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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.
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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,
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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.
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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
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT333781 | 1981-07-28 | ||
| AT0333781AAT369990B (en) | 1981-07-28 | 1981-07-28 | METHOD FOR PRODUCING A TISSUE ADHESIVE |
| Publication Number | Publication Date |
|---|---|
| DK300682A DK300682A (en) | 1983-01-29 |
| DK157977Btrue DK157977B (en) | 1990-03-12 |
| DK157977C DK157977C (en) | 1990-08-13 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK300682ADK157977C (en) | 1981-07-28 | 1982-07-05 | PROCEDURE FOR MANUFACTURING A TEXTILE SUBSTANCE |
| Country | Link |
|---|---|
| JP (1) | JPH0696039B2 (en) |
| AR (1) | AR227252A1 (en) |
| AT (1) | AT369990B (en) |
| BE (1) | BE893851A (en) |
| CA (1) | CA1168982A (en) |
| CH (1) | CH659187B (en) |
| DE (1) | DE3225102A1 (en) |
| DK (1) | DK157977C (en) |
| ES (1) | ES514441A0 (en) |
| FR (1) | FR2510408B1 (en) |
| GB (1) | GB2102811B (en) |
| IT (1) | IT1157313B (en) |
| NL (1) | NL192665C (en) |
| SE (1) | SE459848B (en) |
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| AT397203B (en)* | 1988-05-31 | 1994-02-25 | Immuno Ag | FABRIC ADHESIVE |
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| FI950194A7 (en)* | 1992-07-18 | 1995-01-17 | Opperbas Holding Bv | Two-component fibrin glue composition to promote in vitro fertilization |
| US5330974A (en)* | 1993-03-01 | 1994-07-19 | Fibratek, Inc. | Therapeutic fibrinogen compositions |
| AU696691C (en)† | 1993-03-12 | 2003-09-18 | American National Red Cross, The | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| ATE187651T1 (en)* | 1993-03-30 | 2000-01-15 | Omrix Biopharm Sa | TWO-COMPONENT FIBRIN ADHESIVE |
| 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 |
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| AT359652B (en)* | 1979-02-15 | 1980-11-25 | Immuno Ag | METHOD FOR PRODUCING A TISSUE ADHESIVE |
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| ES8306023A1 (en) | 1983-05-01 |
| DK300682A (en) | 1983-01-29 |
| SE8204064D0 (en) | 1982-07-01 |
| JPH0696039B2 (en) | 1994-11-30 |
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| NL192665C (en) | 1997-12-02 |
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| NL192665B (en) | 1997-08-01 |
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