SE459848B - TEXTILE FILM CONTAINING FACTOR XIII, THE FIBRINOGEN AND ANTIBIOTIC, AND SUCH BEFORE ITS PREPARATION - Google Patents
TEXTILE FILM CONTAINING FACTOR XIII, THE FIBRINOGEN AND ANTIBIOTIC, AND SUCH BEFORE ITS PREPARATIONInfo
- Publication number
- SE459848B SE459848B SE8204064A SE8204064A SE459848B SE 459848 B SE459848 B SE 459848B SE 8204064 A SE8204064 A SE 8204064A SE 8204064 A SE8204064 A SE 8204064A SE 459848 B SE459848 B SE 459848B
- Authority
- SE
- Sweden
- Prior art keywords
- fibrinogen
- factor xiii
- antibiotic
- units
- tissue adhesive
- Prior art date
Links
- 229940012444 factor xiii Drugs 0.000 title claims description 43
- 229940012952 fibrinogen Drugs 0.000 title claims description 42
- 108010049003 Fibrinogen Proteins 0.000 title claims description 40
- 102000008946 Fibrinogen Human genes 0.000 title claims description 40
- 230000003115 biocidal effect Effects 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 12
- FBPFZTCFMRRESA-ZXXMMSQZSA-N D-iditol Chemical compound OC[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-ZXXMMSQZSA-N 0.000 title 1
- 239000004753 textile Substances 0.000 title 1
- 108010071289 Factor XIII Proteins 0.000 claims description 42
- 239000003106 tissue adhesive Substances 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 13
- 239000003242 anti bacterial agent Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 7
- 210000002381 plasma Anatomy 0.000 claims description 7
- 108090000190 Thrombin Proteins 0.000 claims description 6
- 229960004072 thrombin Drugs 0.000 claims description 6
- 229940122791 Plasmin inhibitor Drugs 0.000 claims description 5
- 102000010752 Plasminogen Inactivators Human genes 0.000 claims description 5
- 108010077971 Plasminogen Inactivators Proteins 0.000 claims description 5
- 239000007853 buffer solution Substances 0.000 claims description 5
- 239000002806 plasmin inhibitor Substances 0.000 claims description 5
- 239000002797 plasminogen activator inhibitor Substances 0.000 claims description 5
- 108010039627 Aprotinin Proteins 0.000 claims description 4
- 229960004405 aprotinin Drugs 0.000 claims description 4
- 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 4
- 239000004098 Tetracycline Substances 0.000 claims description 3
- 229940126575 aminoglycoside Drugs 0.000 claims description 3
- 210000003918 fraction a Anatomy 0.000 claims description 3
- 230000004048 modification Effects 0.000 claims description 3
- 238000012986 modification Methods 0.000 claims description 3
- 229920001184 polypeptide Polymers 0.000 claims description 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 229960002180 tetracycline Drugs 0.000 claims description 3
- 229930101283 tetracycline Natural products 0.000 claims description 3
- 235000019364 tetracycline Nutrition 0.000 claims description 3
- 150000003522 tetracyclines Chemical class 0.000 claims description 3
- 238000010257 thawing Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims description 2
- 229960000401 tranexamic acid Drugs 0.000 claims description 2
- 150000003952 β-lactams Chemical class 0.000 claims description 2
- 235000021120 animal protein Nutrition 0.000 claims 2
- 150000003951 lactams Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 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
- 238000004132 cross linking Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 239000001110 calcium chloride Substances 0.000 description 4
- 229910001628 calcium chloride Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960002449 glycine Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229940075469 tissue adhesives 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
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108010080865 Factor XII Proteins 0.000 description 1
- 102000000429 Factor XII Human genes 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
- 229930193140 Neomycin Natural products 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000004026 adhesive bonding Methods 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
- 230000008901 benefit Effects 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
- 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
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 238000002474 experimental method 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
- 239000003292 glue Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000023597 hemostasis Effects 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
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 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
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-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
459 848 Slutligen föreslås enligt PCT-ansökan BO/00083 att bereda en fibrinogen-antibiotikumgel, varvid en blandning som skall beredas vid sjukbädden av kryoprecipitat med tobramycin och gentamycin kommer till användning som antibiotikum. Finally, according to PCT application BO / 00083, it is proposed to prepare a fibrinogen antibiotic gel, wherein a mixture to be prepared in the sickbed of cryoprecipitate with tobramycin and gentamycin is used as antibiotic.
Efter egna försök kunde fastställas, att de beskrivna och förut kända vävnadslimmen, som innehåller fibrinogen, fak- tor XIII och ett antibiotikum, inte besitter den önskade kombinationen av egenskaper, nämligen en hög belastnings- förmåga för limningarna och en antimikrobiell verkan, utan att en negativ växelverkan inträder mellan antibiotika och faktorn XIII med den följd, att fibrinogenets förnätnings- förmåga starkt går tillbaka och att flytförmâgan påverkas i ogynnsam riktning. Beroende härpå erhålles en lägre häll- fasthet och vidhäftningsförmåga för limmet på sår- vävnadsytorna. resp En ytterligare nackdel vid de förut kända preparaten består i att avgivningen av antibiotikumet till vävnaden sker för snabbt, till så att retardationen av antibiotikumet inte räcker för att åstadkomma en verkan över längre tid och för uppnående av en hög material-avgivning. Ändamålet med uppfinningen är att eliminera dessa nackdelar och svårigheter och att åstadkomma ett vävnadslim med humant eller djurursprung, vilket uppfyller de ovan angivna kombina- tionsegenskaperna och garanterar en bättre verkan av anti- biotikumet.On their own experiments, it could be determined that the described and previously known tissue adhesives, which contain fibrinogen, factor XIII and an antibiotic, do not possess the desired combination of properties, namely a high loading capacity for the adhesions and an antimicrobial effect, without a A negative interaction occurs between antibiotics and factor XIII, with the result that the cross-linking ability of fibrinogen is greatly reduced and that the ability to float is affected in an unfavorable direction. Depending on this, a lower pour strength and adhesion is obtained for the adhesive on the wound tissue surfaces. A further disadvantage of the previously known preparations is that the delivery of the antibiotic to the tissue takes place too quickly, so that the retardation of the antibiotic is not sufficient to achieve an effect over a longer period of time and to achieve a high material release. The object of the invention is to eliminate these disadvantages and difficulties and to provide a tissue adhesive of human or animal origin, which fulfills the above-mentioned combination properties and guarantees a better effect of the antibiotic.
Den ställda uppgiften löses vid ett vävnadslim av det i _ inledningen definierade slaget genom att förhållandet av faktor XII till fibrinogen, uttryckt i enheter av faktor XIII per gram fibrinogen, uppgår till åtminstone S00 och att ett antibiotikum ur gruppen omfattande aminoglykosid, betalaktam, polypeptid och tetracyklin, ingår. 1459 848 Företrädesvis ingår vid ett djupfryst vävnadslim faktor XIII i en mängd av åtminstone 40 enheter/ml.The task is solved in the case of a tissue adhesive of the type defined in the introduction in that the ratio of factor XII to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, amounts to at least S00 and that an antibiotic from the group comprising aminoglycoside, beta-lactam, polypeptide and tetracycline, included. Preferably, in the case of a frozen tissue adhesive, factor XIII is present in an amount of at least 40 units / ml.
Enligt en andra utföringsform ingår vid ett lyofiliserat vävnadslim åtminstone 33 vikt-% fibrinogen, varvid faktor XIII föreligger i en mängd av åtminstone 170 enheter/g lyofilisat.According to a second embodiment, a lyophilized tissue adhesive contains at least 33% by weight of fibrinogen, factor XIII being present in an amount of at least 170 units / g of lyophilisate.
Lämpligen ingår dessutom en plasmin-inhibitor resp plasmino- gen-aktivator-inhibitor ur gruppen aprotinin, G,-antiplasmin, U2-makroglobulind ü1~antitrypsin, É-aminokapronsyra och tranEXaIflSyIä .Suitably, a plasmin inhibitor or plasminogen activator inhibitor is also included from the group aprotinin, G
Företrädesvis föreligger vävnadslimmet som tvåkomponentpre- parat, varvid i den första komponenten faktor XIII fibrino- gen och plasmin-inhibitorn resp plasminogen-aktivator-inhi- bitorn ingår, under det att vid den andra komponenten ingår antibiotikumet, trombin och tvåvärt kalcium.Preferably, the tissue adhesive is present as a two-component preparation, the first component including factor XIII fibrinogen and the plasmin inhibitor and plasminogen activator inhibitor, respectively, while the second component includes the antibiotic, thrombin and bivalent calcium.
Pöreträdesvis ingår antibiotikumet i form av ett svårlös- ligt derivat. En variant av denna utföringsform består i, att förutom det svârlösliga derivatet också användes ett lättlösligt sådant, eventuellt fördelat i vävnadslimmets båda komponenter. Denna utföringsform har den fördelen, att det lättlösliga derivatet avges snabbt och säkerställer en hög initialverkan, under det att det svårlösliga deriva- tet grundlägger en långvarig verkan.Preferably, the antibiotic is included in the form of a sparingly soluble derivative. A variant of this embodiment consists in that, in addition to the sparingly soluble derivative, an easily soluble one is also used, possibly distributed in both components of the tissue adhesive. This embodiment has the advantage that the readily soluble derivative is released quickly and ensures a high initial effect, while the sparingly soluble derivative establishes a long-lasting effect.
Uppfinningen omfattar dessutom ett förfarande för framställ- ning av vävnadslimmet, varvid en modifikation består i att i en fibrinogenhaltig blodplasmafraktion inställes ett kon- centrationsförhållande av faktor XIII till fibrinogen, ut- tryckt i enheter av faktor XIII per gram fibrinogen, på åtminstone 500 genom tillsats av faktor XIII, varpå anti- biotikumet tillföras och preparatet djupfryses eller lyo- filiseras. 459 Enligt en andra modifikation inställes i 848 r en fibrinogen- haltig blodplasmafraktion ett koncentrationsförhâllande av faktor XIII till fibrinogen, uttryckt i enheter av faktor XIII per gram fíbrinogen, på minst 500 genom till- sats av faktor XIII, varpå preparatet djupfryses eller lyofiliseras och efter upptining resp rekonstitution före- nas med en antibiotikumhaltig lösning. Vid denna utförings- form kan antibiotikumet tillsättas efter upptiningen eller tillföras rekonstitutionslösningen. Vid denna utföringsform skall emellertid beaktas att en minsta koncentration av faktor XIII icke underskrides, 40 enheter/ml. utan denna skall ligga över Enligt en föredragen utföringsform, vid vilken den fibrino- genhaltiga blodplasmafraktionen tvättas med en buffertlös- ning, genomföres tvättprocessen till uppnående av en faktor XIII-koncentration på 200 enheter faktor XIII per gram fib- rinogen, varpå faktor XIII tillföres i en mängd av åtminstone 300 enheter per gram fibrínogen i form av ett koncentrat eller lyofilisat.The invention further comprises a process for the preparation of the tissue adhesive, wherein a modification consists in setting in a fibrinogen-containing blood plasma fraction a concentration ratio of factor XIII to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, of at least 500 by addition of factor XIII, after which the antibiotic is added and the preparation is deep-frozen or lyophilized. 459 According to a second modification, in 848 r a fibrinogen-containing blood plasma fraction, a concentration ratio of factor XIII to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, is adjusted to at least 500 by the addition of factor XIII, thawing or reconstitution is combined with an antibiotic-containing solution. In this embodiment, the antibiotic can be added after thawing or added to the reconstitution solution. In this embodiment, however, it should be noted that a minimum concentration of factor XIII is not exceeded, 40 units / ml. According to a preferred embodiment, in which the fibrinogen-containing blood plasma fraction is washed with a buffer solution, the washing process is carried out to achieve a factor XIII concentration of 200 units of factor XIII per gram of fibrinogen, whereupon factor XIII is added in an amount of at least 300 units per gram of fibrinogen in the form of a concentrate or lyophilisate.
Vävnadslimmet enligt uppfinningen respektive förfarandet för dess framställning beskrives närmare i de efterföljande exemplen.The tissue adhesive according to the invention and the method for its preparation are described in more detail in the following examples.
Exempel 1 Av human infrusen färsk plasma utvanns genom uppvärmning till 2°C kryoprecipitat (100 g), avseparerades genom centri- fugering och tvättades i en buffertlösning, innehållande Na3-citrat, NaCl, glycin, glykos, aprotinin och heparin, tvâ gånger vid ett pH-värde av 6,5 och den avseparerade fällningen upplöstes i en glycinhaltig buffertlösning (255 ml) vid ett pH-värde av 7,9. Det fastställdes att i denna lösning förelåg ett förhållande av faktor XIII till fibrino- gen på 226 enheter faktor XIII/g fibrinogen. För inställ- 459 848 ningen av det enligt uppfinningen eftersträvade förhållan- det på mer än 500 E/g fibrinogen tillsattes till lösningen ett faktor XIII-preparat i pulverform med 9000 enheter, vari- genom koncentrationsförhâllandet i lösningen förstärkts till 826 enheter faktor XIII/g fibrinogen. Denna lösning steril- filtrerades, varefter tillsattes 1,7 g gentamycin under sterila betingelser, varefter blandningen påfylldes i en slutbehållare (2,5 ml), djupfrystes och lyofiliserades.Example 1 Cryoprecipitate (100 g) was recovered from human-frozen fresh plasma by heating to 2 ° C, separated by centrifugation and washed in a buffer solution containing Na3 citrate, NaCl, glycine, glucose, aprotinin and heparin, twice 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 there was a ratio of factor XIII to the fibrinogen of 226 units of factor XIII / g fibrinogen. To adjust the desired ratio of more than 500 U / g fibrinogen to the solution, a factor XIII preparation in powder form with 9000 units was added to the solution, whereby the concentration ratio in the solution was strengthened to 826 units factor XIII / g fibrinogen. This solution was sterile filtered, then 1.7 g of gentamycin was added under sterile conditions, after which the mixture was filled into a final container (2.5 ml), frozen and lyophilized.
Exemgel 2 Framställning av vävnadslimbasen av kryoprecipitat genom- fördes på samma sätt som i exempel 1, men med den skillna- den, att efter en tvättning av kryoprecipitatfällningen denna gjordes flytande genom värmning till 37°C och 13600 enheter faktor XIII i pulverform tillsattes. Därvid erhölls ett förhållande av faktor XIII till fibrinogen av 967 faktor XIII-enheter/g fibrinogen.Example 2 Preparation of the tissue adhesive base of cryoprecipitate was carried out in the same manner as in Example 1, but with the difference that after washing the cryoprecipitate precipitate it was liquefied by heating to 37 ° C and 13600 units of factor XIII in powder form were added. Thereby a ratio of factor XIII to fibrinogen of 967 factor XIII units / g fibrinogen was obtained.
Lösningen tillfördes antibiotikum i form av 5,67 g 7-ÅTtienyl)- -(2)-acetamidg7-cefalosporansyra. Den så erhållna suspensio- nen fylldes i slutbehállare (1 ml) och djupfrystes. Faktor XIII ingår i det påfyllda preparatet i en mängd av 8,7 E/ml.To the solution was added antibiotic in the form of 5.67 g of 7-α-thienyl) - - (2) -acetamide 77-cephalosporanic acid. The suspension thus obtained was filled into a final container (1 ml) and deep-frozen. Factor XIII is included in the refilled preparation in an amount of 8.7 U / ml.
Applikationen av det enligt exemplen 1 och 2 framställda vävnadslimmet sker företrädesvis därigenom att den upptinade respektive rekonstituerade blandningen blandas med trombin och kalciumklorid och påföres vävnaden som skall förbindas.The application of the tissue adhesive prepared according to Examples 1 and 2 preferably takes place by mixing the thawed and reconstituted mixture with thrombin and calcium chloride and applying it to the tissue to be bonded.
Det är också möjligt att pâföra de båda komponenterna åt- skilt på vävnaden som skall förbindas eller fyllas ut.It is also possible to apply the two components separately to the tissue to be connected or filled in.
Exemgel 3 Förfarandet enligt exempel 1 upprepades fram till tillsatsen av antibiotikum. Den tvättade fällningen sterilfiltrerades efter upplösning i buffertlösning, pâfylldes i slutbehållare (2,5 ml), djupfrystes och lyofiliserades, varmed den första 459 848 komponenten av vävnadslimmaterialet enligt uppfinningen gjorts lagringsbar. Den andra komponenten bereddes före applikationen av en lösning av trombin och kalciumklorid genom tillsats av 7-Åítienyl)-(2)-acetamid97-cefalosporan- syra (30 mg/ml).Example gel 3 The procedure of Example 1 was repeated until the addition of antibiotic. The washed precipitate was sterile filtered after dissolution in buffer solution, filled into final containers (2.5 ml), deep-frozen and lyophilized, thereby making the first 459,848 component of the tissue adhesive material of the invention storable. The second component was prepared before the application of a solution of thrombin and calcium chloride by the addition of 7-acetyl) - (2) -acetamide97-cephalosporanic acid (30 mg / ml).
Exempel 4 Förfarandet enligt exempel 2 upprepades, varvid efter upp- lösning av kryoprecipitatfällningen gentamycin (1,89 g) tillsattes, lösningen_pâfylldes i slutbehâllare (1 ml) och djupfrystes. Därmed föreligger den första komponenten av limmet enligt uppfinningen i lagringsbar form. Den andra komponenten innehållande 30 mg 7-Lïtienyl)-(2)-acetamidg7- cefalosporansyra per ml av en kalciumklorid-trombinlösning bereddes före applikationen.Example 4 The procedure of Example 2 was repeated, whereupon after dissolving the cryoprecipitate precipitate gentamycin (1.89 g) was added, the solution was filled into a final container (1 ml) and frozen. Thus, the first component of the adhesive according to the invention is in storable form. The second component containing 30 mg of 7-Litienyl) - (2) -acetamide g7- cephalosporanic acid per ml of a calcium chloride thrombin solution was prepared before application.
I stället för det enligt exemplen 1 till 4 tillförda aproti- ninet kan som plasmin-inhibitor resp plasminogen-aktivator inhibitor användas en eller flera av följande föreningarz- 42-antiplasmin,'dz-makroglobulin, dï-antitrypsin, 2-amino- kapronsyra och tranexamsyra.Instead of the aprotinin supplied according to Examples 1 to 4, one or more of the following compounds z-42-antiplasmin,'dz-macroglobulin, dï-antitrypsin, 2-amino-caproic acid and tranexamic acid.
Det enligt uppfinningen framställda vävnadslimmet besitter en generell användbarhet för trådlös förbindning av mänsk- lig eller djurvävnad eller organdelar för sårvård och blod- stillande med väsentligt förbättrad antimikrobiell verkan.The tissue adhesive produced according to the invention possesses a general utility for wireless connection of human or animal tissue or organ parts for wound care and hemostasis with significantly improved antimicrobial action.
De förbättrade limningsegenskaperna vid på samma sätt för- bättrad antimikrobiell verkan hos vävnadslimmet enligt upp- finningen framgâr av de följande i tabellform sammanfattade jämförelseexemplen. Härvid har jämförts förnätningsgraden hos vävnadslimmaterial enligt uppfinningen med förhöjt faktor XIII-fibrinogen-förhållande med förnätningsgraden hos kända vävnadslim utan förhöjt faktor XIII-fibrinogen- förhållande, varje gång med användning av olika antibiotika. 459 848 }X-förnätningsgraden bestämmes enligt natriumlaurylsulfat- (SDS)-polyakrylamid-gelelektroforesmetoden, som genomföras på så sätt att efter blandningen av vävnadslimmet med lika volym av en lösning innehållande 40 pmol kalciumklorid och 15 NIH-enheter (US National Institute of Healthlenheter) trombin per ml, blandningen inkuberas vid 37°C.(1-förnät- ningsgraden bestämmes efter reaktionens slut och reduktiv spaltning av de i proteinerna ingående disulfidbryggorna genom tillsats av en blandning av urinämne, natriumdodecyl- sulfat och.ß-merkaptoetanol medelst gelelektrofores.The improved gluing properties with a similarly improved antimicrobial effect of the tissue adhesive according to the invention appear from the following comparative examples summarized in tabular form. The degree of crosslinking of tissue adhesive materials according to the invention with elevated factor XIII-fibrinogen ratio has been compared with the degree of crosslinking of known tissue adhesives without elevated factor XIII-fibrinogen ratio, each time using different antibiotics. The degree of crosslinking is determined according to the sodium lauryl sulfate (SDS) polyacrylamide gel electrophoresis method, which is carried out so that after mixing the equal volume of tissue adhesive of a solution containing 40 pmol of calcium chloride and 15 NIHs (US National Institute of Health units) thrombin per ml, the mixture is incubated at 37 ° C. (The degree of crosslinking is determined after the end of the reaction and reductive cleavage of the disulfide bridges contained in the proteins by adding a mixture of urea, sodium dodecyl sulfate and .beta.-mercaptoethanol by gel electrophoresis.
I nästa del av tabellen jämföres propphàllfastheten i thrombelastograf för ett vävnadslimmaterial enligt upp- finningen med ett förut känt vävnadslim, varvid gentamycin användes som antibiotikum.In the next part of the table, the plug strength in thrombelastograph for a tissue adhesive material according to the invention is compared with a prior art tissue adhesive, where gentamycin is used as an antibiotic.
Slutligen innehåller tabellen jämförande värden på rivhåll- fastheten för ett vävnadslimmaterial enligt uppfinningen jämfört med ett förut känt, vid användning av gentamycin som antibiotikum.Finally, the table contains comparative values of the tear strength of a tissue adhesive material according to the invention compared to a prior art, when using gentamycin as an antibiotic.
Pibrin-ol-förnäfning (vid 37°c efter so minuter) Antibiotikum- Vävnadslim enligt upp- Vävnadslim utan tillsats finningen med förhöjt förhöjt faktor faktor XIII-innehåll XIII-innehåll >500 E/g fibrinogen Gentamycin 70 % 30 % Neomycin 41 % 21 % Fosfomycin 47 % 24 % Azlocillin 66 % 42 % Doxycyclin 65 % 26 % Cefoxitin 54 % 44 % 459 848 Propphâllfasthet i trombelastografen (37°C - 60 minuter) 2=elasticitetsmodul ____________________ Antibiotikum- Vävnadslim enligt upp- Vävnadslim utan tillsats finningen med förhöjt förhöjt faktor faktor XIII-innehåll XIII-innehåll )>500 E/g fibrinogen Gentamycin 1150 426 Rivhållfasthet 1 g/cmz (37°c - 30 minuter) Gentamycin 1283 999 Slutligen genømfördes ett jämförande exempel med avseende på antibiotika-avgången ur ett enligt exempel 4 framställt vävnadslim, varvid i ett in vitro-försök efter 72 timmar redan 85 % av gentamycinet avgivits från ett med detta lim framställd propp. Efter 96 timmar kunde inte längre iakt- tagas någon avgång av gentamycin, under det att 7-¿Itienyl)- -(2)-acetamidg7-cefalosporansyra fortfarande kunde påvisas efter 8 dagar.Pibrin-ol-naming (at 37 ° C after so minutes) Antibiotic- Tissue glue according to up- Tissue glue without additive finding with increased elevated factor factor XIII content XIII content> 500 U / g fibrinogen Gentamycin 70% 30% Neomycin 41% 21 % Phosphomycin 47% 24% Azlocillin 66% 42% Doxycycline 65% 26% Cefoxitin 54% 44% 459 848 Plug resistance in the thrombelastograph (37 ° C - 60 minutes) 2 = modulus of elasticity ____________________ Antibiotic- Tissue glue according to up- elevated factor factor XIII content XIII content)> 500 U / g fibrinogen Gentamycin 1150 426 Tear strength 1 g / cm 2 (37 ° c - 30 minutes) Gentamycin 1283 999 Finally, a comparative example was carried out with respect to the antibiotic release from an example 4, in an in vitro test after 72 hours already 85% of the gentamycin has been released from a plug made with this glue. After 96 hours, no release of gentamycin could be observed, while 7-β-Thienyl) - - (2) -acetamide g7-cephalosporanic acid could still be detected after 8 days.
Claims (9)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0333781A AT369990B (en) | 1981-07-28 | 1981-07-28 | METHOD FOR PRODUCING A TISSUE ADHESIVE |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| SE8204064D0 SE8204064D0 (en) | 1982-07-01 |
| SE8204064L SE8204064L (en) | 1983-01-29 |
| SE459848B true SE459848B (en) | 1989-08-14 |
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ID=3548998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| SE8204064A SE459848B (en) | 1981-07-28 | 1982-07-01 | TEXTILE FILM CONTAINING FACTOR XIII, THE FIBRINOGEN AND ANTIBIOTIC, AND SUCH BEFORE ITS PREPARATION |
Country Status (14)
| 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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| JPH06102628B2 (en) * | 1984-03-27 | 1994-12-14 | イムノ・アクチエンゲゼルシャフト | Tissue adhesive manufacturing method |
| 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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| AT359653B (en) * | 1979-02-15 | 1980-11-25 | Immuno Ag | METHOD FOR PRODUCING A TISSUE ADHESIVE |
| AT359652B (en) * | 1979-02-15 | 1980-11-25 | Immuno Ag | METHOD FOR PRODUCING A TISSUE ADHESIVE |
| JPS56501129A (en) * | 1979-08-31 | 1981-08-13 |
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1981
- 1981-07-28 AT AT0333781A patent/AT369990B/en not_active IP Right Cessation
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1982
- 1982-07-01 SE SE8204064A patent/SE459848B/en not_active IP Right Cessation
- 1982-07-05 DE DE19823225102 patent/DE3225102A1/en active Granted
- 1982-07-05 DK DK300682A patent/DK157977C/en active
- 1982-07-05 CH CH409482A patent/CH659187B/de unknown
- 1982-07-06 GB GB08219500A patent/GB2102811B/en not_active Expired
- 1982-07-13 CA CA000407154A patent/CA1168982A/en not_active Expired
- 1982-07-16 BE BE0/208601A patent/BE893851A/en not_active IP Right Cessation
- 1982-07-21 AR AR290039A patent/AR227252A1/en active
- 1982-07-22 JP JP57126829A patent/JPH0696039B2/en not_active Expired - Lifetime
- 1982-07-23 NL NL8202982A patent/NL192665C/en not_active IP Right Cessation
- 1982-07-23 FR FR8212918A patent/FR2510408B1/en not_active Expired
- 1982-07-27 IT IT22595/82A patent/IT1157313B/en active
- 1982-07-27 ES ES514441A patent/ES514441A0/en active Granted
Also Published As
| Publication number | Publication date |
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| DE3225102A1 (en) | 1983-02-17 |
| 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 |
| DK157977B (en) | 1990-03-12 |
| 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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