EP0613377A1 - Hemostatic composition for local hemostasis - Google Patents
Hemostatic composition for local hemostasisInfo
- Publication number
- EP0613377A1 EP0613377A1 EP92922509A EP92922509A EP0613377A1 EP 0613377 A1 EP0613377 A1 EP 0613377A1 EP 92922509 A EP92922509 A EP 92922509A EP 92922509 A EP92922509 A EP 92922509A EP 0613377 A1 EP0613377 A1 EP 0613377A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- biologically compatible
- compatible carrier
- fviia
- hemostatic composition
- composition according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
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- 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
- A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
-
- 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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0047—Specific proteins or polypeptides not covered by groups A61L26/0033 - A61L26/0042
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
Definitions
- the present invention relates to a method for arresting local bleedings by topical use of FVIIa and a hemostatic composition containing FVIIa.
- physiological hemostasis blood coagulation
- the extrinsic pathway involves plasma factors as well as components present in tissue extracts.
- Factor VII a proenzyme present in plasma, participates also in the extrinsic pathway of blood coagulation by converting (upon its activation to Vila) Factor X to Xa in the presence of tissue factor and calcium ions.
- Factor Xa in turn then converts prothrombin to thrombin in the presence of Factor Va, calcium ions and phospholipid. Finally, thrombin converts the plasma fibrinogen into fibrin, which in the presence of Factor XHIa and calcium ions is cross-linked and thus forming the blood clot
- Blood factors such as Factor VIII:C (see US Patents 4,831 ,119; 4,868,112; 4,886,876; 4,657,894; Re. 32,011 and 4,649,132) and Factor Vila (see US Patents 4,784,950; 4,382,083; 4,479,938 and 4,357,321) purified from natural sources or made via recombinant techniques have been used for treating patients, such as hemophiliacs, having blood-clotting deficiencies or inhibitors to blood-clotting factors. These blood-clotting factors have been delivered to the patient needing treatment as an aqueous solution by infusion or bolus injection depending on the blood factor to be delivered and the condition of the patient. Cessation of the bleeding is expected to occur typically between 15 minutes to 3 hours or more after the delivery of the blood-clotting factor.
- Factor VIII:C see US Patents 4,831 ,119; 4,868,112; 4,886,876; 4,657,894; Re. 32,011 and 4,6
- Surgical arrest of bleeding comprises ligation or suture of disrupted blood vessels, plugging by using tampons in cavities, coagulating tissue surfaces including their exposed disrupted blood vessels by heated instruments or by the application of cauterizing agents or heated air.
- Surgical hemostasis may also be aided by the application at the injured site of appropriately sized blocks, plates, or films of biologically absorbable hemostatic sponges.
- bovine thrombin or other blood clotting factors such as Factor VIII, Factor XIII or calcium ions are currently used in some places as hemostatic adjuncts in surgery, said adjuncts being administered e.g. by spraying a suitable solution thereof onto the site of bleeding such as in US 4,298,598.
- textile materials such as gauze or cotton wool fabrics or biologically absorbable sponges, which prior to the application have been soaked in a solution of one or more of said hemostatic compounds, are used such as in US 4,363,319.
- US patent 2,558,395 discloses a ready-to-use undenatured gelatine hemostatic sponge containing thrombin.
- US 4,265,233 discloses wound healing material comprising a structure made from compounds such as gelatine, collagen, polyglycolic and polylactic acid to which FXIII has been fixed by covalent binding.
- EP 277096 A discloses a wound dressing comprising a stable thrombin composition and a substrate such as hemostatic, porous sponges of collagen or denatured gelatine
- WO 90/13320 discloses a porous sponge containing a hemostatically effective amount of thrombin, and hemostatically effective amounts of one or more blood coagulation factors other than thrombin.
- US patent 4,563,387 and US patent 4,642,111 relate to, respectively, a method and device for treating cancer and which disclose an anti-cancer drug and a blood coagulation factor being fixed to a structure, such as a polymer, capable of being delivered by injection to the site of bleeding directly caused by the cancer treatment.
- Japanese published patent application No. 59-116213 discloses an aerosol containing FXIII and thrombin and Japanese published patent application No. 02-167234 discloses adhesive for living tissues containing fibrinogen, prothrombin, FVII, FIX, FX, FXIII, ant ⁇ thrombin, protease inhibitor and calcium ions.
- bovine derived products e.g. thrombin or prothrombin
- BSE Bovine Spongiform Encephalopathy
- the virus-like agent may be the reason for one or more well known diseases characterized by degenerative encephalopathy e.g. Creutzfeldt-Jacob disease and Kuru.
- clinical investigators have observed that the topical use of bovine thrombin in humans may cause the development of antibodies cross-reacting to human thrombin and causing bleeding problems.
- an object of the present invention to provide a safe and effective means to topically arrest bleedings at the site of an injury.
- the present invention is based on the surprising recognition that FVIIa is capable of momentarily arrest of bleedings when applied topically to the site of injury without the presence of thrombin or other coagulation factors and when FVIIa is in association, together with or incorporated into a biologically compatible carrier (which, as used herein, is intended to include a composition or material) capable of preventing FVIIa from being washed away from the site of injury.
- a biologically compatible carrier which, as used herein, is intended to include a composition or material
- FVIIa is incorporated into a biologically compatible carrier which does not contain thrombin and is unaccompanied or uncontaminated by any other blood clotting factors.
- the present invention is thus related to a hemostatic composition comprising a hemostatically effective amount of FVIIa incorporated into biologically compatible carrier said composition containing no thrombin.
- this invention provides a hemostatic composition for inducing hemostasis at a bleeding wound comprising a hemostatically effective amount of FVIIa which is uncontaminated or unaccompanied by other blood clotting factors and which has sufficient activity alone to produce a hemostatic effect, together with a biologically compatible carrier which permits said factor Vila to remain affixed to, in association with or contacting said wound site.
- Hemostat or Hemostatic Agent An agent that arrests hemorrhage.
- Hemostatic Composition A composition that contains a Hemostat or Hemostatic Agent.
- Blood clot The final outcome of the blood coagulation cascade, formed by conversion of soluble plasma fibrinogen into insoluble fibrin, which physically stops the bleeding.
- the blood clot covers the surface, keeps the wound edges together and forms the matrix for the following cell proliferation and wound healing.
- Blood clotting factors Plasma proteins which participate in the blood coagulation cascade.
- Activated blood clotting factors Blood clotting factors converted to active enzymes by the action of an activator, often itself being an activated blood clotting factor. They are generally designated by the addition of a lower case postscript "a" (e.g. Factor Vila).
- Proenzymes An enzyme precursor that in general has reduced or no activity as compared to the mature enzyme.
- Biologically absorbable Material which can be degraded in the body to smaller molecules having a size which allows transport into the blood stream and gradual removal from the site of application.
- Sponge A porous structure being reticulate and having an inner surface considerably larger than the outer surface.
- the porous structure will contain hollow spaces within the reticulate structure and can absorb many times its own weight in liquids.
- Covalent binding A bond between two atoms in which both of the atoms concerned contribute the electron or electrons.
- Dressing Material applied to a wound and fastened in place to provide protection and to promote healing.
- Biolactin The ability to be accepted in the body and remain functional for a period without rejection.
- Gel A colloidal system comprising a solid and a liquid phase which exists as a solid or semisolid mass.
- Paste An ointment-like preparation of one or more substances in a hydrogel or fatty base. It is less greasy and better absorbed than an ointment.
- Granule A minute particle or mass.
- Film Any thin covering, coating, or layer.
- Plaster A substance intended for external application, made of such material and of such consistency as to adhere to the skin.
- Bandage A strip of gauze, muslin, flannel, or other material used to hold dressings in place, or to check hemorrhage.
- FVIIa is to be used in a hemostatically effective amount.
- hemostatically effective amount is meant an amount which will preferably cause arrest of the bleeding if kept in association with or contacting the site of the injury for a sufficient amount of time, preferably from about 60 seconds in patients not having an impaired hemostatic mechanism to less than about 10 minutes in patients having an impaired hemostatic mechanism.
- FVIIa should be used in an amount ranging from about 0.2 to about 2.0 mg, preferably from about 0.5 to about 1.5 mg and more preferably from about 0.9 to about 1.1 mg per application.
- FVIIa may be derived from plasma as described in EP 0082182B or by recombinant DNA-technology as described in EP 0200421 A.
- Human purified factor Vila is preferably made by the methods described by Broze and Majerus, J. Bio. Chem. 255, 4: 1242-1247, 1980, and Hedner and Kisiel, J. Clin. Invest. 71 : 1836-1841 , 1983. These methods yield factor VII without detectable amounts of other blood coagulation factors.
- An even further purified factor VII preparation may be obtained by including an additional gel filtration as the final purification step.
- Factor VII is then converted into activated factor Vila by known means, e.g.
- factor VII may be activated by passing it through an ion-exchange chromatography column, such as MonoQ (Pharmacia Fine Chemicals, Uppsala, Sweden) or the like.
- a suitable factor Vila for use in the present invention may also be produced by recombinant DNA technology, e.g., by insertion of the cDNA or gene encoding factor VII (Hagen et al., Proc. Natl. Acad. Sci. USA 83: 2412-2416, 1986) in a suitable vector, transforming of suitable cell lines with the vector and growing the transformed cells in an appropriate medium whereupon the expressed product is isolated and activated into factor Vila. Production of FVII by recombinant DNA technology is also described in US Patent 4,784,950 which is incorporated herein by reference in its entirety.
- Factor Vila produced by recombinant DNA technology may be authentic factor Vila or a more or less modified factor Vila, provided that such modified factor Vila has substantially the same biological activity for blood coagulation as authentic factor Vila.
- modified factor Vila may be prepared by modifying the DNA sequence encoding factor VII either by altering the amino acid codons or by removal of some of the amino acid codons in the natural gene by known means, e.g., by site-specific mutagenesis.
- the carrier material may be a gel, a paste, a solid or other suitable biologically compatible/acceptable carrier for topical application of pharmaceuticals or other biologically active compositions.
- the viscosity of the gel or paste will preferably be from about 200 cps to about 30,000 cps.
- the biologically compatible carrier will typically be made of natural macromolecules such as gelatine, collagen, alginic acid, cellulose, chitin, fibrinogen, fibrin, fibrin split products, fibronectin, fibronectin fragments, globulin, myoglobulin, casein, keratin, albumin, polysaccharides e.g. dextrans, glycosaminglycans, agar, pectin, starch or from chemical modified natural molecules such as denatured gelatine, alginicacid-alginates e.g. calcium alginate, oxidized cellulose, substituted cellulose ethers e.g.
- natural macromolecules such as gelatine, collagen, alginic acid, cellulose, chitin, fibrinogen, fibrin, fibrin split products, fibronectin, fibronectin fragments, globulin, myoglobulin, casein, keratin, albumin, polysaccharides e.g. dextrans
- glycol cellulose methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, substituted cellulose esters e.g. acetylated cellulose, substituted cellulose ether-esters e.g. acetylated ethyl cellulose, chithosan or from synthetic polymers such as vinyl polymers, e.g.
- poiyacrylic acid poiyacrylic acid, polymethacrylic acid, polyvinyl pyrrolidone and polyvinyl alcohol, polyglycolic acid, polylactic acid, polydextroses or copolymers such as polyoxyethylene-polyoxypropylene copolymers or from natural fibers, synthetic fibers or mixtures of any of the above materials/compounds.
- a solid biologically compatible carrier will preferably be a granule, powder, sponge, film, plaster, surgical dressing or a bandage.
- Solid biologically compatible carriers will typically be selected from those already used as hemostats such as modified cellulose, collagen, gelatine, alginate or synthetic polymers.
- the biologically compatible carrier may furthermore contain a fibrinolysis inhibitor, such as aprotinin, epsilon-aminocaproic acid or tranexamic acid. It may also contain a stabilizer, such as naturally occurring amino acids, mono- or disaccha des, polyglycols, glycerol, proteins or a metal salt, such as calcium salts, and mixtures thereof. Also buffering salts may be added, such as alkaline metal acetates, alkaline metal carbonates or hydrogen carbonates, alkaline metal citrates, alkaline metal phosphates or hydrogen phosphates, alkaline metal succinates, imidazole, TRIS, and zwitteranionic buffering systems, and mixtures thereof. Furthermore, antimicrobial or bacteriostatic agents, such as antibiotics, sulphonamides, antimycotic agents, antiviral compounds, and preservatives may be added.
- a fibrinolysis inhibitor such as aprotinin, epsil
- the present method and hemostatic composition will be useful for enhancing the arrest of bleedings in several instances of surgical interventions or other injuries such as in the accidental injury of the skin and/or adjacent tissues or of larger abdominal organs (liver, spleen, or intestines); in lung surgery; in neurosurgery to prevent pressure damages of the cerebral or nerve tissues; in orthopedic surgery during which extensive hemorrhages frequently occur which are difficult to arrest by other means; in vascular surgery to arrest seepage of blood from the sites of suturing; in oral or dental surgery such as extraction of teeth; and in nose-bleeding (ep ⁇ staxis).
- surgical interventions or other injuries such as in the accidental injury of the skin and/or adjacent tissues or of larger abdominal organs (liver, spleen, or intestines); in lung surgery; in neurosurgery to prevent pressure damages of the cerebral or nerve tissues; in orthopedic surgery during which extensive hemorrhages frequently occur which are difficult to arrest by other means; in vascular surgery to arrest seepage of blood from the sites of suturing; in oral or dental surgery
- incorporation of FVIIa into the carrier material may be done by various known methods, such as co-precipitation, swelling, dispersion, mixing, soaking, spraying, embedding, injection or a combination thereof.
- FVIIa is preferably incorporated into the carrier material under aseptical conditions. This may be carried out by adding a suitable solution of FVIIa to the carrier material which is then stirred gently by suitable means to obtain a uniform distribution of FVIIa within the gel or paste.
- the FVIIa loaded carrier material is then transferred to a suitable package form e.g. a tube, a plastic container or a syringe. Terminal sterilization may be carried out by means of, for instance, heat or ionizing irradiation.
- the carrier may be loaded with FVIIa by placing the material in a suitable solution of FVIIa for a period sufficient to ensure that the carrier material is adequately soaked with the FVIIa solution.
- FVIIa may also be incorporated into the solid carrier by means of spraying, embedding or multiple injections. After vacuum drying or freeze drying to evaporate excess of water the FVIIa impregnated carrier is transferred to a suitable package, such as paper bags or a blister package and terminally sterilized by means of, for instance, heat, ethyleneoxide or ionizing irradiation.
- FVIIa may be fixed to the carrier by electrostatic interaction between FVIIa and the carrier material.
- FVIIa may also be covalently bound to the carrier by means of chemical crosslinking reagents, such as bifunctional N-hydroxy succinimide esters or other bifunctional chemical crosslinking reagents.
- chemical crosslinking reagents such as bifunctional N-hydroxy succinimide esters or other bifunctional chemical crosslinking reagents.
- FVIIa may be fixed to the carrier by physical means such as absorption, dispersion or adsorption.
- FVIIa may also be added to the carrier just before use, e.g. by spraying a suitable solution of FVIIa onto the carrier material or by embedding the carrier into a FVIIa solution. Alternatively, the FVIIa solution may be injected into the carrier.
- a preferred carrier is a biodegradable sponge material known in the prior art as hemostatic sponges.
- Materials for the preparation of hemostatic sponges are conventionally selected from biodegradable or biologically absorbable compounds such as collagen, gelatine, chitin, cellulose, polyglycolic acid and polyacetic acid.
- Such absorbable hemostats can be left at the site of bleeding even after suturing of internal injuries and will exert their effect over a period of time, dependent on their water solubility, degradability, and size.
- the characteristics of the above materials may be conditioned by various chemical or physical treatments resulting in e.g. a preferred improved mechanical strength of the structure or in rendering the material less water soluble thereby retarding the rate of absorption which may extend the period of hemostatic activity.
- gelatine may be denatured by treatment at temperatures in the range of 100 - 160°C for several hours. After such treatment the originally water soluble gelatine will become substantially water insoluble but can still be degraded to absorbable molecules by proteolytic enzymes present in the body.
- hemostatic sponges prepared from undenatured gelatine will dissolve rather rapidly and turn into a soft gel when brought into contact with aqueous solutions or bleeding wounds.
- the FVIIa containing dry hemostatic sponge may be prepared either by forming a foam of undenatured gelatine and FVIIa which is thereafter freeze-dried or by saturating a preformed dried sponge with a solution of FVIIa, the wet sponge thereafter being freeze-dried.
- the carrier is a ready-to-use hemostatic sponge to which FVIIa has been added prior to packaging and terminal sterilization.
- a 450 gram Spraque-Dawley rat was anesthetized with halothane, followed by 0.2 ml/kg of a stock anesthetic solution, which was given intraperitoneally.
- the rat was placed on a warming pad and the abdomen was opened with a long, mid-line incision to expose the liver. Gut contents were packed with warm saline swabs.
- a piece of steel was placed behind the liver to provide a firm bed.
- Four 5 mm biopsies were cored through the full thickness of the liver and removed and the four prepared pieces of gelatine sponge were placed into the holes.
- test series did also include four different, commercially available hemostatic sponges moistened with an isotonic Sodium chloride solution.
- the individual time for hemostasis ranged from 1.8 minutes to 7.5 minutes.
- Vials containing 562.5 ⁇ g of lyophilized Factor Vila or placebo preparations resembling Factor Vila were reconstituted with 3.7 ml of sterile water immediately before use and transferred into syringes with sprinkler needles. All 3.7 ml were syringed at each administration.
- Factor Vila had no effect in the control of venous bleeding. The likely reason was considered to be that Factor Vila was washed away from the wound when applied only in an aqueous solution and not incorporated into a matrix or a biologically compatible carrier which would have allowed factor Vila to remain in contact with the bleeding wound.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Materials Engineering (AREA)
- Hematology (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Materials For Medical Uses (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
L'invention se rapporte à un procédé pour stopper les hémorragies locales par l'application locale du facteur FVIIa, et à une composition hémostatique contenant le facteur FVIIa et un vecteur biologiquement compatible qui permet au facteur FVIIa de rester en contact avec ladite lésion hémorragique.The invention relates to a method for stopping local bleeding by the local application of factor FVIIa, and to a hemostatic composition containing factor FVIIa and a biologically compatible vector which allows factor FVIIa to remain in contact with said hemorrhagic lesion.
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US77566491A | 1991-10-11 | 1991-10-11 | |
US775664 | 1991-10-11 | ||
PCT/DK1992/000296 WO1993006855A1 (en) | 1991-10-11 | 1992-10-09 | Hemostatic composition for local hemostasis |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0613377A1 true EP0613377A1 (en) | 1994-09-07 |
Family
ID=25105103
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP92922509A Withdrawn EP0613377A1 (en) | 1991-10-11 | 1992-10-09 | Hemostatic composition for local hemostasis |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0613377A1 (en) |
JP (1) | JPH07500095A (en) |
AU (1) | AU2793292A (en) |
CA (1) | CA2121028A1 (en) |
CZ (1) | CZ83194A3 (en) |
FI (1) | FI941628A (en) |
HU (1) | HUT67693A (en) |
NO (1) | NO941285L (en) |
WO (1) | WO1993006855A1 (en) |
Families Citing this family (36)
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ES2227542T3 (en) * | 1993-11-03 | 2005-04-01 | Clarion Pharmaceuticals, Inc. | HEMOSTATIC PATCH. |
DE19903693A1 (en) * | 1998-04-24 | 1999-10-28 | Centeon Pharma Gmbh | Protease for activation of coagulation factor VII |
FR2754183A1 (en) * | 1996-10-08 | 1998-04-10 | Lefebvre Jean Marie | VISCOUS HEMOSTATIC COMPOSITION, IN PARTICULAR IN THE CONDITION OF FROST |
DE19710190A1 (en) * | 1997-03-12 | 1998-09-17 | Immuno Ag | Activated vitamin K-dependent blood factor and method for its production |
WO1998058661A1 (en) * | 1997-06-23 | 1998-12-30 | Novo Nordisk A/S | Use of fviia for the treatment of bleedings in patients with a normal blood clotting cascade and normal platelet function |
AU5807500A (en) * | 1999-07-14 | 2001-02-05 | Novo Nordisk A/S | Use of fviia or a tissue factor antagonist for regulating gene expression and cell migration or chemotaxis |
GB0011053D0 (en) | 2000-05-09 | 2000-06-28 | Hudson John O | Medical device and use thereof |
IL152554A0 (en) * | 2000-05-10 | 2003-05-29 | Novo Nordisk As | PHARMACEUTICAL COMPOSITION COMPRISING A FACTOR VIIa AND A FACTOR XIII |
US7015194B2 (en) | 2000-05-10 | 2006-03-21 | Novo Nordisk A/S | Pharmaceutical composition comprising factor VIIa and anti-TFPI |
ATE316387T1 (en) | 2000-09-22 | 2006-02-15 | Perlei Medical Produkte Gmbh | USE OF ANTIFIBRINOLYTICS FOR THE PREPARATION AND MANUFACTURING OF SWABS, COMPRESSES OR PLASTERS |
JP2005508985A (en) * | 2001-11-09 | 2005-04-07 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Pharmaceutical composition comprising a Factor VII polypeptide and an aprotinin polypeptide |
US7291587B2 (en) | 2001-11-09 | 2007-11-06 | Novo Nordisk Healthcare A/G | Pharmaceutical composition comprising factor VII polypeptides and TAFI polypeptides |
JP2005510513A (en) | 2001-11-09 | 2005-04-21 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Pharmaceutical compositions comprising factor VII polypeptide and TAFI polypeptide |
US7125846B2 (en) | 2001-11-09 | 2006-10-24 | Novo Nordisk Healthcare A/G | Pharmaceutical composition comprising factor VII polypeptides and factor V polypeptides |
JP2006510568A (en) * | 2001-11-09 | 2006-03-30 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | A pharmaceutical composition comprising a Factor VII polypeptide and epsilon-aminocaproic acid |
EP1446147A1 (en) * | 2001-11-09 | 2004-08-18 | Novo Nordisk Health Care AG | Pharmaceutical composition comprising factor vii polypeptides and tranexamic acid |
US7078479B2 (en) | 2001-11-09 | 2006-07-18 | Novo Nordisk Healthcare A/G | Pharmaceutical composition comprising factor VII polypeptides and alpha2-antiplasmin polypeptides |
GB2409162B (en) * | 2004-10-06 | 2005-12-14 | Bhk Holding Ltd | Materials,methods,and apparatus for treating a body cavity |
AR048742A1 (en) * | 2004-12-22 | 2006-05-24 | Gador Sa | INTRA-ORAL MEDICINES APPLICATION SYSTEM |
FR2894831B1 (en) | 2005-12-16 | 2008-02-15 | Lab Francais Du Fractionnement | THROMBIN FREE BIOLOGICAL GLUE AND USE THEREOF AS MEDICAMENT. |
WO2007104317A1 (en) * | 2006-03-16 | 2007-09-20 | Drugrecure Aps | Methods for local treatment with factor vii |
GB2447012B (en) | 2007-02-21 | 2011-03-16 | Pharmacure Health Care Ab | Composition for combating epistaxis |
WO2009109194A2 (en) | 2008-02-29 | 2009-09-11 | Ferrosan A/S | Device for promotion of hemostasis and/or wound healing |
ES2421642T3 (en) * | 2008-03-03 | 2013-09-04 | Omrix Biopharmaceuticals Ltd | A jelly sponge comprising an active ingredient, its preparation and use |
RU2501556C2 (en) * | 2011-10-06 | 2013-12-20 | Владимир Лазаревич Адамян | Heamostatic match |
IN2014DN08122A (en) | 2012-03-06 | 2015-05-01 | Ferrosan Medical Devices As | |
EP2825216B1 (en) | 2012-06-12 | 2015-08-19 | Ferrosan Medical Devices A/S | Dry haemostatic composition |
AU2014283170B2 (en) | 2013-06-21 | 2017-11-02 | Ferrosan Medical Devices A/S | Vacuum expanded dry composition and syringe for retaining same |
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RU2715235C2 (en) | 2014-10-13 | 2020-02-26 | Ферросан Медикал Дивайсиз А/С | Dry composition for use in haemostasis and wound healing |
AU2015371184B2 (en) | 2014-12-24 | 2020-06-25 | Ferrosan Medical Devices A/S | Syringe for retaining and mixing first and second substances |
CN107771093B (en) | 2015-07-03 | 2021-06-15 | 弗罗桑医疗设备公司 | Syringe for mixing two components and for maintaining vacuum under storage conditions |
AU2016313773B2 (en) * | 2015-09-01 | 2020-11-26 | Baxter International Inc. | Hemostatic material |
WO2019215274A1 (en) | 2018-05-09 | 2019-11-14 | Ferrosan Medical Devices A/S | Method for preparing a haemostatic composition |
WO2021128050A1 (en) * | 2019-12-25 | 2021-07-01 | Guangzhou Bioseal Biotech Co., Ltd. | Hemostatic paste and uses thereof |
WO2024042148A1 (en) | 2022-08-26 | 2024-02-29 | Stellaris Pharmaceuticals Aps | Haemorrhage inhibiting compositions and methods involving the same |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4382083A (en) * | 1981-06-25 | 1983-05-03 | Baxter Travenol Laboratories, Inc. | Therapeutic method for treating blood-clotting defects with factor VIIa |
ES2037664T3 (en) * | 1985-11-26 | 1993-07-01 | Novo Nordisk A/S | COMPOSITIONS AND METHODS FOR THE TREATMENT OF HEMORRHAGIC DISORDERS. |
-
1992
- 1992-10-09 CZ CS94831A patent/CZ83194A3/en unknown
- 1992-10-09 CA CA002121028A patent/CA2121028A1/en not_active Abandoned
- 1992-10-09 JP JP5506562A patent/JPH07500095A/en active Pending
- 1992-10-09 EP EP92922509A patent/EP0613377A1/en not_active Withdrawn
- 1992-10-09 HU HU9401008A patent/HUT67693A/en unknown
- 1992-10-09 WO PCT/DK1992/000296 patent/WO1993006855A1/en not_active Application Discontinuation
- 1992-10-09 AU AU27932/92A patent/AU2793292A/en not_active Abandoned
-
1994
- 1994-04-08 NO NO941285A patent/NO941285L/en unknown
- 1994-04-08 FI FI941628A patent/FI941628A/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO9306855A1 * |
Also Published As
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WO1993006855A1 (en) | 1993-04-15 |
FI941628A0 (en) | 1994-04-08 |
HU9401008D0 (en) | 1994-07-28 |
HUT67693A (en) | 1995-04-28 |
NO941285D0 (en) | 1994-04-08 |
CZ83194A3 (en) | 1994-11-16 |
JPH07500095A (en) | 1995-01-05 |
AU2793292A (en) | 1993-05-03 |
FI941628A (en) | 1994-06-08 |
NO941285L (en) | 1994-06-07 |
CA2121028A1 (en) | 1993-04-15 |
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