WO1998015292A1 - Viscous hemostatic composition, in particular in gel state - Google Patents

Viscous hemostatic composition, in particular in gel state Download PDF

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Publication number
WO1998015292A1
WO1998015292A1 PCT/FR1997/001797 FR9701797W WO9815292A1 WO 1998015292 A1 WO1998015292 A1 WO 1998015292A1 FR 9701797 W FR9701797 W FR 9701797W WO 9815292 A1 WO9815292 A1 WO 9815292A1
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Prior art keywords
hemostatic
product according
hemostatic product
acid
composition
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PCT/FR1997/001797
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French (fr)
Inventor
Jean-Marie Lefebvre
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Lefebvre Jean Marie
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Priority to EP97944945A priority Critical patent/EP1011727A1/en
Publication of WO1998015292A1 publication Critical patent/WO1998015292A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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 hemostatic product, biocompatible and biodegradable, having prohemostatic properties even in the presence of drugs acting on coagulation such as heparin, anti-platelet aggregating agents.
  • the hemostatic products used act to initialize or accelerate the physiological processes of coagulation involved in the formation of the thrombus or clot which produces the hemostasis of the vascular breach. This allows operative intervention even if the patient has vascular fragility or impaired coagulation, whether this alteration is spontaneous or follows treatments such as the injection of heparin.
  • Local hemostasis is also necessary for certain surgical procedures for which the operating field must be perfectly bloodless, such as in microsurgery, neurology or ophthalmology.
  • Hemostasis of the puncture site is usually achieved when the catheter or introducers are removed by manual compression in a few minutes.
  • manual compression can be difficult, long, source of hematomas or haemorrhages.
  • local hemostasis is carried out at the puncture site.
  • Local hemostasis techniques use collagen buffers or fibrin and thrombin solutions or mechanical processes such as the application of a bioresorbable tablet inside the vessel or by thread suturing surgical. All these techniques are difficult to carry out.
  • Certain products are not degradable, are not bio-eliminable and are therefore currently only used on external and superficial wounds such as products based on alginate or derivatives of cellulose. Because of the risks of infectious and viral contamination (hepatitis, AIDS, ...) there is currently an indisputable reluctance to use products of human origin. In addition, due to recent developments in Creutzfeld-Jacob disease and the risk of contamination by prions, there is currently a significant reluctance to use collagen due to its bovine origin.
  • the bleeding site is at a distance from the skin opening area.
  • collagen buffers have been developed, buffers which are biocompatible, biodegradable and which have the particularity of accelerating hemostasis, and therefore of being hemostatic despite the possible presence of heparin or anti-platelet aggregation agents.
  • the placement of the collagen buffer, in interventional radiology or in endoscopic surgery requires the use of particular devices, such as that which is the subject of document EP A-0476178.
  • This device is specially designed for the installation, at the end of the intervention procedure, of a hemostatic product in contact with the area to be closed, that is to say in contact with the wall of the blood vessel without having the risk of penetration. hemostatic product inside the vessel.
  • Such a device is marketed by the firm Datascope and specially designed for the introduction of a local hemostatic product in the form of a fibrous collagen buffer.
  • the goal that the applicant has set is to offer a hemostatic product which overcomes the aforementioned drawbacks in that on the one hand it is not collagen and it is free of products of human origin and on the other hand it avoids the use of particular introductory devices in the case of interventional radiology or endoscopic surgery, and finally it is active in all patients including those who are subjected to an anti-coagulation treatment, by example with heparin.
  • the hemostatic product of the invention which, typically, consists of a viscous composition, optionally in the gel state, biocompatible, biodegradable and / or bioeliminable, which is not a collagen composition , in which is included at least one hemostatic extract of venom from se ⁇ ent, with thrombin-like activity.
  • a hemostatic product is said to have thrombin-like activity when it acts on fibrinogen to form fibrin monomers, the polymerization of which is essential for the formation of a blood clot.
  • the enzymes, thrombin-like, extracted from snake venoms are glycoproteins, molecules of small dimensions which, under normal conditions, diffuse very quickly in the organism.
  • the fact of using the hemostatic extract of snake venom, with thrombin-like activity, in a viscous composition makes it possible to slow down the too rapid absorption of the active molecules in the tissues and their diffusion in the general circulation of the body. .
  • the composition has a viscosity greater than 50 Pa.s. (Pascal / second), the fluidity necessary for routing through the catheter being variable depending on the length and section of the catheter.
  • hemostatic extracts of snake venom are effective despite the presence of anti-coagulant treatments, for example with heparin.
  • the hemostatic agent used is tranexamic acid which is a ti-fibronoly tic year whose action is exerted when the clot is formed; this agent cannot therefore be effective in the case of a patient subjected to an anticoagulant treatment, for example with heparin, insofar as this treatment will not form the clot.
  • the viscous, biocompatible, biodegradable, collagen-free, water-soluble composition is formed from a high acetyl glucosamine polymer and glucuronic acid, namely hyaluronic acid, which is a polysaccharide functionalized by acetamide groups.
  • a certain number of polymers of natural, synthetic or semi-synthetic origin, alone or in combination, are capable of forming viscous compositions or gels which will be biodegradable or bioeliminable.
  • polyvinylpyrolidone polyvinylalcohol, polyethylene glycol
  • natural or semi-synthetic polysaccharides such as Dextran, dextran sulfate, pentosan sulfate, keratane sulfate, chondroitin sulfate, agar -agar, chitin and chitosan, carrageenate
  • proteins and their derivatives such as protamine sulphate, various peptide fractions, acid or basic site poly-alpha-amino acids such as polyglutamic acid, polyaspartic acid or polylysine, finally polydeoxyribonucleotides, alphacyclodextrin, certain triglycerides.
  • snake venom extracts there are around forty which have thrombin-like pro-hemostatic properties, even in the presence of drugs which act on coagulation such as heparin, anti-platelet aggregants or fibrinolytics .
  • hemostatic composition of the invention such as 1-naphthylamine-4-sulfonic acid, 1, 2 naphthoquinone marketed under the name of Naftazone, ellagic acid marketed under the name Lagistase, adrenalone marketed under the name Adrenalone, derivatives of arachidonic acid, ristocetin, Edenosine, cephalins.
  • Alginic acid and alginates in addition to their local hemostatic properties, also have significant gelling power.
  • Protamine sulfate which is a heparin neutralizer known and marketed as Protamine can have hemostatic activity by local route and can be used in addition to form a stable salt with heparin contained in the blood.
  • Methylene blue and hexadimetrine, which are antidotes to heparin, can also be used.
  • the hemostatic product of the invention also comprises means promoting the solidity of the clot.
  • These means may consist of different hemostatic products falling within the group of anti-fibrinolytics such as tranexamic acid marketed under the name of Exacyl or alternatively derivatives of tranexamic acid, derivatives of aminocaproic acid, cimetidine and its derivatives. Adding Calcium and / or lowering the pH will promote the polymerization of fibrin monomers and increase the stability of the clot.
  • the extract of venom of se ⁇ ent is the Ancrod marketed under the names of Ancrod or Arwin by the pharmaceutical laboratory KNOLL.
  • the present invention will be better understood on reading the description which will be given of an exemplary embodiment of a viscous hemostatic composition consisting of the combination of hyaluronic acid and Ancrod.
  • the object of the present invention is to provide a hemostatic product which makes it possible to avoid any risk of contamination by prions and by an infectious or viral agent of human origin, which is biocompatible, bioeliminable and / or biodegradable. It must also remain in contact with the vascular breach and not penetrate inside the arterial lumen, for a time sufficient for initiation of coagulation and the blood clot is formed.
  • the product of the invention must be able to be introduced under the skin without having to resort to a particular device but by using the means of introduction usually used in interventional radiology or in endoscopic surgery.
  • the hemostatic product of the invention consists of a viscous composition, optionally in the gel state, biocompatible, biodegradable or bioeliminable, which is not a collagen composition and in which is included as hemostatic active product at minus a hemostatic venom extract of se ⁇ ent with thrombin-like activity.
  • the viscous composition is syringable, that is to say it can move in the catheters and the introducers by simple manual pressure on the syringe but has a viscosity and a cohesiveness such that it remains in contact with the vascular breach and does not enter not inside the arterial lumen.
  • the viscous composition is hyaluronic acid and the active product is Ancrod.
  • the 1% hyaluronic acid composition is prepared with a hyaluronic acid with an average molecular weight of 1.10 6 Daltons.
  • the Ancrod is marketed in the form of a 1 ml solution containing 70 Units.
  • Ancrod in the composition does not affect the pro-haemostatic properties of Ancrod.
  • the hemostatic composition of the invention once introduced at the level of the wall of the vessel having the vascular breach to be closed, does not penetrate said breach because of its viscosity and its cohesive nature; the blood escaping from the vascular breach comes into contact with said composition.
  • the blood is then subjected to the progressive action of the Ancrod which initiates the start of the formation of the clot in approximately 30 seconds.
  • the formation of the clot allows hemostasis of the vascular breach to be obtained in 10 to 15 minutes. It's here retention of the Ancrod in hyaluronic acid which allows the Ancrod to have a local action.
  • Hyaluronic acid being bio-degradable will later degrade gradually to disappear from the body without causing harmful consequences for it.
  • the pro-hemostatic action of Ancrod has been widely reported in the literature, the pro-hemostatic action of Ancrod is validly obtained by adding 4 cc of hyaluronic acid, 1/2 ampoule of Ancrod, i.e. 35 units.
  • the present invention is not limited to the embodiment which has just been described by way of a preferred example of the invention.
  • it is up to the person skilled in the art to choose from all the viscous compositions, possibly in the form of biodegradable gels already used in the medical sector and from hemostatic extracts of venom from se ⁇ ent, those which are suitable for fulfilling the functions imparted to the hemostatic composition of the invention.
  • it is up to the person skilled in the art to mix several hemostatic products with a viscous composition in order to potentiate the effects of each product and to be able to be used in patients with combined treatments associating more than one drug acting on hemostasis, for example.

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Abstract

The hemostatic product of the invention is active in all patients including those treated with heparin. It consists of a viscous, biologically compatible, biodegradable composition and/or capable of being biologically eliminated but which is not a collagen composition, in which is contained a hemostatic extract of snake venom, for instance batroxobin or ancrod. The viscous composition is formed in particular from hyaluronic acid, optionally esterified.

Description

COMPOSITION VISQUEUSE HEMOSTATIQUE, NOTAMMENT A HEMOSTATIC VISCOUS COMPOSITION, ESPECIALLY A
L'ETAT DE GELTHE FREEZE STATE
La présente invention concerne un produit hémostatique, biocompatible et biodégradable, ayant des propriétés pro-hémostatiques même en présence de médicaments agissant sur la coagulation tels que l'héparine, les anti-aggrégants plaquettaires.The present invention relates to a hemostatic product, biocompatible and biodegradable, having prohemostatic properties even in the presence of drugs acting on coagulation such as heparin, anti-platelet aggregating agents.
L'hémostase locale est utilisée depuis très longtemps en chirurgie, par exemple en chirurgie viscérale, dermatologique, neurologique et ophtalmologique. Les produits hémostatiques mis en oeuvre agissent en sorte d'initialiser ou d'accélérer les processus physiologiques de la coagulation entrant dans la formation du thrombus ou caillot qui réalise l'hémostase de la brèche vasculaire. Ceci permet une intervention opératoire même si le patient présente une fragilité vasculaire ou une altération de la coagulation, que cette altération soit spontanée ou fasse suite à des traitements tels que l'injection d'héparine. L'hémostase locale est également nécessaire pour certaines interventions chirurgicales pour lesquelles le champ opératoire doit être parfaitement exsangue, comme en micro-chirurgie, neurologie ou ophtalmologie.Local hemostasis has been used for a very long time in surgery, for example in visceral, dermatological, neurological and ophthalmological surgery. The hemostatic products used act to initialize or accelerate the physiological processes of coagulation involved in the formation of the thrombus or clot which produces the hemostasis of the vascular breach. This allows operative intervention even if the patient has vascular fragility or impaired coagulation, whether this alteration is spontaneous or follows treatments such as the injection of heparin. Local hemostasis is also necessary for certain surgical procedures for which the operating field must be perfectly bloodless, such as in microsurgery, neurology or ophthalmology.
S 'agissant de la chirurgie vasculaire, la mise en oeuvre localisée de produits hémostatiques permet de contrôler les sutures artérielles qui présentent parfois des suintements hémorragiques.In the case of vascular surgery, the localized use of hemostatic products makes it possible to control the arterial sutures which sometimes present hemorrhagic oozing.
En dehors de la chirurgie, les produits hémostatiques locaux sont utilisés en radiologie interventionnelle. Dans ce domaine, bon nombre de procédures sont réalisées sous anti-aggrégants et sous anti-coagulants, voire sous thromboly tiques, ces médicaments pouvant être utilisés seuls ou en association. On obtient généralement l'hémostase du point de ponction lors du retrait du cathéter ou des introducteurs par compression manuelle, en quelques minutes. Cependant lorsque les paramètres de la coagulation ont été modifiés par des traitements médicamenteux, la compression manuelle peut être difficile, longue, source d'hématomes ou d'hémorragies. Pour pallier ces inconvénients, on peut procéder à une fenêtre thérapeutique avant de réaliser l'ablation des introducteurs, par exemple en arrêtant le traitement à l'héparine pendant une période préalable suffisamment longue ; mais ceci complique la surveillance du traitement anti-coagulant et peut entraîner des à-coups d'hyper et d'hypo-coagulabilité.Apart from surgery, local hemostatic products are used in interventional radiology. In this area, a good number of procedures are carried out using anti-aggregants and anti-coagulants, or even thrombolytics, these drugs being able to be used alone or in combination. Hemostasis of the puncture site is usually achieved when the catheter or introducers are removed by manual compression in a few minutes. However, when the coagulation parameters have been modified by drug treatments, manual compression can be difficult, long, source of hematomas or haemorrhages. To overcome these drawbacks, it is possible to proceed with a therapeutic window before removing the introducers, for example by stopping the heparin treatment for a sufficiently long prior period; but this complicates the monitoring of the anti-coagulant treatment and can lead to hyper and hypo-coagulability jerks.
Pour éviter ces difficultés complémentaires, on réalise l'hémostase locale, au niveau du point de ponction. Les techniques locales d'hémostase font appel à des tampons de collagène ou à des solutions de fibrine et de thrombine ou encore à des procédés mécaniques tels que l'application d'une pastille biorésorbable à l'intérieur du vaisseau ou à la suture par fils chirurgicaux. Toutes ces techniques sont délicates à réaliser.To avoid these additional difficulties, local hemostasis is carried out at the puncture site. Local hemostasis techniques use collagen buffers or fibrin and thrombin solutions or mechanical processes such as the application of a bioresorbable tablet inside the vessel or by thread suturing surgical. All these techniques are difficult to carry out.
L'hémostase locale concerne d'autres domaines d'application tels l'endoscopie diagnostique ou thérapeutique ou encore la chirurgie endoscopique. Ce dernier cas est à rapprocher de la radiologie interventionnelle puisque la zone hémorragique est à distance de la zone d'ouverture cutanée de sorte que le produit hémostatique doit pouvoir être apporté in-situ et rester en place pour initialiser la coagulation et être dégradé par la suite.Local hemostasis concerns other fields of application such as diagnostic or therapeutic endoscopy or even endoscopic surgery. This last case is to be compared to interventional radiology since the hemorrhagic area is distant from the skin opening area so that the hemostatic product must be able to be brought in situ and remain in place to initiate coagulation and be degraded by after.
L'hémostase locale est réalisée actuellement avec un certain nombre de produits différents , certains produits sont à base de collagène ou de produits dérivés sanguins comme le fibrinogène ou la thrombine et sont dégradés progressivement par l'organisme, ils sont donc éliminés.Local hemostasis is currently performed with a number of different products, some products are based on collagen or blood derivatives such as fibrinogen or thrombin and are gradually degraded by the body, so they are eliminated.
Certains produits ne sont pas dégradables, ne sont pas bio-éliminables et ne sont donc actuellement utilisés que sur des plaies externes et superficielles tels que les produits à base d'alginate ou des dérivés de la cellulose. En raison des risques de contamination infectieuse et virale (hépatite, sida,...) il existe actuellement une réticence indiscutable à utiliser des produits d'origine humaine. De plus en raison des développements récents de la maladie de Creutzfeld-Jacob et du risque de contamination par les prions, il existe actuellement une réticence importante à utiliser le collagène en raison de son origine bovine.Certain products are not degradable, are not bio-eliminable and are therefore currently only used on external and superficial wounds such as products based on alginate or derivatives of cellulose. Because of the risks of infectious and viral contamination (hepatitis, AIDS, ...) there is currently an indisputable reluctance to use products of human origin. In addition, due to recent developments in Creutzfeld-Jacob disease and the risk of contamination by prions, there is currently a significant reluctance to use collagen due to its bovine origin.
Par ailleurs les produits hémostatiques locaux actuels existent soit sous forme de solution liquide, soit sous forme de compresses ou de tampons hémostatiques. L'inconvénient de la solution liquide est de s'écouler immédiatement et de ne pas rester au contact de la zone à coaguler. Certes il est possible d'imbiber une compresse ou un tampon de ladite solution liquide, pour autant que la zone à coaguler soit d'accès immédiat et soit visible.Furthermore, current local hemostatic products exist either in the form of a liquid solution, or in the form of compresses or hemostatic pads. The disadvantage of the liquid solution is that it drains immediately and does not remain in contact with the area to be coagulated. It is certainly possible to soak a compress or tampon with said liquid solution, provided that the area to be coagulated is of immediate access and is visible.
Dans le cas de procédures en radiologie interventionnelle ou en chirurgie endoscopique, le site de saignement est à distance de la zone d'ouverture cutanée. C'est pour de tels cas que les tampons de collagène ont été développés, tampons qui sont biocompatibles, biodégradables et qui présentent la particularité d'accélérer l'hémostase, et donc d'être hémostatiques malgré la présence éventuelle d'héparine ou d 'anti-aggrégants plaquettaires. Cependant la mise en place du tampon de collagène, en radiologie interventionnelle ou en chirurgie endoscopique, nécessite l'utilisation de dispositifs particuliers, tel celui faisant l'objet du document EP A-0476178. Ce dispositif est conçu spécialement pour la mise en place, en fin de procédure d'intervention, d'un produit hémostatique au contact de la zone à obturer c'est à dire au contact de la paroi du vaisseau sanguin sans avoir de risques de pénétration du produit hémostatique à l'intérieur du vaisseau. Un tel dispositif est commercialisé par la firme Datascope et spécialement conçu pour l'introduction d'un produit hémostatique local sous forme d'un tampon fibreux de collagène.In the case of interventional radiology or endoscopic surgery procedures, the bleeding site is at a distance from the skin opening area. It is for such cases that collagen buffers have been developed, buffers which are biocompatible, biodegradable and which have the particularity of accelerating hemostasis, and therefore of being hemostatic despite the possible presence of heparin or anti-platelet aggregation agents. However, the placement of the collagen buffer, in interventional radiology or in endoscopic surgery, requires the use of particular devices, such as that which is the subject of document EP A-0476178. This device is specially designed for the installation, at the end of the intervention procedure, of a hemostatic product in contact with the area to be closed, that is to say in contact with the wall of the blood vessel without having the risk of penetration. hemostatic product inside the vessel. Such a device is marketed by the firm Datascope and specially designed for the introduction of a local hemostatic product in the form of a fibrous collagen buffer.
Le but que s'est fixé le demandeur est de proposer un produit hémostatique qui pallie les inconvénients précités en ce que d'une part il ne s'agit pas de collagène et il est exempt de produits d'origine humaine et d'autre part il évite l'utilisation de dispositifs particuliers d'introduction dans le cas de radiologie interventionnelle ou de chirurgie endoscopique, et enfin il est actif chez tous les patients y compris ceux qui sont soumis à un traitement d' anti-coagulation, par exemple à l'héparine.The goal that the applicant has set is to offer a hemostatic product which overcomes the aforementioned drawbacks in that on the one hand it is not collagen and it is free of products of human origin and on the other hand it avoids the use of particular introductory devices in the case of interventional radiology or endoscopic surgery, and finally it is active in all patients including those who are subjected to an anti-coagulation treatment, by example with heparin.
Ce but est parfaitement atteint par le produit hémostatique de l'invention qui, de manière caractéristique, consiste en une composition visqueuse, éventuellement à l'état de gel, biocompatible, biodégradable et/ou bioéliminable, qui n'est pas une composition de collagène, dans laquelle est inclus au moins un extrait hémostatique de venin de seφent, à activité thrombin-like.This object is perfectly achieved by the hemostatic product of the invention which, typically, consists of a viscous composition, optionally in the gel state, biocompatible, biodegradable and / or bioeliminable, which is not a collagen composition , in which is included at least one hemostatic extract of venom from seφent, with thrombin-like activity.
On dit qu'un produit hémostatique a une activité thrombin-like lorsqu'il agit sur le fibrinogène pour former des monomères de fibrine, dont la polymérisation est indispensable pour la formation du caillot sanguin. Les enzymes, thrombin-like, extraites des venins de serpent sont des glycoprotéines , molécules de petites dimensions qui , dans des conditions normales , diffusent très rapidement dans l'organisme. Le fait de mettre en oeuvre l'extrait hémostatique de venin de serpent , à activité thrombin-like, dans une composition visqueuse permet de ralentir l'absorption trop rapide des molécules actives dans les tissus et leur diffusion au niveau de la circulation générale du corps. Cette rétention des molécules actives doit laisser un temps de contact suffisant entre lesdites molécules actives et le sang au niveau de la brèche vasculaire pour obtenir l'effet recherché à savoir la mise en route de la coagulation sous l'effet de ces enzymes. Cependant les propriétés physiques de la composition, en terme de viscosité, doivent également permettre son introduction à travers les cathéters ou les systèmes d'introduction vasculaire habituellement utilisés en chirurgie ou en radiologie.A hemostatic product is said to have thrombin-like activity when it acts on fibrinogen to form fibrin monomers, the polymerization of which is essential for the formation of a blood clot. The enzymes, thrombin-like, extracted from snake venoms are glycoproteins, molecules of small dimensions which, under normal conditions, diffuse very quickly in the organism. The fact of using the hemostatic extract of snake venom, with thrombin-like activity, in a viscous composition makes it possible to slow down the too rapid absorption of the active molecules in the tissues and their diffusion in the general circulation of the body. . This retention of active molecules must allow sufficient contact time between said active molecules and the blood at the level of the vascular breach to obtain the desired effect, namely the initiation of coagulation under the effect of these enzymes. However, the physical properties of the composition, in terms of viscosity, must also allow its introduction through catheters or vascular introduction systems usually used in surgery or radiology.
Ces dispositifs possèdent une lumière interne de l'ordre de 1 ,5 à 3 millimètre, la section de certains cathéters utilisés pouvant descendre jusqu'à 0,4 millimètre. La composition visqueuse, éventuellement à l'état de gel, doit donc avoir une viscosité et une cohésivité suffisantes pour rester au contact de la zone à coaguler sans pénétration à l'intérieur de la lumière vasculaire et pour avoir le temps d'effectuer une action d'initialisation ou d'accélération des phénomènes biologiques de la coagulation mais doit être suffisamment fluide pour cheminer à travers les systèmes d'introduction décrits ci-dessus.These devices have an internal lumen of the order of 1.5 to 3 millimeters, the cross section of certain catheters used being able to descend to 0.4 millimeters. The viscous composition, possibly in the gel state, must therefore have sufficient viscosity and cohesiveness to remain in contact with the area to be coagulated without penetration inside the vascular lumen and to have time to perform an action. initialization or acceleration of phenomena biological coagulation but must be sufficiently fluid to travel through the introduction systems described above.
Pour rester au contact au niveau de la brèche vasculaire, il est préférable que la composition ait une viscosité supérieure à 50 Pa.s. (Pascal/seconde), la fluidité nécessaire au cheminement à travers le cathéter étant variable en fonction de la longueur et de la section du cathéter.To remain in contact at the level of the vascular breach, it is preferable that the composition has a viscosity greater than 50 Pa.s. (Pascal / second), the fluidity necessary for routing through the catheter being variable depending on the length and section of the catheter.
Il est à souligner que les extraits hémostatiques de venin de serpent sont efficaces malgré la présence de traitements anti-coagulants, par exemple à l'héparine. Ceci n'est pas le cas du facteur spécifique hémostatique qui est décrit dans le document WO.93/06855, à savoir le facteur VII activé, qui de plus est d'origine humaine, contrairement au but visé par la présente invention. Dans le document EP.O.241.179, l'agent hémostatique mis en oeuvre est l'acide tranexamique qui est un an ti-fibronoly tique dont l'action s'exerce lorsque le caillot est constitué ; cet agent ne peut donc pas être efficace lorsqu'il s'agit d'un patient soumis à un traitement anti-coagulant, par exemple à l'héparine, dans la mesure où du fait de ce traitement le caillot ne sera pas constitué. Dans les documents WO.85/OO969 et WO.94/O3155 il s'agit de gels insolubles dans l'eau et donc dans les liquides physiologiques ; ces gels ne sont pas biorésorbables et l'on ne peut donc pas obtenir , comme cela est recherché dans la présente invention, une diffusion des molécules actives qui soit suffisante pour obtenir la mise en route de la coagulation dans un temps rapide.It should be noted that hemostatic extracts of snake venom are effective despite the presence of anti-coagulant treatments, for example with heparin. This is not the case for the specific hemostatic factor which is described in document WO.93 / 06855, namely the activated factor VII, which moreover is of human origin, contrary to the aim of the present invention. In document EP.O. 241.179, the hemostatic agent used is tranexamic acid which is a ti-fibronoly tic year whose action is exerted when the clot is formed; this agent cannot therefore be effective in the case of a patient subjected to an anticoagulant treatment, for example with heparin, insofar as this treatment will not form the clot. In documents WO.85 / OO969 and WO.94 / O3155 these are gels insoluble in water and therefore in physiological liquids; these gels are not bioresorbable and it is therefore not possible to obtain, as is sought in the present invention, a diffusion of the active molecules which is sufficient to obtain the start of coagulation in a rapid time.
Dans un mode de réalisation, la composition hydrosoluble visqueuse, biocompatible, biodégradable, exempte de collagène, est formée d'un haut polymère d'acétyle glucosamine et d'acide glucuronique, à savoir l'acide hyaluronique, qui est un polysaccharide fonctionnalisé par des groupes acétamides.In one embodiment, the viscous, biocompatible, biodegradable, collagen-free, water-soluble composition is formed from a high acetyl glucosamine polymer and glucuronic acid, namely hyaluronic acid, which is a polysaccharide functionalized by acetamide groups.
Un certain nombre de polymères d'origine naturelle, synthétique ou semi- synthétique, seuls ou en association, sont capables de former des compositions visqueuses ou des gels qui seront biodégradables ou bioéliminables. On peut citer à titre d'exemples non limitatifs, le polyvinylpyrolidone, le polyvinylalcool, le polyéthylène-glycol, les polysaccharides naturels ou semi-synthétiques tels le Dextran, le sulfate de dextrane, le pentosane sulfate, le keratane sulfate, la chondroitine sulfate, l'agar-agar,la chitine et le chitosane, le carrageenate, des protéines et leurs dérivés tels que le sulfate de protamine, différentes fractions peptidiques, les poly-alpha-amino-acides à site acide ou basique tels que l'acide polyglutamique, l'acide polyaspartique ou la polylysine, enfin les polydésoxyribonucléotides, l'alphacyclodextrine, certains triglycérides.A certain number of polymers of natural, synthetic or semi-synthetic origin, alone or in combination, are capable of forming viscous compositions or gels which will be biodegradable or bioeliminable. We can cite by way of nonlimiting examples, polyvinylpyrolidone, polyvinylalcohol, polyethylene glycol, natural or semi-synthetic polysaccharides such as Dextran, dextran sulfate, pentosan sulfate, keratane sulfate, chondroitin sulfate, agar -agar, chitin and chitosan, carrageenate, proteins and their derivatives such as protamine sulphate, various peptide fractions, acid or basic site poly-alpha-amino acids such as polyglutamic acid, polyaspartic acid or polylysine, finally polydeoxyribonucleotides, alphacyclodextrin, certain triglycerides.
S'agissant des extraits de venin de serpent, il en existe une quarantaine qui ont des propriétés pro-hémostatiques thrombin-like, même en présence de médicaments agissant sur la coagulation tels que l'héparine, les anti-aggrégants plaquettaires ou les fibrinoly tiques.As for snake venom extracts, there are around forty which have thrombin-like pro-hemostatic properties, even in the presence of drugs which act on coagulation such as heparin, anti-platelet aggregants or fibrinolytics .
Des produits disponibles sur le marché actuellement , on peut citer la batroxobine commercialisée sous le nom de Defibrase ou d'Ophistasin ou entrant dans la composition de la Reptilase et venant des serpents Bothrops, ainsi que l'Ancrod ou Ar in venant des Calloselasma Rhodostoma. D'autres molécules extraites des venins de seφent telles que : Acutine Bilinéobine, Vensin, Gabonine, Aspérase, Serastobine, Crotalase, Geroxine, Defibrisine et Clotase sont aussi connues pour avoir une action thrombin-like. D'autres produits présentant des propriétés hémostatiques peuvent être inclus dans une composition hémostatique de l'invention, tel que la 1- naphtylamine-4-sulfonic acid, la 1 ,2 naphthoquinone commercialisé sous le nom de Naftazone, l'acide ellagique commercialisé sous le nom de Lagistase, l'adrenalone commercialisé sous le nom d'Adrenalone, les dérivés de l'acide arachidonique, la ristocétine, l'Adenosine, les céphalines.Products currently available on the market include batroxobin sold under the name Defibrase or Ophistasin or used in the composition of Reptilase and coming from Bothrops snakes, as well as Ancrod or Ar in coming from Calloselasma Rhodostoma. Other molecules extracted from venoms of seφent such as: Acutine Bilineobine, Vensin, Gabonine, Asperase, Serastobine, Crotalase, Geroxine, Defibrisine and Clotase are also known to have a thrombin-like action. Other products having hemostatic properties can be included in a hemostatic composition of the invention, such as 1-naphthylamine-4-sulfonic acid, 1, 2 naphthoquinone marketed under the name of Naftazone, ellagic acid marketed under the name Lagistase, adrenalone marketed under the name Adrenalone, derivatives of arachidonic acid, ristocetin, Edenosine, cephalins.
L'acide alginique et les alginates en plus de leurs propriétés hémostatiques locales possèdent aussi un pouvoir de gélification important.Alginic acid and alginates, in addition to their local hemostatic properties, also have significant gelling power.
Le sulfate de protamine qui est un neutralisant de l'héparine connu et commercialisé sous le nom de Protamine peut avoir une activité hémostatique par voie locale et peut pour former un sel stable avec l'héparine contenue dans le sang être utilisé en complément. Le bleu de méthylène, l'hexadimétrine qui sont des antidotes de l'héparine sont aussi utilisables.Protamine sulfate which is a heparin neutralizer known and marketed as Protamine can have hemostatic activity by local route and can be used in addition to form a stable salt with heparin contained in the blood. Methylene blue and hexadimetrine, which are antidotes to heparin, can also be used.
Une difficulté particulière apparaît lorsque le produit hémostatique de l'invention est utilisé chez des patients soumis à un traitement anti-coagulant par l'héparine, puisque ces patients sont incapables de compenser localement la fibrinolyse physiologique par la création de nouveaux polymères de fibrine en raison du traitement à l'héparine. Cette incapacité peut entraîner un risque de saignements secondaires par redissolution du caillot. Pour éviter ce risque , selon l'invention, le produit hémostatique comporte également des moyens favorisant la solidité du caillot. Ces moyens peuvent consister dans différents produits hémostatiques rentrant dans le groupe des anti-fibrinolytiques tels que l'acide tranexamique commercialisé sous le nom d'Exacyl ou encore des dérivés de l'acide tranexamique, des dérivés de l'acide aminocaproique, la cimetidine et ses dérivés. L'adjonction de Calcium et/ou l'abaissement du pH va favoriser la polymérisation des monomères de fibrine et augmenter la stabilité du caillot.A particular difficulty appears when the hemostatic product of the invention is used in patients subjected to an anticoagulant treatment with heparin, since these patients are unable to compensate locally for physiological fibrinolysis by the creation of new fibrin polymers due to heparin therapy. This incapacity can involve a risk of secondary bleeding by redissolution of the clot. To avoid this risk, according to the invention, the hemostatic product also comprises means promoting the solidity of the clot. These means may consist of different hemostatic products falling within the group of anti-fibrinolytics such as tranexamic acid marketed under the name of Exacyl or alternatively derivatives of tranexamic acid, derivatives of aminocaproic acid, cimetidine and its derivatives. Adding Calcium and / or lowering the pH will promote the polymerization of fibrin monomers and increase the stability of the clot.
Dans un mode préférentiel, l'extrait de venin de seφent est l' Ancrod commercialisé sous les noms d'Ancrod ou d'Arwin par le laboratoire pharmaceutique KNOLL. La présente invention sera mieux comprise à la lecture de la description qui va être faite d'un exemple de réalisation d'une composition visqueuse hémostatique constituée de la combinaison d'acide hyaluronique et d'Ancrod.In a preferred mode, the extract of venom of seφent is the Ancrod marketed under the names of Ancrod or Arwin by the pharmaceutical laboratory KNOLL. The present invention will be better understood on reading the description which will be given of an exemplary embodiment of a viscous hemostatic composition consisting of the combination of hyaluronic acid and Ancrod.
L'objet de la présente invention est de proposer un produit hémostatique qui permet d'éviter tout risque de contamination par les prions et par un agent infectieux ou viral d'origine humaine, qui soit biocompatible, bioéliminable et/ou biodégradable. Il doit de plus rester au contact de la brèche vasculaire et ne pas pénétrer à l'intérieur de la lumière artérielle, pendant un temps suffisant pour que soit initiée la coagulation et se forme le caillot sanguin.The object of the present invention is to provide a hemostatic product which makes it possible to avoid any risk of contamination by prions and by an infectious or viral agent of human origin, which is biocompatible, bioeliminable and / or biodegradable. It must also remain in contact with the vascular breach and not penetrate inside the arterial lumen, for a time sufficient for initiation of coagulation and the blood clot is formed.
Il doit impérativement être efficace en présence d'un traitement modifiant l'hémostase ou de médicaments qui ralentissent la coagulation comme les anti-aggrégants ou les héparines ou qui agissent sur la fibrinolyse.It must imperatively be effective in the presence of a treatment modifying hemostasis or drugs which slow coagulation such as anti-aggregants or heparins or which act on fibrinolysis.
De plus le produit de l'invention doit pouvoir être introduit sous la peau sans avoir recours à un dispositif particulier mais en utilisant les moyens d'introduction habituellement mis en oeuvre en radiologie interventionnelle ou en chirurgie endoscopique.In addition, the product of the invention must be able to be introduced under the skin without having to resort to a particular device but by using the means of introduction usually used in interventional radiology or in endoscopic surgery.
De manière caractéristique, le produit hémostatique de l'invention consiste en une composition visqueuse, éventuellement à l'état de gel, biocompatible, biodégradable ou bioéliminable, qui n'est pas une composition de collagène et dans laquelle est inclus comme produit actif hémostatique au moins un extrait hémostatique de venin de seφent à activité thrombin-like. La composition visqueuse est seringuable, c'est à dire elle peut se déplacer dans les cathéters et les introducteurs par simple pression manuelle sur la seringue mais présente une viscosité et une cohésivité tels qu'elle reste au contact de la brèche vasculaire et n'entre pas à l'intérieur de la lumière artérielle.Typically, the hemostatic product of the invention consists of a viscous composition, optionally in the gel state, biocompatible, biodegradable or bioeliminable, which is not a collagen composition and in which is included as hemostatic active product at minus a hemostatic venom extract of seφent with thrombin-like activity. The viscous composition is syringable, that is to say it can move in the catheters and the introducers by simple manual pressure on the syringe but has a viscosity and a cohesiveness such that it remains in contact with the vascular breach and does not enter not inside the arterial lumen.
Dans l'exemple préféré de réalisation, donné à titre non exhaustif, la composition visqueuse est l'acide hyaluronique et le produit actif est l'Ancrod.In the preferred embodiment, given non-exhaustively, the viscous composition is hyaluronic acid and the active product is Ancrod.
La composition d'acide hyaluronique à 1 % est préparée avec un acide hyaluronique de masse moléculaire moyenne de 1 ,3.1O6 Daltons. L'Ancrod est commercialisée sous la forme d'une solution de 1 ml contenant 70 Unités.The 1% hyaluronic acid composition is prepared with a hyaluronic acid with an average molecular weight of 1.10 6 Daltons. The Ancrod is marketed in the form of a 1 ml solution containing 70 Units.
L'inclusion de l'Ancrod dans la composition n'affecte pas les propriétés pro-hémostatiques de l'Ancrod.The inclusion of Ancrod in the composition does not affect the pro-haemostatic properties of Ancrod.
La composition hémostatique de l'invention, une fois introduite au niveau de la paroi du vaisseau présentant la brèche vasculaire à obturer, ne pénètre pas dans ladite brèche du fait de sa viscosité et de son caractère cohésif ; le sang s'échappant de la brèche vasculaire vient en contact avec ladite composition . Le sang est alors soumis à l'action progressive de l'Ancrod qui initie le démarrage de la formation du caillot en environ 30 secondes. La formation du caillot permet d'obtenir en 10 à 15 minutes l'hémostase de la brèche vasculaire. C'est la rétention de l'Ancrod dans l'acide hyaluronique qui permet à l'Ancrod d'avoir une action locale. L'acide hyaluronique étant bio-dégradable va ultérieurement se dégrader progressivement pour disparaître de l'organisme sans entraîner de conséquence néfaste pour celui-ci. L'action pro-hémostatique de l'Ancrod a été largement rapportée dans la littérature , l'action pro-hémostatique de l'Ancrod est valablement obtenue en ajoutant à 4 ce d'acide hyaluronique , 1/2 ampoule d'Ancrod, soit 35 unités.The hemostatic composition of the invention, once introduced at the level of the wall of the vessel having the vascular breach to be closed, does not penetrate said breach because of its viscosity and its cohesive nature; the blood escaping from the vascular breach comes into contact with said composition. The blood is then subjected to the progressive action of the Ancrod which initiates the start of the formation of the clot in approximately 30 seconds. The formation of the clot allows hemostasis of the vascular breach to be obtained in 10 to 15 minutes. It's here retention of the Ancrod in hyaluronic acid which allows the Ancrod to have a local action. Hyaluronic acid being bio-degradable will later degrade gradually to disappear from the body without causing harmful consequences for it. The pro-hemostatic action of Ancrod has been widely reported in the literature, the pro-hemostatic action of Ancrod is validly obtained by adding 4 cc of hyaluronic acid, 1/2 ampoule of Ancrod, i.e. 35 units.
La présente invention n'est pas limitée au mode de réalisation qui vient d'être décrit à titre d'exemple préféré de l'invention. En particulier, il revient à l'homme du métier de choisir parmi toutes les compositions visqueuses, éventuellement à l'état de gels biodégradables déjà utilisés dans le secteur médical et parmi les extraits hémostatiques de venin de seφent, ceux qui conviennent pour remplir les fonctions imparties à la composition hémostatique de l'invention. De plus il appartient à l'homme du métier de mélanger à une composition visqueuse plusieurs produits hémostatiques pour potentialiser les effets de chaque produit et pouvoir être utilisés chez des patients présentant des traitements combinés associant plus d'un médicament agissant sur l'hémostase, par exemple lorsque des patients sont soumis à un traitement fibrinolytique associé à l'héparine et à un ou deux anti-aggrégants plaquettaires. Différents procédés permettent d'augmenter la rétention de la molécule active dans la composition visqueuse permettant ainsi d'obtenir un ralentissement de l'absoφtion de la molécule active par le sang. L'augmentation de la concentration en acide hyaluronique à 1,6 ou à 2% permet d'augmenter significativement l'efficacité de la composition. L'utilisation d'acide hyaluronique ayant un degré de polymérisation plus élevé améliore aussi la rétention de la molécule active. La rétention de la molécule active peut aussi être augmentée par l'estérification de l'acide hyaluronique, celle-ci pouvant être effectuée avec différents types d'alcool. Enfin, la rétention de la molécule peut être augmentée par la création d'interactions ioniques. L'acidification de l'acide hyaluronique en dessous du point isoélectrique de la molécule active par exemple en-dessous de 6.6 pour la Batroxobine va entraîner des interactions ioniques, par l'intermédiaire des groupements cationiques de la batroxobine qui vont interagir avec des groupements carboxyles de la molécule d'acide hyaluronique acidifié. Enfin, l'adjonction de produits viscosants , par exemple la gélatine entraîne une augmentation de la rétention de la molécule du fait d'une augmentation de l'encombrement stérique au niveau de la composition. The present invention is not limited to the embodiment which has just been described by way of a preferred example of the invention. In particular, it is up to the person skilled in the art to choose from all the viscous compositions, possibly in the form of biodegradable gels already used in the medical sector and from hemostatic extracts of venom from seφent, those which are suitable for fulfilling the functions imparted to the hemostatic composition of the invention. In addition, it is up to the person skilled in the art to mix several hemostatic products with a viscous composition in order to potentiate the effects of each product and to be able to be used in patients with combined treatments associating more than one drug acting on hemostasis, for example. example when patients are undergoing fibrinolytic treatment combined with heparin and one or two antiplatelet agents. Different methods make it possible to increase the retention of the active molecule in the viscous composition, thus making it possible to obtain a slowing down of the absorption of the active molecule by the blood. Increasing the concentration of hyaluronic acid to 1.6 or 2% makes it possible to significantly increase the effectiveness of the composition. The use of hyaluronic acid having a higher degree of polymerization also improves the retention of the active molecule. The retention of the active molecule can also be increased by the esterification of hyaluronic acid, which can be carried out with different types of alcohol. Finally, the retention of the molecule can be increased by the creation of ionic interactions. Acidification of hyaluronic acid in below the isoelectric point of the active molecule, for example below 6.6 for Batroxobin will cause ionic interactions, through the cationic groups of batroxobin which will interact with carboxyl groups of the acidified hyaluronic acid molecule. Finally, the addition of viscous products, for example gelatin leads to an increase in the retention of the molecule due to an increase in steric hindrance at the level of the composition.

Claims

REVENDICATIONS
1. Produit hémostatique, actif chez tous les patients y compris ceux soumis à un traitement à l'héparine, caractérisé en ce qu'il consiste en une composition visqueuse, biocompatible, biodégradable et/ou bioéliminable qui n'est pas une composition de collagène, dans laquelle est inclus un extrait hémostatique de venin de seφent.1. Hemostatic product, active in all patients including those undergoing heparin treatment, characterized in that it consists of a viscous, biocompatible, biodegradable and / or bioeliminable composition which is not a collagen composition , in which is included a hemostatic extract of venom from seφent.
2. Produit hémostatique selon la revendication 1 caractérisé en ce que l'extrait de venin de seφent est la batroxobine.2. Hemostatic product according to claim 1 characterized in that the venom extract of seφent is batroxobin.
3. Produit hémostatique selon la revendication 1 caractérisé en ce que l'extrait de venin de seφent est l' ancrod.3. Hemostatic product according to claim 1 characterized in that the venom extract of seφent is the ancrod.
4. Produit hémostatique selon l'une des revendications 1 à 3 caractérisé en ce que la composition visqueuse est formée à partir d'acide hyaluronique.4. Hemostatic product according to one of claims 1 to 3 characterized in that the viscous composition is formed from hyaluronic acid.
5. Produit hémostatique selon l'une des revendications 1 à 3 caractérisé en ce que la composition visqueuse est formée à base d'acide hyaluronique estérifié. 5. Hemostatic product according to one of claims 1 to 3 characterized in that the viscous composition is formed based on esterified hyaluronic acid.
6. Produit hémostatique selon la revendication 1 caractérisé en ce que la composition visqueuse est formée à partir de polysaccharides naturels ou semi- synthétiques et de leurs dérivés tels que notamment le Dextran, le sulfate de dextrane, le keratane sulfate, la chondroitine sulfate, l'agar-agar, le carrageenate, les alginates, la chitine et le chitosane, le pentosane sulfate, les protéines et leurs dérivés tels que le sulfate de protamine ou des fractions peptidiques, les poly- alpha-acides aminés à site acide ou basique, seul ou en association.6. Hemostatic product according to claim 1 characterized in that the viscous composition is formed from natural or semi-synthetic polysaccharides and their derivatives such as in particular Dextran, dextran sulfate, keratane sulfate, chondroitin sulfate, l agar-agar, carrageenate, alginates, chitin and chitosan, pentosan sulfate, proteins and their derivatives such as protamine sulfate or peptide fractions, poly-alpha-amino acids with an acid or basic site, alone or in combination.
7. Produit hémostatique selon l'une des revendications 1 à 6 caractérisé en ce qu'il contient également un anti-fibrinolytique, par exemple l'acide tranexamique.7. Hemostatic product according to one of claims 1 to 6 characterized in that it also contains an anti-fibrinolytic, for example tranexamic acid.
8. Produit hémostatique selon la revendication 1 caractérisé en ce qu'il comporte de plus, comme autre produit actif un sel de protamine, l'acide l-naphtylamine-4- sulfonique, la 1-2 naphtoquinone, l'acide ellagique, l'acide amino-caproïque, l'acide alginique, l'adrénalone, la cimétidine, le bleu de méthylène, l'hexadimétrine, les dérivés de l'acide arachidonique, la ristocétine, l'adénosine, les céphalines. 8. Hemostatic product according to claim 1 characterized in that it further comprises, as another active product a protamine salt, l-naphthylamine-4-sulfonic acid, 1-2 naphthoquinone, ellagic acid, l amino-caproic acid, alginic acid, adrenalone, cimetidine, methylene blue, hexadimetrine, derivatives of arachidonic acid, ristocetin, adenosine, cephalins.
9. Produit hémostatique selon l'une des revendications 1 à 8 caractérisé en ce que son pH est abaissé en-dessous du point isoélectrique de la molécule extraite du venin de seφent.9. Hemostatic product according to one of claims 1 to 8 characterized in that its pH is lowered below the isoelectric point of the molecule extracted from the venom of seφent.
10. Produit hémostatique selon l'une des revendications 1 à 9 caractérisé en ce qu'il comprend de plus un agent viscosant, par exemple la gélatine.10. Hemostatic product according to one of claims 1 to 9 characterized in that it further comprises a viscosifying agent, for example gelatin.
11. Produit hémostatique selon l'une des revendications 1 à 10 caractérisé en ce qu'il contient du calcium. 11. Hemostatic product according to one of claims 1 to 10 characterized in that it contains calcium.
PCT/FR1997/001797 1996-10-08 1997-10-08 Viscous hemostatic composition, in particular in gel state WO1998015292A1 (en)

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WO2006053923A1 (en) * 2004-11-16 2006-05-26 Centre De Regulació Genòmica Use of serine-proteinase known as ancrod in the treatment of duchenne muscular dystrophy
JP2008500367A (en) * 2004-05-27 2008-01-10 アビジェン， インコーポレイテッド Method for treating bleeding disorders using sulfated polysaccharides
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US8846620B2 (en) 2011-07-19 2014-09-30 Baxter International Inc. Resorption enhancers as additives to improve the oral formulation of non-anticoagulant sulfated polysaccharides
US9265791B2 (en) 2013-03-12 2016-02-23 Baxalta GmbH Resorption enhancers as additives to improve the oral formulation of low molecular weight heparins
US9417251B2 (en) 2012-08-14 2016-08-16 Baxalta GmbH Methods and systems for screening compositions comprising non-anticoagulant sulfated polysaccharides

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Publication number Priority date Publication date Assignee Title
JP2008500367A (en) * 2004-05-27 2008-01-10 アビジェン， インコーポレイテッド Method for treating bleeding disorders using sulfated polysaccharides
JP2012046551A (en) * 2004-05-27 2012-03-08 Baxter Internatl Inc Method for treating of hemorrhagic disease by using sulfated polysaccharide
US8771973B2 (en) 2004-05-27 2014-07-08 Baxter Healthcare S.A. Methods for treating bleeding disorders using sulfated polysaccharides
US8859526B2 (en) 2004-05-27 2014-10-14 Baxter Healthcare S.A. Methods for treating bleeding disorders using sulfated polysaccharides
WO2006053923A1 (en) * 2004-11-16 2006-05-26 Centre De Regulació Genòmica Use of serine-proteinase known as ancrod in the treatment of duchenne muscular dystrophy
WO2009098029A2 (en) * 2008-02-06 2009-08-13 Beiersdorf Ag Wound dressing articles
WO2009098029A3 (en) * 2008-02-06 2010-07-01 Beiersdorf Ag Wound dressing articles
US8846620B2 (en) 2011-07-19 2014-09-30 Baxter International Inc. Resorption enhancers as additives to improve the oral formulation of non-anticoagulant sulfated polysaccharides
US9417251B2 (en) 2012-08-14 2016-08-16 Baxalta GmbH Methods and systems for screening compositions comprising non-anticoagulant sulfated polysaccharides
US9265791B2 (en) 2013-03-12 2016-02-23 Baxalta GmbH Resorption enhancers as additives to improve the oral formulation of low molecular weight heparins

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