CZ83194A3 - Haemostatic preparation for inducing blood precipitation on a bleeding wound - Google Patents

Abstract

Method for arresting local bleedings by topical use of FVIIa and a hemostatic composition containing FVIIa together with a biologically compatible carrier which permits said FVIIa to remain in contact with said bleeding wound.

Description

llemostatic means for causing blood clotting nn of a bleeding wound

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Rounds with th e tions

The invention relates to a heterostatic composition comprising a Factor VIIa for controlling local bleeding and a method of arresting local bleeding by toxic use of Factor VIIa.

BACKGROUND OF THE INVENTION

If the blood vessels are damaged by physical injury, including surgery, bleeding occurs. If left untreated, the bleeding is stopped by a progressive spontaneous physiological process marked by a series of events involving the combined effect of vascular platelets and plasma agents leading to the formation of a blood clot. This process is referred to as physiological haemostasis (blood coagulation), which is described in more detail below. In minor superficial bleeding, the physiological cessation of the bleeding is sufficient to stop the bleeding.

There are two separate systems that can promote blood clotting. These systems are referred to as internal and external coagulation paths.

Only clot forming agents present in the plasma are used in the internal route. The transient event in the intrinsic pathway is the activation of factor IX to factor IXa, a reaction catalysed by factor XIa and calcium ions. Factor IXa is then involved in the activation of Factor X to Factor Xa in the presence of Factor VIIIa, phospholipid and calcium ions.

The external pathway includes plasma factors as well as components present in the tissue extracts. Factor VII, a plasma proenzyme, also participates in the external blood coagulation pathway by converting (upon its activation to Factor VIIa) Factor X to Factor Xa in the presence of tissue factor and calcium ions.

Factor Xa then converts protlirorabine to thrombin in the presence of factor Va, calcium ion, and phospholipids. Subsequently, the i-piles converts the plasma fibrinogen to fibrin, which crosslinks in the presence of the XTIIa factor and calcium ions, thereby forming a blood clot.

Blood factors such as Factor VIII: C (see US Pat. Nos. 4,831,119; 4,868,112; 4, S8G.S7G; 4, G57.894; Ro. 32.011 and 4,649.132); and Factor Factor (see US Patents 4,784,950; 4,382,083; 4,479,938; Isolated from natural sources or produced by recombination methods are used in. treating patients, such as hemophiliacs, suffering from insufficient blood clotting or having inhibitors of blood clotting factors. These coagulation factors are administered to patients in need of treatment as an aqueous solution by infusion or bolus injection, depending on the blood factor to be administered to the patient and the patient's condition. The bleeding should typically stop between 15 minutes and 3 hours, and possibly later, from the administration of the blood clotting factor.

However, quicker haemorrhage is more difficult in more severe cases where the bleeding occurs in larger lesions involving larger arteries, or at. nrossakation of blood from larger mucosal surfaces or from cavities without drainage. If, in these cases, the bleeding continues for a shorter period of time, it may result in significant blood loss, which may adversely affect normal body function. Also, when bleeding occurs in the unextensible bone cavities, the accumulation of extracorporeal blood can cause local soft tissue damage due to increased pressure. Conventional treatment of such conditions includes the use of surgical and / or non-surgical techniques.

Surgical cessation of bleeding includes lining of ruptured blood vessels, clogging of tampons in cavities, coagulation of tissue surfaces including their open ruptured vessels with hot instruments, or application of caustic agents or hot air.

Surgical bleeding can also be aided by the application of suitably sized blocks, plates, or films of a bioabsorbable hemostatic tampon to the injured thigh.

In some cases, pharmaceutical compositions containing bovine thronibine or other blood-clotting agents such as factors VIII, XIII or calcium ions are commonly used as a biostasis in surgical procedures, such as being applied, for example, by spraying a suitable solution thereof on. bleeding sites as described in U.S. Pat. No. 4,298,595. U.S. Pat. No. 4,363,319 also discloses textile materials such as gauze or cotton fabrics or bioabsorbable swabs which have been soaked in solution of at least one of said hemostatic compounds prior to application.

U.S. Pat. No. 2,558,395 discloses a non-denatured, ready-to-use gelatin heraostatic tampon containing thrombin. U.S. Pat. No. 4,265,233 discloses a wound treatment material comprising an assembly made up of compounds such as gelatin, collagen, polyglycolic acid and polylactic acid to which Factor XIII has been fixed by covalent bonding. EP 277096 A discloses a wound dressing comprising a stable thrombin compound and a substrate, such as honostatic porous tampons of collagen or denatured gelatin, and 70 90/13320 describes a porous tampon containing a hemostatically effective amount of thrombin and hemostatically an effective amount of at least one blood clotting factor other than thrombin. U.S. Pat. Nos. 4,503,387 and 4,042,111 disclose a method and apparatus for treating cancer as well as an anti-cancer novel blood coagulation factor which is fixed on a substance such as a polymer that can be injected but instead of bleeding directly induced by cancer treatment.

Japanese Patent Application Publication No. 53-116213 discloses an aerosol containing, Factor XII ^T and thrombin, and Japanese Patent Application Publication No. 02-167234 discloses an adhesive tissue dressing comprising fibrinogen, prothrombin, Factors VII, IX, xa XIII, antithroinbin, protease inhibitor, and calcium ions.

In recent years, attention has been increasingly being paid to the safe use of products derived from bovine organs such as thrombin or prothrombin in pharmaceutical compositions for human use. Several reports report the potential risk of transmitting a bovine fungal encephalopathy (BSE) infectious agent to cattle to humans, where the virus-like agent may cause at least one known disease characterized by degenerative disease, such as Crcutzfeldt-Jacob disease and Kuru. Clinical researchers? gives ^: e have found that topical? the use of bovine thrombin in humans may induce the production of antibodies responsive to human thrombin τ causing bleeding problems,

It is therefore an object of the present invention to provide a safe and effective means for localized haemostasis at the site of an injury.

SUMMARY OF THE INVENTION

The invention relies on the surprising finding that Factor VIIa is able to immediately stop bleeding when it is topically applied to a site of injury in the absence of thrombin or other clotting factors and when combined, together or incorporated into a biocompatible carrier (which includes a single substance or a mixture of several substances) capable of preventing Factor VIIa from being washed away from the site of injury.

According to the invention, Factor VIIa is incorporated into a biocompatible carrier that does not contain thrombin and is not. accompanied or contaminated by any other blood clotting factor.

The invention thus relates to a costatic composition comprising a hemostatically effective amount of Factor VIIa incorporated in a biocompatible carrier, wherein the composition does not comprise thrombin.

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Accordingly, the present invention provides a thermostatic device for blood clotting on a bleeding wound, characterized in that a therapeutically effective amount of Factor VIIa which is unpolluted or unaccompanied by others and which is itself sufficiently effective to, together with a biocompatible carrier, Factor VIIa is fixed on the injured Instead, the blood clotting actuators have been used to induce hemostatic efficacy. he or she may contact him or in contact with him.

Dn Pinice

Before proceeding with the description of the invention, it may be useful to better understand it by providing a definition of certain terms to be used hereinafter.

Hcmostat or haemostatic: A substance that stops bleeding.

II. The composition: A composition comprising a composition or a heniostatic substance.

Blood clot: The end result of coagulation of the blood cascade, resulting from the conversion of soluble plasma fibrinogen into insoluble fibrin that physically stops bleeding. The blood clot covers the surface, pulls the edges of the wound together and forms a matrix for subsequent tissue re-formation and wound healing.

Blood coagulation factors: Plasma proteins involved in the coagulation of the blood cascade.

Activated Blood Clotting Factors: Blood clotting factors, converted into active enzymes by the action of an activator, which is often an activated blood clotting factor itself. They are usually referred to by adding a to a factor (for example, factor VIIa).

Proenzymes: An ancestor of an enzyme that typically has less or no activity compared to the enzyme itself.

Biologically absorbable substance: Substance that can be degraded in the body into smaller molecules of a size that allows them to be delivered. DC blood stream and gradual removal with application site.

Tampon: a porous structure with a mesh structure, the inner surface of which is substantially larger than the outer surface. This porous structure will contain hollow spaces within the mesh structure and can absorb liquids in many times greater weight than it weighs.

Covalent bond: A bond between two atoms in which both atoms share at least one electron.

Bandage: Material applied to the wound and fastened in place to provide protection and promote wound healing.

Topical: Local.

- L> Biocompatible: Ability to be absorbed by the calen and remained functional for a period of time without discarding.

Gel: A co-system comprising a solid and a liquid phase that exists as a solid or semi-solid.

Paste: Ointment-like composition of at least one substance contained in a hydrogel or fat base. It is less oily and better sbsorhovshe 'other than ointment.

Grau nu: Small particles of matter.

Film: Any thin coating, coating or layer.

Plaster: Fabric intended for external use, made of such ma-.

and having a consistency to adhere to the skin.

Bandage: A strip of gauze, muslin, flannel or other material used to keep the dressing in place or to control the bleeding.

Detailed description

Factor VIIa is to be used in a hemostatically effective amount, and a hemostatically effective amount is an amount that preferably causes bleeding to stop, whether maintained in conjunction with or in contact with the site of injury for a sufficient period of time, preferably for about 60 seconds. not having an attenuated heniostatic mechanism up to less than about 10 minutes in patients having an attenuated or damaged hemostatic mechanism. The Vila factor should be used in an amount of from about 0.2 to about 2.0 mg, preferably from about 0.5 to about 1, 5 mg, and in particular from about 0.9 to about 1.1 mg per application.

*

Factor VIIa can be obtained from plasma, as described in European patent publication EP G0S2182B or recombinant DNA technology as described in European patent publication EP 0200421A. Human purified Factor VIIa is preferably obtained by the methedes described by Brooch and Majeruser in J.Bio.Chem., 255, 4, 1242-1247, 1980, and by Hcdncm and Isiel in J.Clin.Invest., 71, p. 1836-1241, 1883. By these methods. factor VII is obtained without detectable amounts of other factors causing blood coagulation.

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An even more purified Factor VII preparation can be obtained by including additional gel filtration as the final purification step. The VIT factor then converts the rn-activated factor VIIa by known p-knots, for example by several vigorous plasma proteins, such as f, IXΛ or XA. Orn) tornative, as described; Bjocrn et al. (Activation of Coagulation Factor VII at Vila - Aetiation of Coagulation Factor VII to Vila) in Research Disclosurn, 269, pp. 564-565,] .SSC, may be:

VII activated by passing through an ion exchange dromatographic column, for example MonoQ (Pharmacia Fine Chemicals, Uppsala, Sweden).

For experts will be interesting the fact that the factor Vila. suitable for use in the present invention may also be prepared by recombinant DNA technology, for example by incorporating factor VII encoding a cDNA or gene (Ilagen et al., Proc. Natl. Acad. Sci. U5A 83; pp. 2412-241.6, 1986) into a suitable vector. by converting the appropriate cell lines through this transporter and multiplying the transformed cells in a suitable medium, whereupon the sc-squeezed product is isolated and activated to Factor VII. The recovery of Factor VII by recombinant DNA technology is also described in U.S. Patent 4,784,950, cited herein. The factor VIIa obtained by recombinant DNA technology may be authentic factor VIIa or more or less a modified factor VIIa, provided that such modified factor VIIa has substantially the same biological activity for blood coagulation as authentic factor VIIa. Such modified factor VIIa may be prepared by modifying factor VII. coding sequence ΏΝΑ either by changing the amino acid codons or by removing some of the amino acid codons in the natural gene by known methods, for example site-specific rnutagenesis.

Obviously, the practice of the methed described herein is independent of how Factor VIIa is obtained, and therefore the invention encompasses the use of a composition comprising any Factor VIIa suitable for use in the composition.

*

The carrier material can be a gel, a paste, a solid or other suitable biocompatible / acceptable carrier for topical application of pharmaceuticals or other biology and compositions.

The gel or paste viscosity will preferably be in the range of about 200 cps to about 30,000 cps.

The biocompatible carrier will typically consist of natural macromolecules such as gelatin, collagen, alginic cellulose, chitin, fibrinogen, fibrin, fibrin cleavage products, fibronectin, fibronectin fragments, globulin, myoglobulin, casein, keratin, albumin, polysaccharides such as dextranyaccharides glycosamingTats, agar, poctin, starch, or from chemically modified natural milks] such as denatured gelatin, alginic acid-alginates, for example calcium alginate, oxidized cellulose, substitutable ethers of cellulose, e.g. ce 1 u 1 ose, met 1 ce lu.! anose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, substituted cellulose esters, for example acetylated. cellulose, substituted cellulose ether-esters, for example, acetylated ethyl cellulose, chithosan, or from synthetic polymers such as vinyl polymers, e.g. Rylic, polymethacrylic acid, polyvinylpyrrolidone and polyvinyl alcohol, polyglycolic acid, polylactic acid, polydex * Of a triacet or copolymer, such as polyoxyethylene-polyoxypropylene copolymers, or natural fibers, synthetic fibers or mixtures of any of the aforementioned materials or compounds.

The solid biocompatible carrier will preferably take the form of a granule, a powder, a tampon, a film, a patch, a surgical dressing, or a bandage band (band 1a).

Solid biocompatible carriers will typically be selected from those already used as hemostats, such as tartrate cellulose, collagen, gelatin, alginate or synthetic polymers.

The biocompatible carrier may further comprise a fibrinolysis inhibitor such as aprotinin,? -Aminocaproic acid or tranexamic acid. It may also contain a stabilizer, such as naturally occurring amino acids, mono- or disaccharides, polyglycols, glycerol, proteins or metal salts, such as calcium salts, and mixtures thereof. It is also possible to add buffer salts such as alkali metal acetates, alkali metal carbonates or hydrogen carbonates, alkali metal citrates, alkali metal phosphates or hydrogen phosphates, alkali metal succinates, inidazole, TRIS and zwitterionic buffer systems, and mixtures thereof. Antimicrobial or bacteriostatic agents such as antibiotics, sulfamides, antifungal agents, antiviral compounds as well as preservatives may also be added.

The method and haemostatic composition of the invention are useful for assisting in stopping bleeding in a variety of surgical or other injuries such as accidental injury, skin and / or adjacent tissues, or larger abdominal, organs (liver, spleen or intestines), lung surgery, in neurochirorgia to prevent damage to the brain or nerve tissues by pressure, in orthopedic surgeries often involving extensive bleeding which is difficult to stop in other ways, in vascular surgery to stop blood leakage from the suture site, i. Oral or dental surgery such as tooth tearing and nasal bleeding (epistaxis).

In the ready-to-use product, the incorporation of the Factor VIIa into the carrier material can be accomplished by various known methods, such as co-shrinkage, swelling, dispersion, mixing, impregnation, spraying, implantation, injection, or a combination thereof.

If the carrier is a gel or paste, factor VIIa is incorporated into the carrier material preferably under aseptic conditions. This can be accomplished by adding a suitable Factor VIIa solution to the carrier material, which is then gently mixed with a suitable device to achieve uniform distribution of Factor VIIa in the gel or paste. The scattered Factor Vila sc material is then transferred to a suitable container, such as a tube, for example. jacket. plastic or syringe. Final sterilization can be carried out, for example, by heat or by ionizing radiation.

If the carrier is a solid mass, Factor VIIa can be incorporated into it by incorporating the mass into a suitable Factor VIIa solution for a sufficient period of time to ensure adequate absorption of the Factor VIIa solution. Factor Vila sc can also be injected into a solid support by spraying, implantation or multiple injections. For vacuum drying or freeze-drying to evaporate excess water, the carrier impregnated with Factor VIIa is transferred to a suitable container, such as, for example, sachets or slaves, and π and I: onec - ; It is stabilized, for example, by heat, ethylene oxide or ionizing radiation;

Factor VIIa can also be fixed to the support

J. by my electrostatic action between the Factor VIIa and the carrier material.

Factor Vila can also be bound to a carrier as well. covalently using chemical crosslinking agents such as bifunctional esters of h-hydroxyroxyuccinimide or other bifunctional chemical crosslinking agents.

Also, Factor VII can be fixed to the support using physical phenomena such as absorption, dispersion or absorption.

Factor VIIa can also be added to the carrier just prior to use, for example by spraying a suitable solution of Factor VIIa onto the carrier material or by embedding the carrier in a Factor VI.Ia solution. Alternatively, the Factor VIIa solution may be injected into the carrier.

A preferred carrier is a biodegradable tampon material known as a thermostatic tampon.

Materials for the preparation of hemostatic tampons are selected from biodegradable or biodegradable compounds such as collagen, gelatin, chitin, cellulose, polyglycolic acid and polyacetic acid. Such absorbable neats may be left in place of bleeding even after sewing internal injuries and will exert their effect for a period of time that depends on their water solubility, degradability and size.

The properties of the abovementioned materials can be modified by various chemical or physical treatments which result in, for example, better mechanical strength or lower solubility in water, thereby slowing the rate of absorption so that the duration of hemostatic activity is prolonged.

*

For example, the gelatin may be denatured by heating at temperatures ranging from 100 to 160 ° C for several hours. After such treatment, the initially water-soluble gelatin becomes substantially water-insoluble, but is still capable of being degraded into absorbable molecules by anti-collagen enzymes dark in the body.

Conversely, hemostatic swabs prepared from undenatured gelatin will dissolve fairly quickly and will turn into a soft gel upon contact with aqueous, solutions, or bleeding wounds. A factor VIIa-static tampon can be prepared by either foaming from undenatured gelatin and factor VIIa. which is then freeze-dried or saturation of the preformed dried tampon with a Factor VIIa solution, and then the wet tampon is freeze-dried.

The latter process involves the possibility of using a water-insoluble tampon material, which may be advantageous since such tampons retain their physical structure upon application to the bleeding site for a considerably longer period than undenatured tampons.

In a preferred embodiment of the invention, the carrier is a hemostatic ready-to-use pone to which factor VIIa has been added prior to introduction into the container and final sterilization.

The invention is illustrated by the following examples

Example 1 of the invention

Example:

Four 5 nm were cut using an adenotome: a core of a Jatin swab (Spongostan, a commercially available product from Novo Nordisk A / S). Two of these cores were soaked in sterile water and the other two in two ml of sterile water in which 1.13 mg of Factor VIIa was dissolved. The soaking time was approximately 5 minutes prior to application to the bleeding site prepared as described below

A Spraque-Dawlev rat <150 g was anesthetized with halothane and then an anesthetic solution was administered intraperitoneally at a rate of 0.2 ml / kg (from stock solution).

by 1 a

The rat was then placed on the spindle heating pad. The abdominal cavity with a long incision in the liver. Intestine contents were swabbed with logic solution swabs.

central area to dampened in the body of a physiological plate. Throughout the 5 mm biopsy of said fixed bed twisting cores, the liver thickness was inserted under the liver and excised to remove the specimens and specimens. du t i n by 1 and s o gelatine tampon.

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At this time, the liver was excised and the gel was gently pulled after gripping with the tweezers, and even after the expiration of the new nuclei, the teeth were gradually fine.

Both sites where the cores were inserted into the Factor Vila impregnated tampon stopped bleeding, while the other two sites continued to leak. None of the four cores were difficult to remove from the biopsy site, but found more difficult to remove the cores impregnated with Factor VIIa,

Example

A sponge (Spongostan Standard) was excised x 10 wounds before surgery. The stated dimensions were chosen p tampon will accurately cover the cut with a length of dry that latin small piece of 45 x roto, and it would be 25 mm with an overlap of 10 mm.

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D á I e was. EXAMPLE. pravenvodn characterized solution dried Factor Vlla, containing ion 10.0 mmol), which was prior to surgery (η 1, -.- .. · n · τ] ¹ 1 \ i N * ^il O · ^1.1 · Calcium by the action of freeze-drying of the concentration of waiting at room temperature.

In the anesthetized pig, the abdominal wall was cut through the median plane and the spleen was retracted into the wound. Then cuts of 3.0 µm depth and 25 mm length were made with a special tool made of a scalpel with a fixed block attached and a sample with a linear groove. The first incision was a control, left for free bleeding for 12 minutes, tan coagulation.

to ensure there is no staple13

At a distance of 30 nuu from the first incision, another incision was made, which was. allowed to bleed freely for 00 seconds. A piece of gelatin swab was then placed on the incision and dripped with 1 ml of Factor VIIa solution and gently rubbed into the swab by gentle finger pressure for 30 seconds. Immediately complete bleeding was stopped.

The tests also included the use of four different commercially available hemostatic swabs moistened with isotonic sodium chloride solution. The time required to stop bleeding ranged from 1.8 minutes to 7.5 minutes.

Using the same testing procedure, the bovine thrombin used in the aqueous solution (50 µl units / ml) immediately caused bleeding.

Example 3: To be incorporated into the matrix, Factor VIIa was applied topically as a spray to control venous bleeding from the gallbladder bed and incision during surgical opening of the abdomen. The experiments were divided into two parts, comprising a total of C patients, and were designated as random! placebo study.

Vials containing 5G2.5 µg lyophilized Factor VIIa or Factor VIIa-like placebo preparations were supplemented with 3.7 ml sterile water immediately prior to use and were immediately aspirated into syringes with spear needles.

A total of 3.7 ml was used for each application.

The trial was performed in four patients undergoing gall bladder surgery, two of which were treated with Factor VIIa and the other two with placebo. After removal of the gallbladder, Factor VIIa and placebo, respectively, were applied to the gallbladder by syringe. Efficacy was evaluated after 2 minutes. In all cases, the efficacy of the preparation was evaluated by comparing the degree of compression before and after application.

Further experiments were performed on four patients undergoing vigorous abdominal surgery until each incision was stretched down, but not through the peritoneum, with arterial spray bleeding being handled by conventional surgical techniques. Immediately after the surgical incision, the center of the wound was covered with a thick swab and a Vitus Factor was sprayed onto one end of the wound while the corresponding placebo was sprayed on the other end. The effect was evaluated no longer than 3 minutes after the wound spray. The surgeon judged by the eye that half the wound bleed less.

In these experiments, Factor VIIa had no effect on the management of living bleeding. The likely reason was the fact that Factor VIIa was washed away with the wounds, if applied, only in conscious solution and was not incorporated into a matrix or biologically compatible carrier that would allow Factor VIIa to remain in contact with the bleeding blow.

The scope of the invention is not limited to the above examples, since these are intended to serve as mere illustrations of the invention. Those skilled in the art will appreciate various possible modifications of the invention beyond those shown and described above. These modifications are intended to fall within the scope of the appended claims.

1

A haemostatic means for improving the arrest progress under 1 b of the invention; to the central cause of local bleeding.

Claims (20)

CLAIMS 1. A hemostatic blood clotting agent comprising a hemostatically effective amount of Factor VIIa which is not accompanied by other blood clotting factors and which is sucked; sufficiently effective to produce a homostatic effect, together with a biocompatible carrier that allows Factor VIIa to remain in contact with the bleeding wound. 2. The hemostatic composition of claim 1, wherein the biocompatible carrier is a gel. EAT or PASTA. 3. The hemostatic composition of claim 2, wherein the gel or paste has a viscosity in the range of about 200 to about 30,000 cps. Substance. 4. The hemostatic composition of claim 1 wherein the biocompatible carrier is a solid. 5. The hemostatic composition of claim 1, wherein the biocompatible carrier is selected from the group consisting of natural macromolecules, chemically modified natural molecules, synthetic polymers, natural or synthetic fibers, or mixtures thereof. The haemostatic composition of claim 5, wherein the biocompatible carrier is selected from the group consisting of polysaccharides or proteins or mixtures thereof. GOING 7. The haemostatic composition of claim 4, wherein the biocompatible carrier is a granule, a lipase, a lipase, a lipase, a lipase, and a bio-compatible carrier. 1G 8. The composition according to claim 4, wherein the modified cellulose, collagen biology according to claim 4, is a gelatin or natural or fibrous fiber. 9. The composition of claim 1, wherein the Factor VIIa is fixed to the biocompatible carrier by electrostatic interaction between Factor VIIa and the biocompatible carrier, or covalently bound by Factor VIIa to the biocompatible carrier. 10. The composition of claim 9, wherein the Factor VIIa is covalently bound to a biocompatible carrier by means of demic crosslinking agents, such as bifunctional esters of N-hydroxysuccinimide or other bifunctional demic crosslinking agents. HER. The composition according to claim 1, wherein the Factor VIIa is fixed to a biocompatible carrier by physical means, for example, by absorption, dispersion or adsorption. The ilemostatic composition of claim 1, wherein the amount of Factor VIIa is in the range of 0.2 to about 2.0 mg. GOING 13. The composition of claim 12, wherein the amount of Factor VIIa is in the range of from about 0.9 to about 1.1 mg. An ilemostatic composition according to claim 1, comprising a fitrinolysis inhibitor such as aprotinin, c-aminocaproic acid or tranexamic acid. 15. A composition according to claim 1, further comprising a stabilizer. AND 16. The composition according to claim 1, wherein the stabilizer is selected from the group consisting of naturally occurring amino acids, mono- or disaccharides, polyglycols, glycerol, proteins or ions of divalent metals and mixtures thereof. these 1. a te k. 17. The hemostatic composition of claim 1, comprising at least one buffer salt selected from the group consisting of alkali metal acetate, alkali metal carbonates or bicarbonates, alkali metal succinates, imidazole, TRIS, and a buffer system. with amphibious anions, and a mixture of ec. 18. A hemostatic composition according to claim 1 comprising at least one antimicrobial or bacteriostatic selected from the group consisting of antibiotics, sulfonamides, antifungal agents, antiviral compounds and preservatives. 19. A method of arresting local bleeding from a bleeding sign, characterized in that the stratum area of the bleeding wound is misinformed by administering an ilostatostatically effective amount of Factor VII; which is not accompanied by other bleeding arrest factors and which itself has sufficient efficacy to produce a hemostatic effect, together with a biocompatible carrier which allows Factor VIIa to remain in contact with the bleeding wound. 20. The method of claim 19 wherein the biocompatible carrier is a gel or paste. A method according to claim 20, characterized in that. wherein the gel or has a viscosity in the range of from about 200 eps to about 30,000 cps. Z · 2; 10. The method of claim 19, wherein the biocompatible carrier is a solid. 23. The process of claim 19 wherein the biocompatible carrier is selected from the group consisting of: