WO1999011301A1 - Gewebekleber auf basis von fibrinogen - Google Patents
Gewebekleber auf basis von fibrinogen Download PDFInfo
- Publication number
- WO1999011301A1 WO1999011301A1 PCT/AT1998/000202 AT9800202W WO9911301A1 WO 1999011301 A1 WO1999011301 A1 WO 1999011301A1 AT 9800202 W AT9800202 W AT 9800202W WO 9911301 A1 WO9911301 A1 WO 9911301A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tissue adhesive
- adhesive according
- tissue
- fibrinogen
- inhibitor
- Prior art date
Links
- 239000003106 tissue adhesive Substances 0.000 title claims abstract description 92
- 108010049003 Fibrinogen Proteins 0.000 title claims abstract description 34
- 102000008946 Fibrinogen Human genes 0.000 title claims abstract description 34
- 229940012952 fibrinogen Drugs 0.000 title claims abstract description 34
- 239000003602 elastase inhibitor Substances 0.000 claims abstract description 30
- 229940122858 Elastase inhibitor Drugs 0.000 claims abstract description 22
- 230000009089 cytolysis Effects 0.000 claims description 22
- 108010039627 Aprotinin Proteins 0.000 claims description 21
- 230000003480 fibrinolytic effect Effects 0.000 claims description 21
- 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 21
- 229960004405 aprotinin Drugs 0.000 claims description 20
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- MDCUNMLZLNGCQA-HWOAGHQOSA-N elafin Chemical compound N([C@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H]1C(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H]2CSSC[C@H]3C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N[C@@H](CSSC[C@H]4C(=O)N5CCC[C@H]5C(=O)NCC(=O)N[C@H](C(N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H]5N(CCC5)C(=O)[C@H]5N(CCC5)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)[C@H](C)NC2=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N4)C(=O)N[C@@H](CSSC1)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N3)=O)[C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)C(C)C)C(C)C)C(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)N MDCUNMLZLNGCQA-HWOAGHQOSA-N 0.000 claims description 2
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- 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
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- 108010067372 Pancreatic elastase Proteins 0.000 description 5
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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
Definitions
- the invention relates to a tissue adhesive based on fibrinogen.
- Tissue glue based on fibrinogen which is also known as fibrin glue, imitates the last phase of blood coagulation in its adhesive effect.
- Fibrinogen is broken down into fibrin monomers by the action of thrombin, which is usually added to the fibrinogen solution during the gluing process, but is also present in every wound.
- the fibrin monomers spontaneously assemble into ordered fibrous structures called fibrin.
- This fibrin monomer aggregate is then further stabilized under the influence of factor XHIa by covalent cross-links. Peptide bonds form between specific glutamine and lysine side chains of the fibrin monomers in a transamidation reaction.
- the factor XHIa which is also cleaved by thrombin from inactive factor XIII, is an active transamidase and is also referred to as a "fibrin-stabilizing factor" due to its action.
- tissue to be treated or the organ is not additionally damaged by a sewing process, which is why when using tissue glue based on fibrinogen, there are far fewer complications and less noticeable scars than on conventional surgical sutures.
- tissue adhesives which includes a high resilience and a high internal strength of the bonds as well as good adhesion of the adhesive to the wound or tissue areas
- the processes following the direct bond are also essential for the optimization of tissue adhesives (see AT-B -359 652 and 359 653). This includes the control and monitoring of the durability of the bonds in the body as well as the absorbability and the wound healing properties of the adhesive.
- tissue glue not only is the fast and safe adhesive effect of crucial importance, but also that the adhesive or blood clot formed dissolves in the body again within a definable period of time and the wound is perfect again as a result of the complete absorption of the clot formed heals.
- the fibrin present in the resulting blood clot is broken down or removed, thereby dissolving the blood clot.
- intrinsic or extrinsic plasminogen activators such as blood coagulation factors XI and XII, precallikrein, urokinase or t-PA
- the inactive plasminogen is used to form the fibrinolytically active plasmin, which in addition to fibrin, fibrinogen and the blood coagulation factors V and VIII splits.
- tissue adhesive Piasmininhibitors or a plasminogen activator inhibitor to directly or indirectly inhibit the action of plasmin and so, especially in the initial phase of the adhesive, to prevent it from premature fibrinolysis.
- concentration of the inhibitor the dissolution times (lysis times) of the clot or the adhesive formed can also be controlled in a targeted manner. The more inhibitor is provided, the more stable the clot is against fibrinolysis, the longer this clot remains stable and the longer it takes until the adhesive is completely absorbed.
- Aprotinin which is also referred to as a bovine basic pancreatic trypsin inhibitor, is used as the piasmin inhibitor in the commercially available tissue adhesives.
- Aprotinin is a polyvalent proteinase (kallikrein) inhibitor and inhibits the coagulation factors Xlla, XIa, Villa and above all. Plasmin and piasmin activators, but also trypsin, chymotrypsin and kallikrein.
- Aprotinin was previously mainly made from cattle. Due to the problems associated with the use of bovine material in pharmaceuticals that are used to treat humans, however, recombinantly produced aprotinin is being used more and more.
- Aprotinin is usually used in tissue bonding in an amount of 20-3000 kallikrein inactivator units (KIE) / ml tissue adhesive, the optimal concentration depending on the fibrinolytic activity of the respective tissue.
- KIE kallikrein inactivator units
- the object of the present invention is therefore to provide a tissue adhesive with which the disadvantages in the prior art are overcome, and with which v.a. satisfactory and reliable protection against premature fibrinolysis is ensured in the case of tissue adhesion in wounds with high piasmin activity, the quality of the adhesion must not be impaired.
- tissue adhesive based on fibrinogen which is characterized in that it contains an added elastase inhibitor.
- fibrinolysis process can be prevented not only by inhibiting plasmin or the inhibition of the activation of plasminogen to plasmin, but also by elastase inhibitors or by inhibitors whose fibrinolysis-inhibitory activity predominantly affects is based on a non-plasmin fibrinolysis mechanism.
- non-plasminogen fibrinolysis inhibitors are, for the sake of simplicity, placed under the term "elastase inhibitor".
- inhibitors which have no (essential) plasmin or plasminogen activator-inhibiting effects that is to say the elastase inhibitors according to the invention in fibrin adhesives both in in vitro and in vivo can ensure a very well controllable lysis process of the clot formed.
- This turned out to be particularly advantageous in tissues with increased fibrinolytic activity, in which they can prevent early lysis even at moderate concentrations.
- Premature lysis plays a role in tissues with high fibrinolytic activity. also play a role within the first time after the bond, since premature lysis can lead to a (partial) detachment of the bond and thus to a new bleeding process ("rebleeding").
- the elastase inhibitor to be used in the tissue adhesive according to the invention not only had the fibrinolytic effect in combination with conventional inhibitors which act on plasmin, but also that the entire fibrinolytic inhibition can be ensured by the elastase inhibitor alone.
- a special embodiment of the present invention therefore consists in that the tissue adhesive contains no further active components apart from fibrinogen, the elastase inhibitor and, if appropriate, factor XIII.
- the fibrinogen concentration in the present adhesive corresponds to the known tissue adhesive and should generally be at least over 50 mg, in particular over 70-80 mg fibrinogen / ml, i.e. at least about 20 times the fibrinogen concentration in blood (2-4 mg / ml) .
- the fibrinogen is preferably in a form which is further purified compared to cryoprecipitate.
- preferred elastase inhibitors are selected from the group eglin, elastase-c ... proteinase inhibitor, ⁇ 1 -antiprotease, elafin, leukocyte protease inhibitor, in particular a leukocyte fraction, preferably a fraction derived from granulocytes , or human secretory leukoprotease inhibitor, or mixtures thereof.
- leukocyte protease inhibitor in particular a leukocyte fraction, preferably a fraction derived from granulocytes , or human secretory leukoprotease inhibitor, or mixtures thereof.
- a cell lysate in particular one derived from human cells, can be used as the leukocyte fraction.
- Additional elastase or other fibrinolysis inhibitors which do not act on plasmin can be carried out in a simple manner by the person skilled in the art the test systems disclosed in the examples are examined with regard to their suitability in the tissue adhesive according to the invention or using the elastase inhibition tests known from the prior art.
- the preferred elastase inhibitors also include various derivatives of the elastase inhibitors according to the invention, for example fragments or forms of these inhibitors modified chemically or by (recombinant) protein design, although these derivatives must of course always have the qualitative elastase inhibitor property of the basic inhibitor .
- the tissue adhesive according to the invention preferably consists exclusively of human proteins, whereby "human proteins” also include the recombinantly produced human proteins.
- the proteins used in the tissue adhesive are therefore preferably produced either from blood, plasma, cryoprecipitate or from a recombinant cell culture.
- a particularly preferred tissue adhesive is characterized in that it is composed exclusively of human blood or plasma proteins.
- the ratio of elastase inhibitor to mg of fibrinogen is preferably from 1: 100 to 1: 150 000, preferably 1: 500 to 1: 110 000.
- inhibitor to g of fibrinogen tissue adhesive preferably at least 10 "6 E / g of fibrinogen added A range between 10 "3 and 10 U / g fibrinogen is particularly preferred.
- the amount of inhibitor added in the tissue adhesive according to the invention, which inhibitor can also be naturally present in blood or plasma, is preferably at least 20x, in particular at least 50x higher than its physiological concentration in blood or plasma.
- the tissue adhesive according to the invention can be composed, for example, as follows: 75-115 mg / ml clottable protein, thereof 50-110 mg / ml, preferably 70-110 mg / ml fibrinogen; optionally 1-50, preferably 10-50 IU factor XHI / ml.
- Eglin for example, can be added as an inhibitor in an amount between 1-100 ⁇ g / ml or ot 1 -antiprotease with 0.01-1 U / ml. As a rule, it is sufficient to use the elastase inhibitor in one quantity add which corresponds to the fibrinolysis-inhibiting effect of aprotinin in known tissue adhesives.
- the adhesive according to the invention can contain plasminogen or be free of plasminogen. If plasminogen is included, it should be present in an amount of at least 0.0001 mg / mg fibrinogen, preferably more than 0.001, especially more than 0.01. With the presence of plasminogen in the tissue glue, due to its activation to plasmin, there is also a possibility to define the fibrinolysis properties of the tissue glue even more clearly.
- the tissue adhesive contains no plasminogen at all or only in a small amount.
- a plasmin inhibitor or a plasmin activator inhibitor is also preferably used, which likewise contributes to better control of the lysis of absorption and thus wound healing.
- Preferred plasmin inhibitors or plasminogen activator inhibitors are mainly aprotinin, but also ⁇ . -Macroglobulin, ⁇ ... -antitrypsin, ⁇ -amino-caproic acid, tranexamic acid or mixtures of these substances.
- plasmin or plasminogen activators are regarded as plasmin or plasminogen activators, since this is the primary activity that these substances have in the present field.
- Anti-adhesive additives for example hyaluronic acid, may also be present.
- tissue adhesive according to the invention consists in providing an antibiotic in the adhesive, as has already been proposed in AT-B-369 990.
- antibiotics are selected from the Group of aminoglycosides, beta-lactams, polypeptides, fosfomycin, tetracyclines or mixtures thereof.
- the antibiotic is in the form of a poorly soluble derivative.
- Factor XIII is preferably also provided in the tissue adhesive according to the invention, so that the internal strength of the clot and the strength and durability of the adhesive are positively influenced.
- Factor XIII is preferably used in an amount of 1-50 units / ml, preferably around 10 U / ml.
- factor XIII is preferably present in a minimum concentration of 0.001 U / mg fibrinogen, in particular at least 0.1 U / mg fibrinogen.
- the optimal factor XIII concentration can easily be optimized by any specialist. If an antibiotic is present in the tissue adhesive, it is generally advisable to provide a little more factor XIII (cf. AT-B-369 990).
- the tissue adhesive according to the invention is preferably free of kininogenic proteins (such as, for example, kallikrein, etc.), as a result of which disruptive side reactions can be prevented from the outset.
- kininogenic proteins such as, for example, kallikrein, etc.
- the tissue adhesive according to the invention is presented as a nonwoven in combination with a solid surface, with which, above all, optimal wound closure and coverage is achieved for large-area wounds.
- a solid surface with which, above all, optimal wound closure and coverage is achieved for large-area wounds.
- nonwovens are mentioned in AT-B 374 367.
- the solid surface of the nonwoven is therefore preferably a collagen, gelatin or a polysaccharide surface, although other medically suitable surfaces, which may also be impregnated for the specific purpose, can be used.
- the tissue adhesive containing an elastase inhibitor can achieve resistance to lysis even in a milieu with high fibrinolytic activity for a period of at least 10 hours, preferably 15 hours.
- Lysis-resistant means according to the present invention that a corresponding fibrin clot within of a certain period of time is not mined, so it remains.
- the resistance to lysis is determined, for example, by a photometric measurement as a function of time.
- a preferred tissue adhesive according to the present invention therefore has a resistance to lysis of at least 10 hours, preferably at least 15 hours, in an environment of high fibrinolytic activity.
- “High fibrinolytic activity” means, for example, a piasmin activity that is above the physiological plasmin potential.
- the fibrinolytic potential can be expressed, for example, by the plasminogen concentration (see, for example, Henriksson et al., Thrombosis Research 16: 301-312; 1979). This property of the resistance to lysis can be determined by any person skilled in the art by a simple test, as described in the examples , be checked.
- the tissue adhesive according to the invention When applied, the tissue adhesive according to the invention is preferably in solution, but storage is recommended either by freezing the solution so that the tissue adhesive according to the invention is in deep-frozen form, or by lyophilizing the adhesive, that is to say providing it in lyophilized form.
- "Lyophilized form” is understood, of course, only to mean a tissue adhesive preparation which has been preserved by freeze drying and which can be reconstituted almost completely (i.e. at least 80%) within a few minutes at 37 ° C after subsequent reconstitution.
- the adhesive according to the invention is advantageously in virus-inactivated form.
- This inactivation treatment is preferably ensured with a tenside and / or heat treatment, for example by a heat treatment in the solid state, in particular a steam treatment according to EP-0 159 311, or EP-0 519 901 or EP-0 674 531.
- Further treatments for inactivating viruses also include treatment with chemical or chemical / physical methods, for example with chaotropic substances according to WO94 / 13329, DE 44 34 538 or EP-0 131 740 (solvents) or Photo inactivation.
- Nanofiltration is also a preferred method for depleting viruses in the context of the present invention.
- the elastase inhibitors added according to the invention can also be of recombinant origin.
- the present invention further relates to a tissue adhesive system which, as a component, comprises a tissue adhesive according to the invention containing an elastase inhibitor.
- the tissue adhesive system according to the invention generally contains, as a further component, a thrombin component, in which thrombin is present either in liquid form or as a reconstitutable lyophilizate, the thrombin component being able to be concentrated differently depending on the field of use in the use of adhesive.
- a tissue adhesive system which also falls under the present invention is characterized in that it comprises a fibrinogen component and a component separate therefrom which contains an elastase inhibitor.
- a fibrinogen component As a rule, however, it is favorable to provide the fibrinolysis inhibitor component in the fibrinogen component (see AT-B-359 652 and 359 653).
- the inhibitor component can also be supplied separately from the fibrinogen component.
- the component which contains an elastase inhibitor preferably also contains thrombin at the same time, it being possible for this component to be made available either as a lyophilisate or as a (possibly deep-frozen) solution.
- the tissue adhesive systems according to the invention further comprise suitable application devices for the system component (s).
- Double syringe systems as described in EP 0 037 393, EP 0 210 160 or EP 0 292 472, or application devices as described in EP 0 315 322 or EP 0 669 100, have proven particularly useful.
- the embodiment in which the inhibitor is applied in the thrombin component can also deliver reliable adhesive results.
- the present invention therefore also relates to the use of the tissue adhesive according to the invention or a tissue adhesive system according to the invention for producing a preparation or an application device for use in areas with high fibrinolytic activity, in particular in urology.
- the present invention furthermore relates to a method for using a tissue adhesive according to the invention or a tissue adhesive system according to the invention in surgery in areas with high fibrinolytic activity, in particular in urology.
- Fig. 1 the decrease in absorbance corresponding to an increasing lysis of the clot
- Fibrin glue without aprotinin b) Fibrin glue with aprotinin (1000 U / ml) c) Fibrin glue with Alphal-PI (0.01 U / ml) d) Fibrin glue with Alphal-PI (0.001 U / ml) e) Fibrin glue with Alphal- PI (0.0001 U / ml);
- the blockade of the lysis of a tissue adhesive clot using Eglin or a 1 -antiprotease is shown.
- the STIM3 tissue adhesive (IMMUNO AG, Vienna, AT) (containing 70 mg fibrinogen / ml) is dissolved in water and then diluted 1: 6 with a 0.9 M NaCl solution.
- This tissue adhesive solution is mixed in a ratio of 1: 1 with a thrombin solution diluted in 40 mM CaCl 2 and then with a 40 mM CaCl 2 / 0.9 M NaCl (1: 5) solution and pipetted onto a microplate, 100 ⁇ l / well being provided.
- the microplate was incubated at 37 ° C for about 1.5 hours to harden the adhesive.
- the corresponding lysis reagents (a: cell-free supernatant from leukocyte homogenate (3x freezing / thawing) of 500,000 leukocytes / ⁇ l; b: t-PA 2 mg / ml as a positive control; NaCl 0.9% as a negative control) were then pipetted onto the clot (100 ⁇ l / well).
- the microtiter wells were then measured kinetically overnight at 37 ° C. at a wavelength of 405 nm at 60x900 s in the SLT 340 ATTC photometer. The results are shown in FIGS. 1 and 2. - From posed, the decrease in absorbance corresponding to the increasing lysis of the clot.
- both the effect of the adhesive according to the invention in hyperfibrinolytic systems and also with normal fibrinolytic activity and with adhesives without inhibitors were tested to illustrate hemostasis using tissue adhesive or compared with an adhesive that only contains aprotinin as a plasmin inhibitor.
- tissue glue STIM3 without aprotinin with eglin (10 ⁇ g / ml); adhesive according to the invention
Abstract
Description
Claims
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL13472898A IL134728A0 (en) | 1997-08-28 | 1998-08-26 | Fibrinogen-based tissue adhesive |
AU89637/98A AU743181B2 (en) | 1997-08-28 | 1998-08-26 | Fibrinogen-based tissue adhesive |
AT98941134T ATE235269T1 (de) | 1997-08-28 | 1998-08-26 | Gewebekleber auf basis von fibrinogen |
EP98941134A EP1007109B1 (de) | 1997-08-28 | 1998-08-26 | Gewebekleber auf basis von fibrinogen |
SK256-2000A SK2562000A3 (en) | 1997-08-28 | 1998-08-26 | Fibrinogen-based tissue adhesive |
US09/486,516 US7091015B1 (en) | 1997-08-28 | 1998-08-26 | Fibrinogen-based tissue adhesive |
DK98941134T DK1007109T3 (da) | 1997-08-28 | 1998-08-26 | Vævsklæber på basis af fibrinogen |
CA002302224A CA2302224C (en) | 1997-08-28 | 1998-08-26 | Fibrinogen-based tissue adhesive |
JP2000508402A JP4932082B2 (ja) | 1997-08-28 | 1998-08-26 | フィブリノーゲンに基づく組織接着剤 |
HU0104043A HUP0104043A3 (en) | 1997-08-28 | 1998-08-26 | Fibrinogen-based tissue adhesive |
DE59807667T DE59807667D1 (de) | 1997-08-28 | 1998-08-26 | Gewebekleber auf basis von fibrinogen |
IL134728A IL134728A (en) | 1997-08-28 | 2000-02-24 | Fibrinogen-based tissue adhesive containing an admixed elastase inhibitor |
NO20000921A NO20000921L (no) | 1997-08-28 | 2000-02-24 | Fibrinogenbasert vevklebemiddel |
HR20000100A HRP20000100B1 (en) | 1997-08-28 | 2000-02-25 | Fibrinogen-based tissue adhesive |
US11/443,925 US7459295B2 (en) | 1997-08-28 | 2006-05-30 | Fibrinogen-based tissue adhesive containing an elastase inhibitor |
US12/252,988 US7892802B2 (en) | 1997-08-28 | 2008-10-16 | Fibrinogen-based tissue adhesive containing an elastase inhibitor |
US13/021,551 US8425947B2 (en) | 1997-08-28 | 2011-02-04 | Fibrinogen-based tissue adhesive containing an elastase inhibitor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT0144997A AT406120B (de) | 1997-08-28 | 1997-08-28 | Gewebekleber |
ATA1449/97 | 1997-08-28 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
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US09486516 A-371-Of-International | 1998-08-26 | ||
US11/443,925 Continuation US7459295B2 (en) | 1997-08-28 | 2006-05-30 | Fibrinogen-based tissue adhesive containing an elastase inhibitor |
US12/252,988 Continuation US7892802B2 (en) | 1997-08-28 | 2008-10-16 | Fibrinogen-based tissue adhesive containing an elastase inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999011301A1 true WO1999011301A1 (de) | 1999-03-11 |
Family
ID=3514138
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/AT1998/000202 WO1999011301A1 (de) | 1997-08-28 | 1998-08-26 | Gewebekleber auf basis von fibrinogen |
Country Status (16)
Country | Link |
---|---|
US (4) | US7091015B1 (de) |
EP (1) | EP1007109B1 (de) |
JP (1) | JP4932082B2 (de) |
AT (2) | AT406120B (de) |
AU (1) | AU743181B2 (de) |
CA (1) | CA2302224C (de) |
DE (1) | DE59807667D1 (de) |
DK (1) | DK1007109T3 (de) |
ES (1) | ES2195375T3 (de) |
HR (1) | HRP20000100B1 (de) |
HU (1) | HUP0104043A3 (de) |
IL (2) | IL134728A0 (de) |
NO (1) | NO20000921L (de) |
PT (1) | PT1007109E (de) |
SK (1) | SK2562000A3 (de) |
WO (1) | WO1999011301A1 (de) |
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WO2000071153A2 (de) * | 1999-05-19 | 2000-11-30 | Bio & Bio Licensing Sa | Arzneimittel zur lokalen anwendung, das fibrinogen, thrombin, transglutaminasen und proteinaseinhibitoren enthält |
JP2001327592A (ja) * | 2000-05-22 | 2001-11-27 | Aventis Behring Gmbh | 抗癒着特性が改善された組織接着剤 |
WO2002030445A2 (en) * | 2000-10-13 | 2002-04-18 | Baxter International Inc. | Fibrinogen plus a non-plasmin-acting fibrinolysis inhibitor for the reduction or prevention of adhesion formation |
JP2003516550A (ja) * | 1999-12-08 | 2003-05-13 | アストラゼネカ アクチボラグ | エラスターゼ阻害剤を包含するプラスミノーゲン活性化因子のアッセイ法 |
US7276235B2 (en) | 1998-11-18 | 2007-10-02 | Zlb Behring Gmbh | Tissue glue with improved antiadhesive properties |
US8268362B2 (en) | 1997-11-12 | 2012-09-18 | Bio-Products & Bio-Engineering Aktiengesellschaft | Medicinal product for the promotion of wound healing |
US8377864B2 (en) | 2007-06-19 | 2013-02-19 | Baxter International Inc. | Fibrin gel for controlled release of PDGF and uses thereof |
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CA2594396A1 (en) * | 2005-01-14 | 2006-07-20 | Arblast Co., Ltd. | Sheet-shaped composition utilizing amnion and method of preparing the same |
CN101583383B (zh) * | 2006-11-30 | 2013-12-25 | Bmg株式会社 | 具有自分解性的粉末-液体及粉末-粉末的2反应剂型的医疗用粘接剂 |
WO2011025957A2 (en) * | 2009-08-28 | 2011-03-03 | Ecole Polytechnique Federal De Lausanne | Tg-aprotinin fusion proteins and matrices thereof |
US20130202656A1 (en) | 2012-02-03 | 2013-08-08 | Dynasil Biomedical Corporation | Systems and kits for the fabrication of tissue patches |
US9540548B1 (en) | 2015-08-07 | 2017-01-10 | Xcede Technologies, Inc. | Adhesive compositions and related methods |
WO2017027378A1 (en) | 2015-08-07 | 2017-02-16 | Xcede Technologies, Inc. | Adhesive compositions and related methods |
US9833538B2 (en) | 2015-08-07 | 2017-12-05 | Xcede Technologies, Inc. | Adhesive compositions and related methods |
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US8268362B2 (en) | 1997-11-12 | 2012-09-18 | Bio-Products & Bio-Engineering Aktiengesellschaft | Medicinal product for the promotion of wound healing |
US7276235B2 (en) | 1998-11-18 | 2007-10-02 | Zlb Behring Gmbh | Tissue glue with improved antiadhesive properties |
WO2000071153A3 (de) * | 1999-05-19 | 2001-04-26 | Bio Prod & Bio Eng Ag | Arzneimittel zur lokalen anwendung, das fibrinogen, thrombin, transglutaminasen und proteinaseinhibitoren enthält |
WO2000071153A2 (de) * | 1999-05-19 | 2000-11-30 | Bio & Bio Licensing Sa | Arzneimittel zur lokalen anwendung, das fibrinogen, thrombin, transglutaminasen und proteinaseinhibitoren enthält |
JP2003516550A (ja) * | 1999-12-08 | 2003-05-13 | アストラゼネカ アクチボラグ | エラスターゼ阻害剤を包含するプラスミノーゲン活性化因子のアッセイ法 |
EP1157706A2 (de) * | 2000-05-22 | 2001-11-28 | Aventis Behring GmbH | Verwendung von fibrinogenhaltigem Gewebekleber zur Verhinderung von Gewebsadhäsionen |
EP1157706A3 (de) * | 2000-05-22 | 2002-03-06 | Aventis Behring GmbH | Verwendung von fibrinogenhaltigem Gewebekleber zur Verhinderung von Gewebsadhäsionen |
JP2001327592A (ja) * | 2000-05-22 | 2001-11-27 | Aventis Behring Gmbh | 抗癒着特性が改善された組織接着剤 |
WO2002030445A2 (en) * | 2000-10-13 | 2002-04-18 | Baxter International Inc. | Fibrinogen plus a non-plasmin-acting fibrinolysis inhibitor for the reduction or prevention of adhesion formation |
WO2002030445A3 (en) * | 2000-10-13 | 2003-08-14 | Baxter Int | Fibrinogen plus a non-plasmin-acting fibrinolysis inhibitor for the reduction or prevention of adhesion formation |
US7326412B2 (en) * | 2000-10-13 | 2008-02-05 | Baxter International Inc. | Fibrinogen plus a non-plasmin-acting fibrinolysis inhibitor for the reduction or prevention of adhesion formation |
US8377864B2 (en) | 2007-06-19 | 2013-02-19 | Baxter International Inc. | Fibrin gel for controlled release of PDGF and uses thereof |
US9012393B2 (en) | 2007-06-19 | 2015-04-21 | Baxter International Inc. | Fibrin gel for controlled release of PDGF and uses thereof |
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US20090041748A1 (en) | 2009-02-12 |
SK2562000A3 (en) | 2000-09-12 |
US7091015B1 (en) | 2006-08-15 |
CA2302224C (en) | 2006-11-14 |
DE59807667D1 (de) | 2003-04-30 |
EP1007109B1 (de) | 2003-03-26 |
AU743181B2 (en) | 2002-01-17 |
HRP20000100A2 (en) | 2000-10-31 |
ATA144997A (de) | 1999-07-15 |
US20060216280A1 (en) | 2006-09-28 |
DK1007109T3 (da) | 2003-06-23 |
ATE235269T1 (de) | 2003-04-15 |
PT1007109E (pt) | 2003-08-29 |
US8425947B2 (en) | 2013-04-23 |
AT406120B (de) | 2000-02-25 |
AU8963798A (en) | 1999-03-22 |
IL134728A (en) | 2007-09-20 |
NO20000921L (no) | 2000-04-26 |
US7892802B2 (en) | 2011-02-22 |
HUP0104043A1 (hu) | 2002-02-28 |
HUP0104043A3 (en) | 2004-08-30 |
US20110190812A1 (en) | 2011-08-04 |
CA2302224A1 (en) | 1999-03-11 |
EP1007109A1 (de) | 2000-06-14 |
JP4932082B2 (ja) | 2012-05-16 |
HRP20000100B1 (en) | 2010-09-30 |
NO20000921D0 (no) | 2000-02-24 |
US7459295B2 (en) | 2008-12-02 |
JP2001514050A (ja) | 2001-09-11 |
IL134728A0 (en) | 2001-04-30 |
ES2195375T3 (es) | 2003-12-01 |
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