti-biotic gel, whereby a mixture of cryoprecipitate 2, determined for the hospital bed,
DK 157977 BDK 157977 B
med tobramycin og gentamycin som antibiotikum kommer til anvendelse.with tobramycin and gentamycin as an antibiotic comes into use.
Ifølge egne forsøg blev det fastslået, at de beskrevne og 5 kendte vævsklæbestoffer, som indeholder fibrinogen, faktor XIII og et antibiotikum, ikke har den ønskede kombination af egenskaber, nemlig en høj belastningsevne af klæbningerne og en antimikrobiel virkning, men at der indtræder en uheldig vekselvirkning mellem antibiotika og faktor XIII, 10 med den virkning, at fibrinogenets tværbindingsevne falder stærkt, og koagulationsevnen påvirkes ugunstigt. Som følge deraf bevirker det en forringet styrke og adhæsionsevne af klæbemidlet til sår- eller vævsfladerne.According to their own experiments, it was determined that the described and known tissue adhesives containing fibrinogen, factor XIII and an antibiotic do not have the desired combination of properties, namely a high load-bearing capacity and an antimicrobial effect, but that an adverse effect occurs. interaction between antibiotics and factor XIII, 10 with the effect that the fibrinogen's cross-linking ability is greatly decreased and its clotting ability is adversely affected. As a result, it impairs the strength and adhesiveness of the adhesive to the wound or tissue surfaces.
15 En yderligere ulempe ved de kendte præparater består i at afgivelsen af antibiotikum til vævet foregår for hurtigt, således at antibiotikumretardationen ikke er tilstrækkelig til at virke i længere tid og til opnåelse af en høj afgivelse af virksomt stof.A further disadvantage of the known compositions is that the delivery of antibiotic to the tissue takes place too quickly, so that the antibiotic retardation is not sufficient to last for a long time and to obtain a high release of active substance.
2020
Opfindelsen tager sigte på at undgå disse ulemper og vanskeligheder og tilvejebringe et vævsklæbestof af human eller animalsk oprindelse, som har de ovenfor anførte kombinationsegenskaber og sikrer en bedre virkning af anti-25 biotiket.The invention aims to avoid these drawbacks and difficulties and to provide a tissue adhesive of human or animal origin which has the above combination properties and ensures a better effect of the anti-biotic.
Den stillede opgave løses ved hjælp af en fremgangsmåde af den indledningsvis nævnte art, som er ejendommelig ved, at man i en fibrinogenholdig blodplasmafraktion, eventuelt efter vask-30 ning med en pufferopløsning og tilsætning af en plasmin-inhi-bitor eller plasminogen-aktivator-inhibitor indstiller et koncentrationsforhold mellem faktor XIII og fibrinogen, udtrykt i enheder faktor XIII/g fibrinogen, på mindst 500 ved tilsætning af faktor XIII, hvorpå antibiotiket tilsættes, og præparatet 35 dybfryses eller lyofiliseres, eller efter indstilling af faktor · XIII-/fibrinogenindholdet dybfryser eller lyofiliserer præparatet og efter optøning eller genfortynding forener det med en antibiotikumholdig opløsning.The stated task is solved by a method of the kind mentioned in the beginning, characterized in that in a fibrinogen-containing blood plasma fraction, optionally after washing with a buffer solution and adding a plasmin inhibitor or plasminogen activator. inhibitor sets a concentration ratio of factor XIII to fibrinogen, expressed in units of factor XIII / g fibrinogen, of at least 500 by the addition of factor XIII to which the antibiotic is added and the preparation is frozen or lyophilized or after adjustment of factor · XIII / fibrinogen content or lyophilizes the preparation and after thawing or re-diluting it combines with an antibiotic-containing solution.
33
DK 157977 BDK 157977 B
Ifølge en foretrukken udførelsesform, ved hvilken den fibrino-genholdige blodplasmafraktion vaskes med en pufferopløsning, gennemføres vaskeprocessen indtil opnåelse af en faktor XIII-koncentration på 200 enheder faktor XIII/g fibrinogen, hvoref-5 ter faktor XIII tilsættes i en mængde på mindst 300 enheder/g fibrinogen i form af et koncentrat eller lyofilisat.According to a preferred embodiment, in which the fibrinogen-containing blood plasma fraction is washed with a buffer solution, the washing process is performed until a factor XIII concentration of 200 units of factor XIII / g of fibrinogen is carried out, after which factor XIII is added in an amount of at least 300 units. / g fibrinogen in the form of a concentrate or lyophilisate.
Fordelagtigt er der i et dybfrosset vævsklæbestof indeholdt faktor XIII i en mængde på mindst 40 enheder/ml. I tilfælde af 10 et lyofiliseret vævsklæbestof skal der været indeholdt mindst 33 vægt% fibrinogen, idet faktor XIII er til stede i en mængde på mindst 170 enheder/g lyofilisat.Advantageously, in a frozen tissue adhesive, factor XIII is contained in an amount of at least 40 units / ml. In the case of a lyophilized tissue adhesive, at least 33% by weight fibrinogen must be contained, with factor XIII present in an amount of at least 170 units / g of lyophilisate.
Som plasmininhibitor eller plasminogen-aktivator-inhibitor kan 15 der hensigtsmæssigt anvendes en valgt blandt aprotinin, <X2-an-tiplasmin, o^-makroglobulin, aj-antitrypsin, e-aminocapronsyre og tranexamsyre< Vævsklæbestoffet foreligger fordelagtigt som et tokomponent- 20 præparat, hvor faktor XIII, fibrinogen og plasmin-inhibitoren eller plasminogen-aktivator-inhibitoren er indeholdt i den første komponent, medens antibiotiket, thrombin og divalent calcium er indeholdt i den anden komponent.Conveniently, as a plasmin inhibitor or plasminogen activator inhibitor, one selected from aprotinin, <X2-antiplasmin,? -Macroglobulin, α-antitrypsin, α-aminocaproic acid and tranexamic acid <The tissue adhesive may advantageously be present as wherein the factor XIII, fibrinogen and the plasmin inhibitor or plasminogen activator inhibitor are contained in the first component, while the antibiotic, thrombin and divalent calcium are contained in the second component.
25 Fortrinsvis anvendes antibiotiket i form af et tungt opløseligt derivat. En variant af denne udførelsesform kan bestå i, at der foruden det tungt opløselige derivat også anvendes et let opløseligt, eventuelt fordelt i vævsklæbestoffets to komponenter. Denne udførelsesform har den fordel, at det let op-30 løselige derivat hurtigt afgives og sikrer en høj begyndelsesvirkning, hvorimod det tungt opløselige begrunder en langvarig vi rkni ng.Preferably, the antibiotic is used in the form of a heavily soluble derivative. A variant of this embodiment may consist in that, in addition to the heavily soluble derivative, a slightly soluble, optionally distributed in the two components of the tissue adhesive is also used. This embodiment has the advantage that the readily soluble derivative is rapidly released and ensures a high initial effect, whereas the heavily soluble justifies a long-term effect.
Fremgangsmåden til fremstilling af vævsklædestoffet ifølge op-35 findelsen belyses nærmere i de efterfølgende eksempler.The process for preparing the fabric of the invention according to the invention is elucidated in the following examples.
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Eksempel 1.Example 1.
Ud fra humant nedfrosset, frisk plasma blev der ved opvarmning til 2°C udvundet kryopræcipitat (100 g) , som blev fraskilt ved 5 centrifugering og vasket to gange i en pufferopløsning indeholdende Na^-citrat, NaCl, glycin, glucose, aprotinin og heparin ved en pH-værdi på 6,5, og det fraskilte bundfald blev opløst i en glycinholdig pufferopløsning (255 ml) ved en pH-værdi på 7,9. Det blev fastslået, at der i denne 10 opløsning fandtes et forhold mellem faktor XIII og fibrinogen på 226 enheder faktor XIII/g fibrinogen. Til indstilling af det ved fremgangsmåden ifølge opfindelsen ønskede forhold på mere end 500 E/g fibrinogen blev opløsningen tilsat et faktor XIII-præparat i pulverform med 9.000 enheder, hvor-15 ved opløsningens koncentrationsforhold nu blev forøget til 823 enheder faktor XIII/g fibrinogen. Denne opløsning blev steril-filtreret, hvorpå 1,7 g gentamycin tilsattes under sterile betingelser, og blandingen blev fyldt på siutbeholdere (2,5 ml), dybfrosset og lyofi 1iseret.From human frozen fresh plasma, cryoprecipitate (100 g) was recovered by heating to 2 ° C, which was separated by centrifugation and washed twice in a buffer solution containing Na 2 citrate, NaCl, glycine, glucose, aprotinin and heparin. at a pH of 6.5 and the separated precipitate was dissolved in a glycine-containing buffer solution (255 ml) at a pH of 7.9. It was determined that in this solution 10, a factor of factor XIII and fibrinogen of 226 units of factor XIII / g fibrinogen was found. To adjust the ratio desired by the process of the invention to more than 500 U / g fibrinogen, a 9000 unit powder XIII powder composition was added, whereupon the solution's concentration ratio was now increased to 823 units of factor XIII / g fibrinogen. This solution was sterile filtered, then 1.7 g of gentamycin was added under sterile conditions and the mixture was filled into sieve containers (2.5 ml), frozen and lyophilized.
2020
Eksempel 2.Example 2.
Fremstillingen af vævsklæbestofgrundlag ud fra kryopræcipitat 25 blev udført på samme måde som i eksempel 1, med den forskel, at kryopræcipitatbundfaldet efter én enkelt vask blev gjort flydende ved opvarmning til 37°C og 13.600 enheder af faktor XIII i pulverform blev tilsat. Derved opnåedes et forhold mellem faktor XIII og fibrinogen på 967 faktor XIII-en= 30 heder/g fibrinogen.The preparation of tissue adhesive basis from cryoprecipitate 25 was carried out in the same manner as in Example 1, except that after a single wash, the cryoprecipitate precipitate was liquefied by heating to 37 ° C and 13,600 units of factor XIII in powder form were added. Thereby, a ratio of factor XIII to fibrinogen of 967 factor XIII = 30 h / g fibrinogen was obtained.
Opløsningen blev som antibiotikum tilsat 5,67 g 7-[(thie= nyl)-(2)-acetamido]-cephalosporansyre. Den således opnåede suspension blev fyldt på slutbeholdere (1 ml) og dyb-35 frosset. Faktor XIII er i det påfyldte præparat indeholdt i en mængde på 87 E/ml.To the solution was added 5.67 g of 7 - [(thie = nyl) - (2) -acetamido] cephalosporanoic acid. The suspension thus obtained was filled into final containers (1 ml) and deep-frozen. Factor XIII is contained in the filled preparation in an amount of 87 U / ml.
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Administrationen af de ifølge eksempel 1 og 2 fremstillede vævsklæbestoffer sker fordelagtigt ved, at den optøede eller rekonstituerede blanding blandes med thrombin og calciumchlorid og påføres på vævet, som skal for-5 bindes. Det er også muligt, at påføre de to komponenterne separat på vævet, der skal forbindes eller udfyldes.The administration of the tissue adhesives prepared according to Examples 1 and 2 is advantageously effected by mixing the thawed or reconstituted mixture with thrombin and calcium chloride and applied to the tissue to be bonded. It is also possible to apply the two components separately to the tissue to be joined or filled.
Eksempel 3.Example 3
Fremgangsmåden ifølge eksepel 1 blev gentaget indtil tilsætning af antibiotiket. Den vaskede udfældning blev efter opløsning i pufferopløsning sterilfiltreret, fyldt på slutbeholdere (2,5 ml), dybfrosset og lyofiliseret, hvorved den første komponent af vævsklæbestoffet fremstillet ved 15 fremgangsmåden ifølge opfindelsen blev gjort lagringsegnet.The procedure of Example 1 was repeated until the antibiotic was added. The washed precipitate, after dissolving in buffer solution, was sterile filtered, filled into final containers (2.5 ml), frozen and lyophilized, thereby storing the first component of the tissue adhesive prepared by the method of the invention.
Den anden komponent blev forud for administrationen fremstillet ud fra en opløsning af thrombin og calciumchlorid ved tilsætning af 7-[(thienyl)-(2)-acetamido]-cephalosporansyre (30 mg/ml).Prior to administration, the second component was prepared from a solution of thrombin and calcium chloride by the addition of 7 - [(thienyl) - (2) -acetamido] -cephalosporanoic acid (30 mg / ml).
2020
Eksempel 4.Example 4
Fremgangsmåden ifølge eksempel 2 blev gentaget, hvorved genta-mycin (1,89 g) bTev tilsat efter opløsning af kryopræcipitat-25 bundfaldet, og opløsningen blev fyldt på slutbeholdere (1 ml) og dybfrosset. Dermed foreligger den første komponent af klæbestoffet fremstillet ved fremgangsmåden ifølge opfindelsen i en lagringsegnet form. Den anden komponent indeholdende 30 mg 7-[(thienyl)-(2)-acetamido]-cephalosporansyre pr. ml af en 30 calciumchlorid-throminopløsning blev fremstillet før administrationen .The procedure of Example 2 was repeated, whereby gentamicin (1.89 g) bTev was added after dissolving the cryoprecipitate precipitate, and the solution was filled into final containers (1 ml) and frozen. Thus, the first component of the adhesive produced by the method of the invention is in a storage suitable form. The second component containing 30 mg of 7 - [(thienyl) - (2) -acetamido] cephalosporanoic acid per ml of a calcium chloride-thromine solution was prepared prior to administration.
I stedet for det ifølge eksemplerne 1-4 tilsatte apro= tinin kan der som plasmin-inhibitor eller plasminogen-35 aktivator-inhibitor anvendes én eller flere af følgende: a2-antiplasmin, a2”Kiakroglobulin, α^-antitrypsin, e-amino= capronsyre og tranexamsyre.Instead of the aproctinine added according to Examples 1-4, one or more of the following may be used as a plasmin inhibitor or a plasminogen activator inhibitor: α2-antiplasmin, α2-Kiacroglobulin, α ^-antitrypsin, α-amino = capric acid and tranexamic acid.
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De ved fremgangsmåden ifølge opfindelsen fremstillede vævsklæ-bestoffer har en generel anvendelighed til sømløs forbinding af menneskers eller dyrs væv- eller organdele til sårbehandling og blodstandsning samtidig med væsentligt forbedret anti-5 mikrobiel virkning.The tissue adhesives prepared by the method of the invention have a general utility for seamlessly joining human or animal tissue or organ portions for wound treatment and blood clotting, while significantly enhancing anti-microbial activity.
De forbedrede klæbeegenskaber samtidig med på samme måde forbedret antimikrobiel virkning af vævsklæbestoffet fremstillet ved fremgangsmåden ifølge opfindelsen fremgår af de følgende i 10 tabel sammenfattede sammeligningseksempler. Herved blev tvær bindingsgraden af vævsklæbestoffet fremstillet ved fremgangsmåden ifølge opfindelsen med forhøjet faktor XIII/fibrinogen-forhold sammenlignet med tværbindingsgraden af kendte vævsklæbestoffer uden forhøjet faktor XIII/fibrinogen-forhold under 15 anvendelse af forskellige antibiotika, α-tværbindingsgraden er bestemt ifølge natriumlaurylsulfat-(SDS)-polyacrylamid-gel-elektroforesemetoden, som gennemføres således, at man, efter blanding af vævsklæbestoffet med det samme volumen af en opløsning indeholdende 40 pmol CaCl2 og 15 NIH-enheder (US Na-20 tional Institute of Health-enhder) thrombin pr. ml, inkuberer blandingen ved 37°C. α-tværbindingsgraden bestemmes ved hjælp af gelelektroforese efter standsning af reaktionen og reduktiv spaltning af de i proteinerne indeholdte disulfidbroer ved tilsætning af en blanding af urinstof, natriumdodecylsulfat og 25 /3-mercaptoethanol.The improved adhesive properties, together with the similarly improved antimicrobial effect of the tissue adhesive prepared by the method of the invention, appear from the following comparative examples summarized in Table 10. Hereby, the cross-linking rate of the tissue adhesive prepared by the method of the invention with elevated factor XIII / fibrinogen ratio was compared to the crosslinking rate of known tissue adhesives without elevated factor XIII / fibrinogen ratio using different antibiotics, the α-crosslinking rate was determined by sodium lauryl sulfate ( ) -polyacrylamide gel electrophoresis method which is carried out so that, after mixing the tissue adhesive with the same volume of a solution containing 40 pmol CaCl2 and 15 NIH units (US National Institute of Health units) ml, incubate the mixture at 37 ° C. The degree of α-crosslinking is determined by gel electrophoresis after stopping the reaction and reductive cleavage of the disulfide bridges contained in the proteins by the addition of a mixture of urea, sodium dodecyl sulfate and 25/3 mercaptoethanol.
I den yderligere del af tabellen blev clotstyrken i thrombela-stograf af et vævsklæbestof fremstillet ved fremgangsmåden ifølge opfindelsen sammenholdt med styrken af et kendt, idet 30 gentamycin blev tilsat som antibiotikum.In the further part of the table, the clot strength in thrombelastograph of a tissue adhesive prepared by the method of the invention was compared with the strength of a known one, with 30 gentamycin added as an antibiotic.
Endelig indeholder tabellen trækstyrkesammenligningsværdier for et vævsklæbestof fremstillet ved fremgangsmåden ifølge opfindelsen og et kendt, idet gentamycin anvendes som antibioti-35 kum.Finally, the table contains tensile strength comparisons of a tissue adhesive prepared by the method of the invention and a known one, using gentamycin as an antibiotic.
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Fibrin-a-tværbinding (ved 37°C efter 60 minutter).Fibrin-α crosslinking (at 37 ° C after 60 minutes).
Antibiotikum- Vævsklæbestof ifølge Vævsklæbestof tilsætning opfindelsen med for- uden forhøjet højet faktor XIII-ind- faktor XIII- 5 hold, >500 E/g fibri- indhold.Antibiotic Tissue Adhesive According to Tissue Adhesive, the invention is added with the addition of elevated factor XIII factor XIII content,> 500 U / g fiber content.
nogen.anyone.
Gentamycin 70% 30%Gentamycin 70% 30%
Neomycin 41% 21%Neomycin 41% 21%
Fosfomycin 47% 24% 10 Azlocillin 66% 42%Phosphomycin 47% 24% Azlocillin 66% 42%
Doxycyklin 65% 26%Doxycycline 65% 26%
Cefoxitin 54% 44%Cefoxitin 54% 44%
Clotstyrke i thrombelastograf *5 (37°C-60 min.) ε = Elasticitetskoefficient.Clot strength in thrombelastograph * 5 (37 ° C-60 min.) Ε = Elasticity coefficient.
Gentamycin 1.150 426 20 2Gentamycin 1.150 426 20 2
Trækstyrke i g/cm (37°C-30 min.) 25Tensile strength in g / cm (37 ° C-30 min) 25
Gentamycin 1.283 999Gentamycin 1,283 999
Endelig blev endnu et sammenligningseksempel vedrørende antibiotikaafgivelsen fra et ifølge eksempel 4 fremstillet vævsklæbestof gennemført, hvorved der i et in vitro 30 forsøg efter 72 timer allerede var afgivet 85% af gentamy= cinet fra en med dette klæbestof fremstillet clot. Efter 96 timer blev en afgivelse af gentamycin ikke mere konstateret, medens 7-[(thienyl)-(2)-acetamido]-cephalosporan= syre stadig var påviselig efter 8 dage.Finally, another comparative example of antibiotic delivery from a tissue adhesive prepared according to Example 4 was performed, whereby, in an in vitro 30-hour trial after 72 hours, 85% of the gentamicin was already delivered from a clot made with this adhesive. After 96 hours, a release of gentamycin was no longer detected, while 7 - [(thienyl) - (2) -acetamido] -cephalosporan = acid was still detectable after 8 days.
3 53 5
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT333781 | 1981-07-28 | ||
| AT0333781A AT369990B (en) | 1981-07-28 | 1981-07-28 | METHOD FOR PRODUCING A TISSUE ADHESIVE |
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| DK300682A DK300682A (en) | 1983-01-29 |
| DK157977B true DK157977B (en) | 1990-03-12 |
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| AR (1) | AR227252A1 (en) |
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| JPS6185304A (en) * | 1984-10-01 | 1986-04-30 | Green Cross Corp:The | Auxiliary for dental treatment |
| DE3622642A1 (en) * | 1986-07-05 | 1988-01-14 | Behringwerke Ag | ONE-COMPONENT TISSUE ADHESIVE AND METHOD FOR THE PRODUCTION THEREOF |
| AT397203B (en) * | 1988-05-31 | 1994-02-25 | Immuno Ag | FABRIC ADHESIVE |
| US4837379A (en) * | 1988-06-02 | 1989-06-06 | Organogenesis Inc. | Fibrin-collagen tissue equivalents and methods for preparation thereof |
| NZ229385A (en) * | 1989-06-01 | 1992-02-25 | Life Technologies Inc | Treatment of processed fish product (surimi) with alpha-2-macroglobulin to neutralise alkaline proteases in the fish |
| IT1243180B (en) * | 1990-07-31 | 1994-05-24 | Nunzio Rapisarda | USE OF PHOSPHOMYCIN AND ITS SALTS AS A TOPICAL CICATRIZING AGENT |
| US6117425A (en) * | 1990-11-27 | 2000-09-12 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, method of their production and use |
| US6559119B1 (en) | 1990-11-27 | 2003-05-06 | Loyola University Of Chicago | Method of preparing a tissue sealant-treated biomedical material |
| US6054122A (en) * | 1990-11-27 | 2000-04-25 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US7208179B1 (en) | 1990-11-27 | 2007-04-24 | The American National Red Cross | Methods for treating disease and forming a supplemented fibrin matrix |
| US6197325B1 (en) * | 1990-11-27 | 2001-03-06 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| KR950702434A (en) * | 1992-07-18 | 1995-07-29 | 로버트 타웁 | A TWO COMPONENT FIBRIN-GLUE COMPOSITION FOR IMPROVING IN VITRO FERTILIZATION Improves In Vitro Fertilization |
| US5330974A (en) * | 1993-03-01 | 1994-07-19 | Fibratek, Inc. | Therapeutic fibrinogen compositions |
| EP0696201B2 (en) † | 1993-03-12 | 2012-09-19 | The American National Red Cross | Supplemented tissue sealants, methods of their production and use |
| AU6536394A (en) * | 1993-03-30 | 1994-10-24 | Opperbas Holding B.V. | Two component fibrin glue |
| DE19521324C1 (en) * | 1995-06-12 | 1996-10-31 | Immuno Ag | Tissue adhesive and use thereof as a hemostatic |
| DE19617369A1 (en) * | 1996-04-30 | 1997-11-06 | Immuno Ag | Storage-stable fibrinogen preparations |
| AT406120B (en) * | 1997-08-28 | 2000-02-25 | Immuno Ag | TISSUE ADHESIVE |
| AT407484B (en) | 1997-11-12 | 2001-03-26 | Bio Prod & Bio Eng Ag | MEDICINES FOR PROMOTING Wound Healing |
| US6762336B1 (en) | 1998-01-19 | 2004-07-13 | The American National Red Cross | Hemostatic sandwich bandage |
| CA2395431C (en) | 1999-12-23 | 2010-08-17 | Csl Limited | Separation of fibrinogen from plasma proteases |
| US6506365B1 (en) | 2000-09-25 | 2003-01-14 | Baxter Aktiengesellschaft | Fibrin/fibrinogen binding conjugate |
| IL144446A0 (en) * | 2001-07-19 | 2002-05-23 | Prochon Biotech Ltd | Plasma protein matrices and methods for their preparation |
| AU2003270401B2 (en) | 2002-09-10 | 2008-03-13 | American National Red Cross | Hemostatic dressing |
| US7067123B2 (en) | 2003-04-29 | 2006-06-27 | Musculoskeletal Transplant Foundation | Glue for cartilage repair |
| US7901457B2 (en) | 2003-05-16 | 2011-03-08 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
| EP1784415A2 (en) | 2004-08-27 | 2007-05-16 | Novo Nordisk Health Care AG | Purification of factor xiii polypeptides from biological materials |
| US7837740B2 (en) | 2007-01-24 | 2010-11-23 | Musculoskeletal Transplant Foundation | Two piece cancellous construct for cartilage repair |
| ES2378777T3 (en) | 2004-11-23 | 2012-04-17 | Zymogenetics, Inc. | Purification of recombinant human factor XIII |
| US7815926B2 (en) | 2005-07-11 | 2010-10-19 | Musculoskeletal Transplant Foundation | Implant for articular cartilage repair |
| EP1926459B1 (en) | 2005-09-19 | 2015-01-07 | Histogenics Corporation | Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof |
| WO2008019129A2 (en) | 2006-08-04 | 2008-02-14 | Stb Lifesaving Technologies, Inc. | Solid dressing for treating wounded tissue |
| US8435551B2 (en) | 2007-03-06 | 2013-05-07 | Musculoskeletal Transplant Foundation | Cancellous construct with support ring for repair of osteochondral defects |
| US20090075891A1 (en) | 2007-08-06 | 2009-03-19 | Macphee Martin | Methods and dressings for sealing internal injuries |
| CA2717725A1 (en) | 2008-03-05 | 2009-09-11 | Musculoskeletal Transplant Foundation | Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles |
| US10077420B2 (en) | 2014-12-02 | 2018-09-18 | Histogenics Corporation | Cell and tissue culture container |
| AU2022426762A1 (en) | 2021-12-30 | 2024-07-04 | Baxter Healthcare Sa | Fibrinogen and thrombin solutions for a fibrin sealant and fibrin sealant kit |
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| JPS56501129A (en) * | 1979-08-31 | 1981-08-13 |
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| FR2510408B1 (en) | 1987-02-27 |
| NL8202982A (en) | 1983-02-16 |
| CA1168982A (en) | 1984-06-12 |
| JPS5826821A (en) | 1983-02-17 |
| NL192665C (en) | 1997-12-02 |
| ES8306023A1 (en) | 1983-05-01 |
| DK157977C (en) | 1990-08-13 |
| IT8222595A0 (en) | 1982-07-27 |
| AT369990B (en) | 1983-02-25 |
| SE8204064L (en) | 1983-01-29 |
| ES514441A0 (en) | 1983-05-01 |
| SE459848B (en) | 1989-08-14 |
| GB2102811A (en) | 1983-02-09 |
| DK300682A (en) | 1983-01-29 |
| SE8204064D0 (en) | 1982-07-01 |
| DE3225102C2 (en) | 1990-05-31 |
| JPH0696039B2 (en) | 1994-11-30 |
| IT1157313B (en) | 1987-02-11 |
| GB2102811B (en) | 1985-01-30 |
| ATA333781A (en) | 1982-07-15 |
| BE893851A (en) | 1982-11-16 |
| FR2510408A1 (en) | 1983-02-04 |
| AR227252A1 (en) | 1982-09-30 |
| CH659187B (en) | 1987-01-15 |
| NL192665B (en) | 1997-08-01 |
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