US20130090291A1 - Hemostatic compositions - Google Patents

Hemostatic compositions Download PDF

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US20130090291A1
US20130090291A1 US13/648,885 US201213648885A US2013090291A1 US 20130090291 A1 US20130090291 A1 US 20130090291A1 US 201213648885 A US201213648885 A US 201213648885A US 2013090291 A1 US2013090291 A1 US 2013090291A1
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hemostatic composition
composition according
polymer
binder
polymeric component
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US13/648,885
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Heinz Gulle
Joris Hoefinghoff
Andreas Goessl
Katarzyna Gorna
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Baxter Healthcare SA
Baxter International Inc
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Baxter Healthcare SA
Baxter International Inc
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Priority to US13/648,885 priority patent/US20130090291A1/en
Assigned to BAXTER INTERNATIONAL INC., BAXTER HEALTHCARE S.A. reassignment BAXTER INTERNATIONAL INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HOEFINGHOFF, JORIS, GOESSL, ANDREAS, GORNA, KATARZYNA, GULLE, HEINZ
Publication of US20130090291A1 publication Critical patent/US20130090291A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/74Synthetic polymeric materials
    • A61K31/765Polymers containing oxygen
    • A61K31/77Polymers containing oxygen of oxiranes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K35/00Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/32Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34Macromolecular 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/06Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001Use of materials characterised by their function or physical properties
    • A61L24/0031Hydrogels or hydrocolloids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043Mixtures of macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0052Mixtures of macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061Use of materials characterised by their function or physical properties
    • A61L26/0066Medicaments; Biocides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061Use of materials characterised by their function or physical properties
    • A61L26/008Hydrogels or hydrocolloids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/04Materials for stopping bleeding

Abstract

The invention discloses a hemostatic composition comprising:
    • a) a biocompatible polymer in particulate form suitable for use in hemostasis, and
    • b) one hydrophilic polymeric component comprising reactive groups.

Description

  • This application claims the benefit of U.S. Ser. No. 61/545,926, filed Oct. 11, 2011, which is incorporated hereby by reference.
  • FIELD OF THE INVENTION
  • The present invention relates to hemostatic compositions and processes for making such compositions.
  • BACKGROUND OF THE INVENTION
  • Hemostatic compositions in dry storage-stable form that compose biocompatible, biodegradable, dry stable granular material are known e.g. from WO98/008550A or WO 2003/007845A. These products have been successfully applied on the art for hemostatis. Floseal® is an example for a powerful and versatile hemostatic agent consisting of a granular gelatin matrix swollen in a thrombin-containing solution to form a flowable paste.
  • Since such products have to be applied to humans, it is necessary to provide highest safety standards for quality, storage-stability and sterility of the final products and the components thereof. On the other hand, manufacturing and handling should be made as convenient and efficient as possible.
  • On the other hand, it has been found that previous hemostatic compositions for wound healing failed to induce hemostatis at conditions with impaired hemostasis (e.g. after heparinization). It is therefore desired to provide materials and compositions with improved hemostasis. Moreover, a strong adherence of the compositions applied to the tissue is needed when the composition is applied to a wound. It is also desired to provide material with suitable swelling behavior after application to a wound.
  • It is an object of the present invention to overcome such problems and provide suitable hemostatic compositions with improved adhering properties and methods for making such hemostatic composition. The compositions should also be provided in a convenient and usable manner. The products should preferably be provided in product formats enabling a convenient provision of “ready-to-use” hemostatic compositions, which can be directly applied to an injury without any time consuming reconstitution steps involved.
  • SUMMARY OF THE INVENTION
  • Therefore, the present invention provides a hemostatic composition comprising:
      • a) a biocompatible polymer in particulate form suitable for use in hemostatis, and
      • b) one hydrophilic polymeric component comprising reactive groups.
  • The combination of a biocompatible polymer in particulate form with one hydrophilic polymeric component provides a composition with improved hemostatic properties and with improved tissue adherence. This is specifically suitable for wound treatment wherein induction of hemostatis failed, e.g. at conditions with impaired hemostatis (e.g. after heparinization). The compositions according to the present invention improve hemostasis. Furthermore, the compositions according to the present invention show a strong adherence to the tissue when applied to a wound.
  • Upon contact with bleeding tissue, a crosslinking reaction of the hydrophilic polymeric component with the blood proteins leads to formation of a gel with sealing and hemostatic properties. Crosslinking also occurs to the tissue surface proteins and, depending on the nature of the biocompatible polymer material, may also occur to the biocompatible polymer material. The latter reaction contributes to an improved adhesion of the composition material to the wounded tissue surface.
  • A further aspect relates to a method of treating an injury comprising administering a hemostatic composition to the site of injury.
  • Also provided is a kit for the treatment of an injury, comprising a hemostatic composition as herein disclosed and instructions for use.
  • The present invention also refers to a method for producing the hemostatic composition according to the invention in a convenient manner allowing the composition to be easily at hand for medical use. The invention further relates to a method for delivering a hemostatic composition to a target site in a patient's body, said method comprising delivering a hemostatic composition produced by the process of the present invention to the target site. According to another aspect, the present invention relates to a finished final container obtained by the process according of the present invention containing the present hemostatic composition. The invention also relates to a method for providing a ready-to-use hemostatic composition comprising contacting a hemostatic composition produced by the process of the present invention with a pharmaceutical acceptable binder as well as to a kit comprising the finished final container and other means for applying the composition (e.g. a container for the binder). The compositions according to the present invention are particularly useful for providing hemostasis at bleeding sites, including surgical bleeding sites, traumatic bleeding sites and the like. An exemplary use of the compositions may be in sealing the tissue tract above a blood vessel penetration created for vascular catheterization.
  • DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION
  • The present invention provides an improvement in hemostatic compositions. The hemostatic compositions according to the invention contain biocompatible polymers in particulate form, e.g. granules of a biocompatible polymer (e.g. gelatin, fibrin, chitosan, fibronectin, collagen, especially gelatin) suitable for use in hemostasis (the “hemostatic biocompatible polymer component” or the “hemostatic polymer”). Admixed to this biocompatible polymer for hemostasis is one hydrophilic polymeric component comprising reactive groups. According to the present invention, the reactive groups of the polymeric component have retained their reactivity until the composition is brought to the place of clinical action, e.g. on to the wound.
  • The biocompatible polymers in particulate form suitable for use in hemostasis may include dimensionally isotropic or non-isotropic forms. For example, the biocompatible polymers according to the present invention may be granules, particles or fibers; and may be present in discontinuous structures, for example in powder forms.
  • According to a preferred embodiment, the biocompatible polymer is liquid absorbing. For example, upon contact with liquids, e.g. aqueous solutions or suspensions (especially a buffer or blood) the polymer takes up the liquid and will display a degree of swelling, depending on the extent of hydration. The material preferably absorbs from about 200% to about 2000%, especially from about 400% to about 1300% water or aqueous buffer by weight, corresponding to a nominal increase in diameter or width of an individual particle of subunit in the range from e.g. approximately 50% to approximately 500%, usually from approximately 50% to approximately 250%. For example, if the (dry) granular particles have a preferred size range of 0.01 mm to 1.5 mm, especially of 0.05 mm to 1 mm, the fully hydrated composition (e.g. after administration on a wound or after contact with an aqueous buffer solution) may have a size range of 0.05 mm to 3 mm, especially of 0.25 mm to 1.5 mm.
  • The equilibrium swell of preferred biocompatible polymers of the present invention may generally range e.g. from 400% to 1300%, preferably being from 500% to 1100%, depending on its intended use. Such equilibrium swell may be controlled e.g. (for a crosslinked polymer) by varying the degree of crosslinking, which in turn is achieved by varying the crosslinking conditions, such as the type of crosslinking method, duration of exposure of a crosslinking agent, concentration of a crosslinking agent, crosslinking temperature, and the like. Materials having differing equilibrium swell values perform differently in different applications. For example, the ability to inhibit bleeding in a liver divot model was most readily achieved with crosslinked gelatin materials having a swell in the range from 700% to 950%. For a femoral artery plug, lower equilibrium swell values in the range from 500% to 600% were more successful. Thus, the ability to control crosslinking and equilibrium swell allows the compositions of the present invention to be optimized for a variety of uses. In addition to equilibrium swell, it is also important to control the hydration of the material immediately prior to delivery to a target site. Hydration and equilibrium swell are, of course, intimately connected. A material with 0% hydration will be non-swollen. A material with 100% hydration will be at its equilibrium water content. Hydrations between 0% and 100% will correspond to swelling between the minimum and maximum amounts.
  • According to a preferred embodiment of the present invention, the biocompatible polymer and the hydrophilic polymeric component are present in paste form, preferably with a binder wherein the reactivity of the polymeric component is retained.
  • The biocompatible polymer in particulate form suitable for use in hemostasis of the present invention may be formed from biologic and non-biologic polymers. Suitable biologic polymers may contain a protein, a polysaccharide, a biologic polymer, a non-biologic polymer; and derivatives and combinations thereof. Suitable proteins include gelatin, collagen, albumin, hemoglobin, fibrinogen, fibrin, casein, fibronectin, elastin, keratin, and laminin; and derivatives and combinations thereof. Particularly preferred is the use of gelatin or soluble non-fibrillar collagen, more preferably gelatin, and exemplary gelatin formulations are set forth below. Other suitable biologic polymers include polysaccharides, such as glycosaminoglycans, starch, cellulose, dextran, hemicellulose, xylan, agarose, alginate and chitosan; and derivatives and combinations thereof. Suitable non-biologic polymers will be selected to be degradable by either of two mechanisms, i.e. (1) break down of the polymeric backbone or (2) degradation of side chains which result in aqueous solubility. Exemplary non-biologic biocompatible polymers suitable for use in hemostasis include synthetics, such as polyacrylates, polymethacrylates, polyacrylamides, polymethacrylamides, polyethyleneimines, polyvinyl resins, polylactide-glycolides, polycaprolactones, and polyoxyethlenes; and derivatives and combinations thereof. Also combinations of different kinds of polymers are possible (e.g. proteins with polysaccharides, proteins with non-biologic hydrogel-forming polymers, etc.).
  • “A derivative thereof” includes any chemically modified polymer, such as e.g. a crosslinked polymer.
  • Preferred hemostatic polymers comprise nucleophilic groups, such as e.g. amino-groups, specifically if the hydrophilic polymeric component has reactive groups which react with amino-groups upon administration (e.g. in the wound environment).
  • According to a preferred embodiment of the present invention, the biocompatible polymer is selected from the group consisting of gelatin, collagen, albumin, fibrinogen, fibrin and derivatives thereof (as defined above); especially preferred the polymer is gelatin or collagen; especially preferred is crosslinked gelatin.
  • According to a preferred embodiment of the present invention, the biocompatible polymer suitable for use in hemostasis contains a crosslinked protein, a crosslinked polysaccharide, a crosslinked biologic polymer, a crosslinked non-biologic polymer; or mixtures thereof.
  • A non-crosslinked polymer may be crosslinked in any manner suitable to reconstitute, e.g. to form a suitable hydrogel base of the hemostatic polymer. For example, polymeric molecules may be crosslinked using bi- or poly-functional crosslinking agents which covalently attach to two or more polymer molecules chains. Exemplary bifunctional crosslinking agents include aldehydes, epoxides, succinimides, carbodiimides, maleimides, azides, carbonates, isocyanates, divinyl sulfone, alcohols, amines, imidates, anhydrides, halides, silanes, diazoacetate, aziridines, and the like. Alternatively, crosslinking may be achieved by using oxidizers and other agents, such as periodates, which activate side-chains or moieties on the polymer so that they may react with other side-chains or moieties to form the crosslinking bonds. An additional method of crosslinking comprises exposing the polymers to radiation, such as gamma radiation, to activate the polymer chains to permit crosslinking reactions. Dehydrothermal crosslinking methods may also be suitable. Preferred methods for crosslinking gelatin molecules are described below.
  • The biocompatible hemostatic polymer—once applied to a wound—forms an efficient matrix which can form a barrier for blood flow. Specifically the swelling properties of the biocompatible polymer can make it an effective mechanical barrier against bleeding and rebleeding processes.
  • In a preferred embodiment, the hemostatic compositions according to the present invention are provided or used as granular preparations. According to a preferred embodiment, the biocompatible polymer granulates suitable for use in hemostasis contain a crosslinked protein, a crosslinked polysaccharide, or a crosslinked non-biologic polymer; or mixtures thereof.
  • As mentioned above, the biocompatible polymer suitable for use in hemostasis is preferably a granular material. This granular material can rapidly swell when exposed to a fluid (i.e. the binder) and in this swollen form is capable of contributing to a flowable paste that can be applied to a bleeding site. The biocompatible polymer, e.g. gelatin, may be provided as a film which can then be milled to form a granular material. Most of the particles contained in this granular material (e.g. more than 90% w/w) have preferably particle sizes of 10 to 1.000 μm, especially 50 to 700 μm.
  • According to a preferred embodiment, the biocompatible polymer in particulate form suitable for use in hemostasis is a crosslinked gelatin. Dry crosslinked gelatin powder can be prepared to re-hydrate rapidly if contacted with a suitable diluent. The gelatin granules, especially in the form of a gelatin powder, preferably comprise relatively large particles, also referred to as fragments or sub-units, as described in WO 98/08550 A and WO 2003/007845A. A preferred (median) particle size will be the range from 10 to 1,000 μm, preferably from 50 to 700 μm, but particle sizes outside of this preferred range may find use in many circumstances. The dry compositions will also display a significant “equilibrium swell” when exposed to a liquid, e.g. body liquid. Preferably, the swell will be in the range from 400% to 1000%. “Equilibrium swell” may be determined by subtracting the dry weight of the gelatin hydrogel powder from its weight when fully hydrated and thus fully swelled. The difference is then divided by the dry weight and multiplied by 100 to give the measure of swelling. The dry weight should be measured after exposure of the material to an elevated temperature for a time sufficient to remove substantially all residual moisture, e.g., two hours at 120° C. The equilibrium hydration of the material can be achieved by immersing the dry material in a suitable diluent, such as aqueous saline, for a time period sufficient for the water content to become constant, typically for from 18 to 24 hours at room temperature.
  • Exemplary methods for producing crosslinked gelatins are as follows. Gelatin is obtained and suspended in an aqueous solution to form a non-crosslinked hydrogel, typically having a solids content from 1% to 70% by weight, usually from 3% to 10% by weight. The gelatin is crosslinked, typically by exposure to either glutaraldehyde (e.g., 0.01% to 0.05% w/w, overnight at 0° C. to 15° C. in aqueous buffer), sodium periodate (e.g., 0.05 M, held at 0° C. to 15° C. for 48 hours) or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (“EDC”) (e.g., 0.5% to 1.5% w/w overnight at room temperature), or by exposure to about 0.3 to 3 megarads of gamma or electron beam radiation. Alternatively, gelatin particles can be suspended in an alcohol, preferably methyl alcohol or ethyl alcohol, at a solids content of 1% to 70% by weight, usually 3% to 10% by weight, and crosslinked by exposure to a crosslinking agent, typically glutaraldehyde (e.g., 0.01% to 0.1% w/w, overnight at room temperature). In the case of aldehydes, the pH should be held from about 8 to 11, preferably from 7 to 10. When crosslinking with glutaraldehyde, the crosslinks are formed via Schiff bases which may be stabilized by subsequent reduction, e.g., by treatment with sodium borohydride. After crosslinking, the resulting granules may be washed in water and optionally rinsed in an alcohol, and dried. The resulting dry powders may then be provided in the final container as described herein.
  • Preferably, the biocompatible polymer is provided in a dry granular form for producing the hemostatic compositions according to the present invention. A “dry granular preparation of a biocompatible polymer” according to the present invention is known e.g. from WO 98/08550 A. Preferably, the polymer is a biocompatible, biodegradable dry stable granular material.
  • The dry polymer according to the present invention is usually provided with particle sizes of 10 to 1,000 μm. Usually, the polymer particles have a mean particle diameter (“mean particle diameter” is the median size as measured by laser diffractometry; “median size” (or mass median particle diameter) is the particle diameter that divides the frequency distribution in half; fifty percent of the particles of a given preparation have a larger diameter, and fifty percent of the particles have a smaller diameter) from 10 to 1000 μm, especially 50 to 700 μm (median size). Applying larger particles is mainly dependent on the medical necessities; particles with smaller mean particle diameters are often more difficult to handle in the production process. The dry polymer is therefore provided in granular form. Although the terms powder and granular (or granulates) are sometimes used to distinguish separate classes of material, powders are defined herein as a special sub-class of granular materials. In particular, powders refer to those granular materials that have the finer grain sizes, and that therefore have a greater tendency to form clumps when flowing. Granules include coarser granular materials that do not tend to form clumps except when wet. For the present application the particles used are those which can be coated by suitable coating techniques Particle size of the polymer granules according to the present invention can therefore easily be adapted and optimized to a certain coating technique by the necessities of this technique.
  • The hydrophilic polymeric component (also referred to as “reactive hydrophilic component” or “hydrophilic (polymeric) crosslinker” of the hemostatic composition according to the present invention is a hydrophilic crosslinker which is able to react with its reactive groups once the hemostatic composition is applied to a patient (e.g. to a wound of a patient or another place where the patient is in need of a hemostatic activity). Therefore it is important for the present invention that the reactive groups of the polymeric component are reactive when applied to the patient, it is therefore necessary to manufacture the hemostatic composition according to the present invention so that the reactive groups of the polymeric component which should react once they are applied to a wound are retained during the manufacturing process.
  • This can be done in various ways. For example, usual hydrophilic polymeric components have reactive groups which are susceptible to hydrolysis after contact with water. Accordingly, premature contact with water or aqueous liquids has to be prevented before administration of the hemostatic composition to the patient, especially during manufacture. However, processing of the hydrophilic polymeric component during manufacturing may be possible also in an aqueous medium at conditions where the reactions of the reactive groups are inhibited (e.g. at a low pH). If the hydrophilic polymeric components can be melted, the melted hydrophilic polymeric components can be sprayed or printed onto the matrix of the biopolymer. It is also possible to mix a dry form (e.g. a powder) of the hydrophilic polymeric component with a dry form of the biocompatible polymer suitable for use in hemostasis. If necessary, then an increase of the temperature can be applied to melt the sprinkled hydrophilic polymeric component to the biocompatible polymer suitable for use in hemostasis to achieve a permanent coating of the hemostatic composition. Alternatively, these hydrophilic polymeric components can be taken up into inert, organic solvents (inert vis-a-vis the reactive groups of the hydrophilic polymeric components) and brought onto the matrix of the biomaterial. Examples of such organic solvents are dry ethanol, dry acetone or dry dichloromethane (which are e.g. inert for hydrophilic polymeric components, such as NHS-ester substituted PEGs).
  • The term “one hydrophilic polymeric component comprising reactive groups” means that the presence of a second or further hydrophilic polymeric component with nucleophilic reactive groups is excluded in a hemostatic composition according to the present invention.
  • In a preferred embodiment the hydrophilic polymer component is a single hydrophilic polymer component and is a polyalkylene oxide polymer, preferably a PEG comprising polymer. The reactive groups of this reactive polymer are preferably electrophilic groups.
  • The reactive hydrophilic component may be a multi-electrophilic polyalkylene oxide polymer, e.g. a multi-electrophilic PEG. The reactive hydrophilic component can include two or more electrophilic groups, preferably a PEG comprising two or more reactive groups selected from succinimidylesters (—CON(COCH2)2), aldehydes (—CHO) and isocyanates (—N═C═O), e.g. a component as disclosed in the WO2008/018983 A (incorporated herein by reference in its entirety) and one of the components of the commercially available ones under the trademark CoSeal®.
  • Preferred electrophilic groups of the hydrophilic polymeric crosslinker according to the present invention are groups reactive to the amino-, carboxy-, thiol- and hydroxy-groups of proteins, or mixtures thereof.
  • Preferred amino group-specific reactive groups are NHS-ester groups, imidoester groups, aldehyde-groups, carboxy-groups in the presence of carbodiimides, isocyanates, or THPP (beta-[Tris(hydroxymethyl)phosphino]propionic acid), especially preferred is Pentaerythritolpoly(ethyleneglycol)ether tetrasuccinimidyl glutarate (=Pentaerythritol tetrakis[1-1′-oxo-5′-succinimidylpentanoate-2-poly-oxoethyleneglycole]ether (=an NHS-PEG with MW 10,000).
  • Preferred carboxy-group specific reactive groups are amino-groups in the presence of carbodiimides.
  • Preferred thiol group-specific reactive groups are maleimides or haloacetyis.
  • Preferred hydroxy group-specific reactive group is the isocyanate group. The reactive groups on the hydrophilic crosslinker may be identical (homofunctional) or different (heterofunctional). The hydrophilic polymeric component can have two reactive groups (homobifunctional or heterobifunctional) or more (homo/hetero-trifunctional or more).
  • In special embodiments the material is a synthetic polymer, preferably comprising PEG. The polymer can be a derivative of PEG comprising active side groups suitable for crosslinking and adherence to a tissue.
  • By the reactive groups the hydrophilic reactive polymer has the ability to crosslink blood proteins and also tissue surface proteins. Crosslinking to the biomaterial is also possible.
  • The multi-electrophilic polyalkylene oxide may include two or more succinimidyl groups. The multi-electrophilic polyalkylene oxide may include two or more maleimidyl groups.
  • Preferably, the multi-electrophilic polyalkylene oxide is a polyethylene glycol or a derivative thereof.
  • In a most preferred embodiment the hydrophilic polymeric component is pentaerythritolopoly(ethyleneglycol)ether tetrasuccinimidyl glutarate (═COH102, also pentaerythritol tetrakis[1-1′-oxo-5′-succinimidylpentanoate-2-poly-oxoethyleneglycole]ether).
  • The hydrophilic polymeric component is a hydrophilic crosslinker. According to a preferred embodiment, this crosslinker has more than two reactive groups for crosslinking (“arms”), for example three, four, five, six, seven, eight, or more arms with reactive groups for crosslinking. For example, NHS-PEG-NHS is an effective hydrophilic crosslinker according to the present invention. However, for some embodiments, a 4-arm polymer (e.g. 4-arms-p-NP-PEG) may be more preferred; based on the same rationale, an 8-arm polymer (e.g. 8-arms-NHS-PEG) may even be more preferred for those embodiments where multi-reactive crosslinking is beneficial. Moreover, the hydrophilic crosslinker according to the present invention is a polymer, i.e. a large molecule (macromolecule) composed of repeating structural units which are typically connected by covalent chemical bonds. The hydrophilic polymer component according to the present invention should have a molecular weight of at least 1000 Da (to properly serve as crosslinker in the hemostatic composition according to the present invention); preferably the crosslinking polymers according to the present invention has a molecular weight of at least 5000 Da, especially of at least 8000 Da.
  • For some hydrophilic crosslinkers, the presence of basic reaction conditions (e.g. at the administration site) is preferred or necessary for functional performance (e.g. for a faster crosslinking reaction at the administration site). For example, carbonate or bicarbonate ions (e.g. as a buffer with a pH of 7.8 or above, preferably of 8.0 or above, especially of 8.3 and above) may be additionally provided at the site of administration (e.g. as a buffer solution or as a fabric or pad soaked with such a buffer), so as to allow an improved performance of the hemostatic composition according to the present invention or to allow efficient use as a hemostatic and/or wound adherent material.
  • The reactivity of the hydrophilic polymeric component (which, as mentioned, acts as a crosslinker) in the composition according to the present invention is retained in the composition. This means that the reactive groups of the crosslinker have not yet reacted with the hemostatic composition and are not hydrolyzed by water (or at least not in a significant amount which has negative consequences on the hemostatic functionality of the present compositions). This can be achieved by combining the hemostatic polymer with the hydrophilic crosslinker in a way which does not lead to reaction of the reactive groups of the crosslinker with the hemostatic polymer or with water. Usually, this includes the omitting of aqueous conditions (or wetting), especially wetting without the presence of acidic conditions (if crosslinkers are not reactive under acidic conditions). This allows the provision of reactive hemostatic materials.
  • According to a specifically preferred hemostatic composition of the invention, the biocompatible polymer is crosslinked gelatin and the hydrophilic polymeric component is pentaerythritolpoly(ethyleneglycol)ether tetrasuccinimidyl glutarate (=NHS-PEG; component COH102 from Coseal).
  • Preferred ratios of the biocompatible polymer to hydrophilic polymeric component in the hemostatic composition according to the present invention are from 0.1 to 50 % w/w. preferably from 5 to 40 % w/w.
  • The hemostatic composition according to the present invention is preferably provided in paste form wherein the pasty form is due to the presence of a binder for the components. A “binder” is a substance which is miscible with or soluble in water or in other ways penetrable by body fluids and is suitable for combination with the biocompatible polymer in particulate form into a pasty composition. The binder according to the present invention may retain long-term reactivity of the hydrophilic polymeric component. The binder is preferably a more or less viscous liquid or viscoelastic substance.
  • According to a preferred embodiment, the binder contains or is a substance selected from the group consisting of glycerol and derivatives thereof (e.g. propyleneglycol, glycerolethoxylate), DMSO, ethanol, polyethyleneglycols and Poloxamers; and combinations thereof.
  • The consistency of such a paste form of the present invention can be adjusted to the specific need and intended use. Depending on e.g. the nature and amount of the binder, the consistency may be adjusted to a spreadable consistency, it may also be adjusted to a more viscous form, if it should be more shapeable and at least for a certain time also keep this shape after administration.
  • In order to keep the biocompatible polymer in the particulate form as long as possible (especially during storage), it is preferred to use a binder with a low water content. Accordingly, it is preferred that the binder has a water content (% v/v) below 5%, preferably below 2%, more preferred below 1%.
  • According to a preferred embodiment, the final container further contains an amount of a stabiliser effective to inhibit modification of the polymer when exposed to the sterilizing radiation, preferably ascorbic acid, sodium ascorbate, other salts of ascorbic acid, or an antioxidant.
  • The hemostatic composition according to the present invention is preferably made storage stable for at least 12 months, especially for at least 24 months.
  • Further components may be present in the hemostatic composition according to the present invention. According to preferred embodiments, the hemostatic compositions according to the present invention may further comprise a substance selected from the group consisting of antifibrinolytic, procoagulant, platelet activator, antibiotic, vasoconstrictor, dye, growth factors, bone morphogenetic proteins and pain killers.
  • The hemostatic composition according to the present invention may comprise a further composition of gelatin and a polyvalent nucleophilic substance, preferably human serum albumin, optionally at a basic pH (e.g. pH 8 to 11, preferably 9 to 10, especially at a pH of 9.5). The 2 components may then be co-applied to an injury.
  • According to another aspect, the present invention relates to the use of a hemostatic composition according to the present invention for the treatment of an injury selected from the group consisting of a wound, a hemorrhage, damaged tissue, bleeding tissue and/or bone defect.
  • The present invention also relates to a method of treating an injury selected from the group consisting of a wound, a hemorrhage, damaged tissue and/or bleeding tissue-comprising administering a hemostatic composition according to the present invention to the site of injury.
  • According to another aspect, the present invention provides a kit for the treatment of an injury selected from the group consisting of a wound, a hemorrhage, damaged tissue and/or bleeding tissue comprising
      • a) a hemostatic composition according to the present invention; and
      • b) instructions for use
  • The present invention also relates to a method for producing a hemostatic composition according to the present invention comprising the step of mixing, preferably blending, a biocompatible polymer suitable for use in hemostasis and one hydrophilic polymeric component comprising reactive groups with a binder wherein the reactivity of the polymeric component is retained.
  • According to another aspect, the present invention also provides a method for delivering a hemostatic composition according to the invention to a target site in a patients body, said method comprising delivering a hemostatic composition produced by the process according to the present invention to the target site. Although in certain embodiments, also the dry composition can be directly applied to the target site (and, optionally be contacted with the diluent a the target site, if necessary), it is preferred to contact the dry hemostatic composition with a pharmaceutical acceptable diluent before administration to the target site, so as to obtain a hemostatic composition in a wetted form, especially a hydrogel form.
  • The present invention also refers to a finished final container obtained by the process according to the present invention. This finished container contains the combined components in a sterile, storage-stable and marketable form. The final container can be any container suitable for housing (and storing) pharmaceutical administratable compounds.
  • The invention is further described in the examples below and the drawing figures, yet without being restricted thereto.
  • FIG. 1 shows crosslinked gelatin mixed with 11 wt % of NHS-PEG and polyethylene glycol (MW-200) (Example 1) as a binder in a liver punch lesion model 5 minutes post application.
  • The following abbreviations are used:
      • RT room temperature
    EXAMPLES Example 1
  • In a 50 ml test tube 4 g of crosslinked gelatin particles were mixed with 1.6 g of NHS-PEG (=11 wt %) using an end-over-end-mixer at RT for at least 30 minutes. A homogenous mixture of both components was obtained. 9 g of polyethylene glycol (MW=-200) as a binder were added and all ingredients were manually mixed. A homogenous paste-like product was obtained.
  • A 5 ml syringe with male luer was filled with 4 ml of the product. The product was ready to be applied direct from the syringe or through an additional applicator tip to a bleeding wound.
  • Example 2
  • In a 50 ml test tube 4 g of crosslinked gelatin particles were mixed with 1.6 g of NHS-PEG (=11 wt %) using an end-over-end-mixer at RT for at least 30 minutes to obtain a homogenous mixture of both components. 9 g of Pluronic L-61™ (MW=2000) as a binder were added and all ingredients were manually mixed to obtain a homogenous paste-like product.
  • A 3 ml syringe with male luer was filled with 4 ml of the paste-like product. The product was ready to be applied direct from the syringe or through additional applicator tip to a bleeding wound.
  • Example 3 In Vivo Study
  • The products of Example 1 and 2 were tested for hemostatic efficacy on heparinized animal (pig) In a punch or biopsy liver lesion. Each lesion in the series was topically treated with the product applied from the syringe through an applicator tip. Moistened gauze was used to help approximate the test product to the lesion and the timer was started. A saline moistened approximation gauze was removed after 30 seconds and the degree of bleeding was assessed at 30 seconds, 1, 2, 5 and 10 minutes after the test articles were applied. Product saturated with blood but without active bleeding was scored as 0. Saline solution was used to irrigate the excess test articles away from the lesions alter the 5 minutes assessment. Performance of selected formulations at 5 minutes assessment is shown in FIG. 1.
  • All patent filings, scientific journals, books, treatises, and other publications and materials discussed in this application are hereby incorporated by reference for all purposes. while exemplary embodiments have been described in some detail, by way of example and for clarity of understanding, those of skill in the art will recognize that a variety of modification, adaptations, and changes may be employed. Hence, the scope of the present invention should be limited solely by the claims.

Claims (19)

1. A hemostatic composition comprising:
a) a biocompatible polymer in particulate form suitable for use in hemostasis; and
b) one hydrophilic polymeric component comprising reactive groups.
2. The hemostatic composition according to claim 1, wherein the biocompatible polymer and the hydrophilic polymeric component are present in paste form.
3. The hemostatic composition according to claim 1, wherein said biocompatible polymer suitable for use in hemostasis contains a member selected from the group consisting of a protein, a polysaccharide, a biologic polymer, a non-biologic polymer, and derivatives and combinations thereof.
4. The hemostatic composition according to claim 1, wherein the hydrophilic polymer component is a polyalkylene oxide polymer.
5. The hemostatic composition according to claim 1, wherein said hydrophilic polymeric component with reactive groups is a polyethylene glycol (PEG).
6. The hemostatic composition according to claim 1, further comprising a binder, wherein the binder contains or is a substance selected from the group consisting of glycerol, a derivative of glycerol, DMSO, ethanol, a polyethyleneglycol, a Poloxamer, and combinations thereof.
7. The hemostatic composition according to claim 1, further comprising a binder, wherein the binder has a water content (% v/v) below 5%.
8. A method of treating a patient, comprising administering to the patient a hemostatic composition according to claim 1 for the treatment of an injury selected from the group consisting of a wound, a hemorrhage, a damaged tissue, a bleeding tissue, qne a bone defect.
9. A kit for the treatment of an injury selected from the group consisting of a wound, a hemorrhage, a damaged tissue, and a bleeding tissue, comprising:
a) a hemostatic composition according to claim 1; and
b) instructions for use
10. A method for producing a hemostatic composition according to claim 1 comprising the step of mixing a biocompatible polymer suitable for use in hemostasis and one hydrophilic polymeric component comprising reactive groups with a binder wherein the reactivity of the polymeric component is retained.
11. The hemostatic composition according to claim 2, wherein the biocompatible polymer and the hydrophilic polymeric component are present with a binder wherein the reactivity of the polymeric component is retained.
12. The hemostatic composition according to claim 2, wherein the polyalkylene oxide polymer is a PEG comprising polymer.
13. The hemostatic composition according to claim 2, wherein the polyalkylene oxide polymer is a multi-electrophilic polyalkylene oxide polymer.
14. The hemostatic composition according to claim 2, wherein the polyalkylene oxide polymer is a multi-electrophilic PEG.
15. The hemostatic composition according to claim 2, wherein the polyalkylene oxide polymer is pentaerythritolpoly(ethyleneglycol)ether tetrasuccinimidyl glutarate.
16. The hemostatic composition according to claim 5, wherein the hydrophilic polymeric component with reactive groups is a polyethylene glycol (PEG) comprising two or more reactive groups selected from succinimidylesters (—CON(COCH2)2), aldehydes (—CHO) and isocyanates (—N═C═O).
17. The hemostatic composition according to claim 7, wherein the binder has a water content (% v/v) below 2%.
18. The hemostatic composition according to claim 7, wherein the binder has a water content (% v/v) below 1%.
19. The method according to claim 10, wherein the mixing step comprises blending.
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