MXPA00001945A - Fibrinogen-based tissue adhesive - Google Patents

Abstract

A fibrinogen-based tissue adhesive contains an elastase inhibitor.

Description

FIBRINOGEN BASE TISSUE ADHESIVE Description of the invention: The invention relates to a fibrinogen-based tissue adhesive. Fibrinogen-based adhesives, which are also called fibrin adhesives, mimic in their adhesive effect the last phase of blood coagulation. The fibrinogen is dissociated into fibrin monomers by the effect of thrombin, which in the adhesion process uses mainly the fibrinogen solution, but is also present in each wound. Fibrin monomers accumulate spontaneously in structures in the form of ordered fibers, which are referred to as fibrin. These monomeric fibrin aggregates are subsequently stabilized by the effect of factor XlIIa through covalent cross-linking. Thus, between the specific glutamine and lysine side chains of the fibrin monomers in a transamidation reaction, the peptide bonds are formed. Factor XlIIa, which also dissociates from inactive factor XIII by means of thrombin, is an active transamidase and is termed as a "fibrin stabilizing factor" because of its effect. Although with the use of a tissue adhesive, in principle the same processes are carried out as in the case of "natural" blood coagulation, in a tissue adhesive REF .: 32780 the components and factors involved are much more concentrated than in the blood. Therefore, blood coagulation takes place much faster and the adhesion of tissues obtained or the clot formed are much safer and also stable.

The conditions for the emergence of fibrin adhesives in the late 1970s were advances in the fractionation and purification of blood coagulation factors. Therefore, it was possible to prepare the natural coagulation factors in such a pure and concentrated manner, as is required for efficient tissue adhesion. The first commercially obtained fabric adhesives reached the market at the end of the 70s and since then they have offered many possibilities of use; especially in the fields in which, with the usual surgical techniques, great problems always appeared, for example in the case of heavy hemorrhages, in adhesion between nerves or in tears in organs such as the liver and spleen. Another advantage of the fibrin adhesive, compared to sewing with needle and thread, is that the tissue or organ to be treated is not damaged additionally by the sewing process, therefore with the use of fibrinogen-based tissue adhesive there is much less complications and scars more imperceptible than with the usual surgical sewing. In addition to the optimum adhesive effect, which represents a high load resistance and internal adhesion resistance as well as strong adhesion of the adhesive to the wound or tissue surfaces, the following direct adhesion processes are essential to optimize tissue adhesion ( see AT-B 359 652 and 359 653). To these belong the management and control of the adhesion between the adhesions in the body as well as the capacity of resorption and the properties promoters of the healing of the adhesive. For this reason, for a tissue adhesive, not only the adhesive effect is decisive, but also that the adhesion or the clot that formed is dissolved again in the body after a certain period of time and the wound as a consequence of the complete resorption of the formed clot, heal completely. For this it is necessary to control the processes (proper to the body) of dissolution of the formed blood clot, of the fibrinolysis, also by the optimization of the tissue adhesive. In fibrinolysis the fibrin present in the formed blood clot is destroyed or removed and thus the blood clot dissolves. For this, first under the influence of intrinsic or extrinsic plasminogen activators, such as blood coagulation factors XI and XII, precalicrein, urokinase or t-PA, the fibrinolytically effective plasmin is formed from the inactive plasminogen, which in addition to the fibrin also dissociates fibrinogen and coagulation factors V and VIII. Since the processes of autonomous fibrinolysis of the body begin immediately after the formation of the clot and with this there is a danger that the adhesion of tissues formed does not remain sufficiently adhesive and that the formed clot will de-stabilize before time. During the adhesion of tissues, the addition of a plasminogen inhibitor, an inhibitor of the plasminogen activity, is usually provided to reduce the effect of plasmin directly or indirectly and, among other things, prevent premature fibrinolysis in the initial phase of adhesion. . With the concentration of the inhibitor, the dissolution times (lysis times) of the formed clot or adhesion can be controlled at will. The more inhibitor is provided, the more stable the clot will be against fibrinolysis, the longer the clot will remain stable and therefore the adhesion will be completely reabsorbed. Also, when using the fibrinolysis inhibitor, an optimal midpoint between the inhibition of early fibrinolysis and a wound healing process can be found as quickly as possible. The commercial tissue adhesive Aportinin, which is also known as bovine basic pancreatic trypsin inhibitor, is used as a plasmin inhibitor. Aprotinin is a polyvalent inhibitor of proteinases (kallikrein) and inhibits the Xlla, Xla, Villa coagulation factors as well as plasmin and "plasmin activators, but also trypsin, chymotrypsin and kallikrein." Aprotinin was prepared primarily from beef. the problems of the use of bovine materials in medicines, which are used to treat humans, aprotinin is used more and more frequently prepared in a recombinant manner.To aprotinin aprotinin is usually used in an amount of 20-300 units of kallikrein inactivator (KIE) / ml tissue adhesive, depending on the optimal concentration of the fibrinolytic activity of the tissue in question, however, it has been shown that in fibrinolytic activity, only the inhibitory effect of fibrinolysis can be controlled. aprotinin despite the use of high concentrations of aprotinin in a very limited way and therefore can p to experience undesirable premature lysis processes.

The task of the present application is therefore to present a tissue adhesive, with which the disadvantages of the prior art are overcome, with which it is also ensured in the case of tissue adhesion in wounds with a high plasmin activity , a satisfactory and permanent protection against premature fibrinolysis, without impairing the quality of the adhesion. This task is solved according to the invention by means of a tissue adhesive based on fibrinogen, which is characterized in that it contains an additional elastase inhibitor. It has been surprisingly shown that the process of fibrinolysis can not only be avoided by means of inhibiting plasmin or inhibiting the activation of plasminogens to plasmin, but also by means of inhibitors of elastase or by inhibitors whose inhibitory effect of fibrinolysis is based mostly on a fibrinolysis mechanism without fibrin. For the purposes of the present invention, those inhibitors of fibrinolysis without plasminogen are found for simplicity under the term "elastase inhibitor". Certainly it was speculated that in addition to the fibrinolysis caused by plasmin there may be other processes of fibrinolysis, which are not based on plasmin (for example a process that takes place in a lysosomal way, see Simón et al., BLOOD 82 (8) (1993). ), pages 2414-2422), and which can not be inhibited by aprotinin, but it was also shown that this "fibrinolytic pathway without plasmin", can not be inhibited by means of specific elastase inhibitor peptides such as N-methoxy-succinyl -L-alanyl-L-prolyl-L-.valanylchloromethyl ketone (AAPVCK) (see Simón et al.). More surprisingly, it was discovered by the present invention that inhibitors that do not have inhibitory effects of plasmin or plasminogen activator, also the elastase inhibitors according to the invention in the case of plasmin adhesives both _ut? Vitro as in vivo can guarantee a very controllable lysis process of the formed clot. This is especially advantageous in tissues with high fibrinolytic activity, in which, at moderate concentrations, premature lysis can be avoided. Premature lysis has a role in tissues with high fibrinolytic activity in the course of the first moment after adhesion, since there, in the chaos of a premature lysis, a (partial) dissolution of the adhesion can be obtained and with this a renewed process of bleeding ("Rebleeding"). It was further shown that the elastase inhibitor according to the invention to be used in the tissue adhesive according to the invention exhibits the fibrinolytic effect not only in combination with inhibitors acting on plasmin, but can also guarantee by itself all the inhibition of fibrinolysis of the elastase inhibitor. A special embodiment of the present invention consists in that the tissue adhesive in addition to fibrinogen, the elastase inhibitor and optionally factor XIII does not contain other active compounds. The concentration of fibrinogen in the present adhesive corresponds to the known tissue adhesives and should usually be at least greater than 50 mg, especially greater than 70-80 mg fibrinogen / ml, also at least 20 times the concentration of fibrinogen in the blood (2-4 mg / ml). Preferably, the fibrinogen is compared to the cryoprecipitate in a more purified form. Preferred elastase inhibitors are selected, within the framework of the present invention from the group of eglin, inhibitor of proteinase elastase < xx, antiprotease or? lephine, leukocyte protease inhibitor, especially a leukocyte fraction, preferably a fraction derived from granulocytes, or secretion leucoprotease inhibitor, or mixtures thereof. As a leukocyte fraction, for example, a cellular lysate, especially one derived from human cells, can be used. Other inhibitors of elastase or fibrinolysis that do not act on plasmin, can be easily deduced by the technician by means of the test system presented in the examples, by seeking their suitability in tissue adhesives according to the invention or by using the test of elastase inhibition known in the state of the art. To the preferred elastase inhibitors are also added different derivatives of the inhibitors according to the invention, for example fragments or chemically modified form or by means of protein design (recombinant) of these inhibitors, these derivatives must of course have the property qualitative inhibitor of elastase of the basic inhibitor. Preferably the tissue adhesive according to the invention consists exclusively of human proteins, wherein human proteins prepared recombinantly are also to be understood as human proteins. Preferably the proteins used in the tissue adhesive are prepared either from blood, plasma, cryoprecipitate or from a recombinant cell culture. An especially preferred tissue adhesive is characterized in that it consists essentially 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 00. Expressed in units of fibrinogen ag inhibitor, they are added to the tissue adhesive, preferably 10"6 U / g fibrinogen, especially in the range between 10" 3 and 10 U / g fibrinogen. The amount of the inhibitor added to the adhesive according to the invention, inhibitor which can also be found naturally in blood or plasma, is preferably at least 20 times, especially at least 50 times greater, than its physiological concentration in the blood. or the plasma. The tissue adhesive according to the invention can have for example the following composition: 75-115 mg / ml binding protein, of these 50-110 mg / ml, preferably 70-110 mg / ml fibrinogen; optionally 1-50, preferably 10-50 IU factor XlII / ml. As an inhibitor, eglin can be used in an amount of between 1-100 μg / ml or rip antiprotease with 0.01-1 U / ml. As a rule, it is sufficient to use the elastase inhibitor in an amount corresponding to the inhibitory effect of apollinin fibrinolysis in the adhesives of known tissues. The adhesive according to the invention, depending on the purpose of the adhesion, may contain plasminogen or be free of plasminogen. When containing plasminogen, this must 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 adhesive due to its activation to plasmin there is also the possibility of defining more clearly the fibrinolytic properties of the tissue adhesive. On the other hand, the tissue adhesive in a preferred embodiment does not contain any plasminogen or contain it only in a very small amount. As mentioned before, the presence of the elastase inhibitor as sole inhibitor of fibrinolysis in the woven adhesive * is surprisingly sufficient for the functionality of the adhesive according to the invention. Preferably, in addition to the elastase inhibitor, a plasmin inhibitor or a plasmin activator inhibitor is also used., which also contributes to improve the control of the lysis of the resorption and with this to the healing of the wound. Preferred plasmin inhibitors or plasminogen activator inhibitors with especially aprotinin, but also macroglobulin a-2, antitrypsin a ^, e-amino-capronic acid, tranexamic acid or mixtures of these substances. Although some authors also attribute, for example, to α-antitrypsin certain effects on elastase, the substances mentioned here are considered as activators of plasmin or plasminogen, since this is the primary activity that these substances present in the present field of application. This obviously also applies to the present invention. In addition, other anti-adhesive additives, such as for example hyaluronic acid, may be present. Another preferred embodiment of the tissue adhesive according to the invention is to provide an antibiotic in the adhesive, as already proposed in AT-B-369 990. Especially preferred antibiotics are selected from the group of aminoglycosides, betalactams, polypeptides, fosfomycin, tetracycline or their mixtures. In another preferred embodiment, the antibiotic is in the form of a hardly soluble derivative. More preferably in the tissue adhesive according to the invention, factor XIII is also provided, in such a way that the internal resistance of the clot and the strength and fixation of the adhesion are positively influenced. Factor XIII is preferably used in an amount of 1-50 units / ml, preferably approximately 10 U / ml. In relation to fibrinogen, factor XIII is preferably found at a minimum concentration of 0.001 U / mg fibrinogen, especially at least 0.1 U / mg fibrinogen. Depending on the type of adhesion or the type of tissue, the optimal concentration of factor XIII can be optimized for each technician. If an antibiotic is present in the tissue adhesive, it is recommended to provide a little more factor XIII (see AT-B-369-990). More preferably, the tissue adhesive according to the invention is free of quininogen proteins (such as kallikrein, etc.), whereby the problematic side reactions of the above can be avoided. According to a preferred embodiment, the fabric adhesive according to the invention can be presented in combination with a solid surface in the form of a dressing, whereby for large surface wounds an optimum wound closure and an optimum coating is obtained . Examples of such dressings are mentioned in AT-B 374 367. The solid surface of the dressing is therefore preferably a surface of collagen, gelatin or psissaccharide, it being possible to use other suitable medicinal surfaces, which may also be impregnated for the purpose of use. special It has been shown that with the tissue adhesive according to the invention, which contains an elastase inhibitor, both in a medium with high fibrinolytic activity for a period of at least 10 hours, preferably 15 hours, a resistance to the lysis can be achieved. . Resistance to the lysis means according to the present invention, that in the course of a determined period of time a corresponding fibrin clot has not been formed. The determination of the resistance to the lysis is carried out for example by means of a photometric measurement depending on the type. A preferred tissue adhesive according to the present invention thus exhibits a resistance to the lysis of at least 10 hours, preferably at least 15 hours, in a medium with high fibrinolytic activity.; Under the term "high fibrinolytic activity" is meant, for example, a plasmin activity, which is above the physiological potential of plasmin. The fribinolytic potential can for example be expressed by the concentration of plasminogen (see, for example, Henrikson et al, Thrombosis Research 16: 301-312, 1979). This property of the resistance to the lysis can be verified by each technician by means of a simple test, like the one described in the examples. In the application the tissue adhesive according to the invention is preferably found as a solution, for storage it is recommended either to freeze the solution, in such a way that the tissue adhesive is in frozen form, or the lyophilization of the adhesive , also to be provided in "lyophilized form" obviously means only a preserved tissue adhesive preparation by means of freeze drying, which by the subsequent reconstitution can be reconstituted almost completely (this by at least 80%) in the course of some minutes at 37 ° C.

The adhesive according to the invention is advantageously in a virally inactivated form. This inactivation treatment is preferably guaranteed by a thermal treatment or by a surfactant, for example by means of the solid state thermal treatment, in particular a steam treatment according to EP-0 159311, or EP-0 519 901 or EP- 0 674 531. Other treatments for virus inactivation also include treatment with chemical or guímico / physical methods for example with chaotropic substances in accordance with 094/13329, DE 44 34 538 OR EP-0 131 740 (solvent) or photoinactivation. Nanofiltration also represents a preferred method for virus reduction within the framework of the present invention. The elastase inhibitors used according to the invention, according to a preferred embodiment, may have a recombinant origin. The present invention further relates to a tissue adhesive system, which contains as a component a tissue adhesive according to the invention, which contains an elastase inhibitor. The tissue adhesive system according to the invention usually contains, as an additional component, a thrombin component, in which the thrombin is in a liquefied form or as a reconstitutable lyophilizate, wherein the thrombin component in the adhesive, depending on the field of application, may present different concentrations. The tissue adhesive system, which is likewise under the present invention, is characterized by comprising a fibrinogen component and a separate component thereof, which contains an elastase inhibitor. Usually, however, it is advantageous to provide a fibrinolysis inhibitor component in the fibrinogen component (see AT-B 359 652 and 359 653). By means of suitable application devices the inhibitory component isolated from the fibrinogen component can be applied. Preferably the component containing an elastase inhibitor, simultaneously contains thrombin, this component can be found either as lyophilized or as a solution (optionally frozen). The adhesive fabric system according to the invention also comprises suitable application devices for the components of the system. In particular, double injection systems have been recommended, such as those described in EP 0 037 393, EP 0 210 160 or EP 0 292 472, or also application devices such as those described in EP 0 315 322 or EP 0 669 100. these special application devices, also that embodiment in which the inhibitor is applied to the thrombin component, reliable adhesion results can be obtained. The present adhesive is suitable for all known application possibilities of the fibrin adhesive. However, it is recommended in particular for adhesion in areas with high fibrinolytic activity. The object of the present application is therefore the use of the fabric adhesive according to the invention or the tissue adhesive system according to the invention for the production of a preparation or an application device for use in areas with high activity fibrinolytic, especially in urology. The object of the present invention is furthermore 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, especially in urology. The invention will be explained with the help of the following examples and drawings, without being limited by them. where it shows: Figure 1 the reduction of the extinction corresponding to the growing lysis of the clot, a) fibrin adhesive without aprotinin b) fibrin adhesive with aprotinin (1000 U / ml) c) fibrin adhesive with alpha-PI ( 0.01 U / ml) d) fibrin adhesive with alpha-PI (0.001 U / ml) d) fibrin adhesive with alpha-PI (0.0001 U / ml) Figure 2 the reduction of the extinction corresponding to the increasing lysis of the clot . a) fibrin adhesive with aprotinin (1000 U / ml) b) fibrin adhesive with eglin (1 μg / ml) c) fibrin adhesive without aprotinin; Figure 3: the value of the rebleeding "Rebleedings" expressed as weight gain of the previously weighted isopos in the hyperfibrinolytic medium, which was induced by means of the infusion of t-PA: and Figure 4: the value of the rebleeding "Rebleedings" expressed as weight gain of previously weighted .isopos, in medium with normal fibrinolytic activity, also without infusion of t-PA. Examples: 1. In vitro test to determine the inhibitory effect of fibrinolysis of the tissue adhesive according to the invention (currently according to the applicant the best embodiment of the invention) In this example the blocking of the lysis of a clot is shown of tissue adhesive by means of eglin or antiprotease a ^. For this, the fabric adhesive STIM3 (IMMUNO AG, Vienna, AT) (containing 70 mg of fibrinogen / ml) is dissolved in water and then diluted to 1: 6 with 0.9 M NaCl solution. Efficiency of the tissue was determined by the dilution of thrombin solution diluted in 40 mM CaCl2 and subsequently diluted to 0.1 E / ml with a solution (1: 5) of CaCl2. 40mM / 0.9 M NaCl and pipette on a microplate, placing 100 μl / well. Different concentrations of the inhibitors were added to each 5 μl of the tissue adhesive (Eglina I-100 μg / ml, antiprotease c ^ 0.01-1 U / ml). To harden the adhesive, the microtiter plate was incubated approximately 1.5 hours at 37 ° C. The corresponding lysis reagents (a: leukocyte homogenate cell free surplus (freeze 3 times / thaw) of 500,000 leukocytes / μl; b: t-PA 2mg / ml as positive control; 0.9% NaCl as negative control) they were pipetted on a clot (100 μl / well). The microtiter wells were then measured in a plate photometer at 37 ° C at a length of 405 nm, kinetically overnight at 60x900 s in the SLT 340 ATTC photometer. The results are given in figure 1 and 2, where the reduction of the extinction corresponds to the increasing lysis of the clot. It has been shown that both with > 1 μg of englin / ml as well as with > .0.01 Antiprotease ai / ml is possible in the course of 15 hours to avoid the lysis of the fibrin clot, which on the one hand allows to attribute the central role of the leukocyte proteases for the destruction of the fibrin clot and shows the excellent effect of the elastase inhibitors according to the invention on the inhibition of that lysis. 2. In vivo effect of the elastase inhibitors used according to the invention In order to determine the meaning of the leukocyte proteases, in particular of elastase inhibitors, within the framework of the present invention, they were examined for the demonstration of hemostasis by means of of the fabric adhesive as well as the effect of the adhesive according to the invention in systems -tefibrinolytic as well as in normal fibrinolytic activity and were compared with adhesives without inhibitors or with an adhesive, which only contains aprotinin as a plasmin inhibitor. 2.a) Hyperfibrinolysis Anesthetized rabbits (2-3 kg) were heparinized (4000 U / kg). Half an hour later, tweezers were placed on the right side of the liver and another one partially away from the tweezers. Hemorrhages of the large vessels were stopped by means of electrocoagulation and the residual diffuse bleeding was plugged -? by means of the application of the tissue adhesive (max 4 ml) in the course of 200 seconds. 10 minutes later the infusion of t-PA (700 U / kg / h) was started and the value of the rebleeding was re-bleeding for 2 hours, for which the weight gain of previously weighted isopos was measured. For this, three fabric adhesives were tested. a) tissue adhesive (STIM3) with aprotinin (3000 U / ml) as negative control b) tissue adhesive (STIM3) without aprotinin as a positive control c) tissue adhesive (STIM3) without aprotinin with eglin (10 μg / ml); adhesive according to the invention. That adhesive was inactivated and applied by means of a Duploject® syringe (IMMUNO signature), Vienna, AT). The results obtained are given in figure 3. b. Normal fibrinolytic activity In addition to the hyperfibrinolysis model, the same experiments were performed without t-PA infusion, however with a prolonged observation time of 4 hours. The results obtained are given in figure 4. It has been shown that both in the hyperfibinolysis model and in normal fibrinolysis a smaller re-bleeding is possible in comparison with the common adhesives, which with longer lysis times also It has improved properties against aprotinin.

The results demonstrate the excellent effects of the tissue adhesive according to the invention, with which premature lysis of the fibrin adhesive can be avoided, thereby preventing rebleeding ("Rebleedings") also in areas with high fibrinolytic activity . It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the products to which it refers.

Claims (28)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: l.- Adhesive for fabrics based on fibrinogens, characterized by containing an additional elastase inhibitor.
2. 2. Adhesive for tissues according to claim 1, characterized in that the elastase inhibitor is selected from the group consisting of eglin, inhibitor of proteinase elastase a1, antiprotease a1 # protensa inhibitor of leukocyte elaphine and mixtures thereof.
3. 3. Adhesive for tissues according to claim 2, characterized in that the leukocyte protease inhibitor is presented as a fraction of leukocytes, especially a fraction derived from granulocytes.
4. 4. Adhesive for tissues according to one of claims 1 to 3, characterized in that it is formed exclusively by human proteins.
5. 5. Adhesive for teats according to one of claims 1 to 4, characterized in that it is formed exclusively by blood or plasma proteins.
6. 6. Adhesive for fabrics according to one of claims 1 to 5, characterized in that the elastase inhibitor is contained in a ratio of 1: 100 to 1: 150,000, preferably 1: 500 to 1: 110,000, in relation to to the mg of fibrinogen.
7. 7. Adhesive for fabrics according to one of claims 1 to 6, characterized in that it contains at least 10"6 U of the elastase inhibitor per g of fibrinogen, preferably between 10" 3 and 10 U / g of fibrinogen.
8. 8. Adhesive for tissues according to one of claims 1 to 7, characterized in that it contains the plasminogen in an amount of at least 0.0001 mg / mg fibrinogen, preferably at least 0.001, and most preferred more than 0.1.
9. 9. Adhesive for tissues according to one of claims 1 to 7, characterized in that it does not contain plasminogen.
10. 10. Adhesive according to one of claims 1 to 9, characterized in that it also contains a plasmin inhibitor or a plasmin activator inhibitor, which is preferably selected from the group of aprotinin, macroglobulin a2, antitrypsin? , e-amino-carprónics acid, tranexamic acid or their mixtures.
11. 11. Adhesive according to one of claims 1 to 10, characterized in that it contains an antibiotic, which is preferably selected from the group of aminoglycosides, betalactams, polypeptides, fosfomycin, tetracycline or mixtures thereof.
12. 12. Adhesive for fabrics according to one of claims 1 to 11, characterized in that it contains factor XIII, preferably in an amount of at least 0.001 U / mg fibrinogen, especially at least 0.1 U / mg is preferred.
13. 13. Adhesive for tissues according to one of claims 1 to 12, characterized in that it is free of guininogenic proteins.
14. 14. Adhesive for fabrics according to one of claims 1 to 13, characterized in that in combination with a solid surface, it is presented in the form of a dressing.
15. 15. Adhesive for fabrics according to claim 14, characterized in that the solid surface is a surface of collagen, gelatin or polysaccharide.
16. 16. Adhesive for fabrics according to claims 1 to 15, characterized in that it is resistant to lysis in a medium with high fibrinolytic activity for a period of time of at least 10 hours, preferably at least 15 hours.
17. 17. Adhesive for tissues according to one of claims 1 to 16, characterized in that it is lyophilized.
18. 18. Adhesive for fabrics according to one of claims 1 to 16, characterized in that it is in solution.
19. 19. - Adhesive for fabrics according to claim 18, characterized in that the solution is frozen.
20. 20. Adhesive for tissues according to one of claims 1 to 19, characterized in that it is in a virally inactivated form.
21. 21. Adhesive for tissues according to one of claims 1 to 20, characterized in that the elastase inhibitor is of recombinant origin.
22. 22. - Adhesive system characterized in that as a component contains a tissue adhesive according to one of claims 1 to 21.
23. 23.- Adhesive system according to the claim 22, characterized in that it contains an additional component that contains thrombin and possibly caycin.
24. 24. - Adhesive system characterized in that it consists of a fibrinogen component and a component containing an elastase inhibitor.
25. 25. Adhesive system according to claim 24, characterized in that the component containing an elastase inhibitor, contains thrombin.
26. 26. Adhesive system according to one of claims 22 to 25, characterized in that it also consists of an application device for the components of the system, especially a double injection system.
27. 27. - Use of a tissue adhesive according to one of claims 1 to 19 to produce a preparation for use in an area with high fibrinolytic activity, especially in urology.
28. 28. Use of a tissue adhesive system according to one of claims 22 to 26 for the preparation of an application device for use in an area with high fibrinolytic activity, especially in urology.