CA2534895A1 - Hemostatic compositions containing sterile thrombin - Google Patents

Hemostatic compositions containing sterile thrombin Download PDF

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Publication number
CA2534895A1
CA2534895A1 CA002534895A CA2534895A CA2534895A1 CA 2534895 A1 CA2534895 A1 CA 2534895A1 CA 002534895 A CA002534895 A CA 002534895A CA 2534895 A CA2534895 A CA 2534895A CA 2534895 A1 CA2534895 A1 CA 2534895A1
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Prior art keywords
thrombin
sterile
liquid phase
hemostatic
composition
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CA002534895A
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CA2534895C (en
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Sanyog M. Pendharkar
Anne J. Gorman
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Ethicon Inc
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Ethicon, Inc.
Sanyog M. Pendharkar
Anne J. Gorman
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    • 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
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/363—Fibrinogen
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4833—Thrombin (3.4.21.5)
    • 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
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/104—Gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0028—Polypeptides; Proteins; Degradation products thereof
    • A61L26/0042—Fibrin; Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0095—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6429—Thrombin (3.4.21.5)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21005—Thrombin (3.4.21.5)
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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

Abstract

The present invention includes sterilized hemostatic compositions that contain a continuous, biocompatible liquid phase having a solid phase of particles of a biocompatible polymer suitable for use in hemostasis and that is substantially insoluble in the liquid phase, and sterile thrombin, each of which is substantially homogenously dispersed throughout the continuous liquid phase, and methods for making such compositions.

Description

HEMOSTATIC COMPOSITIONS CONTAINING STERILE THROMBIN
FIELD OF THE INVENTION
The present invention relates to hemostatic compositions containing sterile thrombin and to methods of making such hemostatic compositions.
BACKGROUND OF THE INVENTION
Gelatin-based hemostats, both in solid sponge or powder form, are commercially available and are used in surgical procedures. Gelatin powder, when mixed with fluid, can be prepared in various forms depending on the contemplated end-use and the ratio of fluid to powder. For example, where higher concentrations of fluid axe employed, a paste or slurry that is useful as a flowable, extrudable and inj ectable hemostat may be prepared for use in diffuse bleeding, particularly from uneven surfaces or hard to reach areas. Such conventional slurries are prepared at the point of use by mechanical agitation and mixing of the powder and liquid to provide uniformity of the composition. The paste then is placed into a delivery means or applicator, e.g. a syringe, and applied to the wound. In other cases, moldable compositions may be prepared with lower amounts of fluid and molded or packed to form a dressing for use on external wounds. Gelatin powders are sterilized prior to preparing such compositions but mixing of the powders and fluids may compromise the sterility of the hemostatic composition due to handling of the materials at the site of use, or in general by exposure to the environment for relatively extended periods of time during mixing and the like.
Thrombin that is not terminally sterilized is known to be used~in combination with such hemostatic compositions. Proteins such as thrombin are prepared aseptically and thus there is a risk that nonsterilized proteins such as thrombin, when used in hemostatic compositions, may compromise the sterility of the previously-sterilized materials, such as sterilized gelatin powder. However, as thrombin is known to be denatured by exposure to sterilizing condition such as ionizing radiation conventionally used to sterilize the powders, which denaturing destroys all enzymatic activity of the thrombin, thrombin has not been reported to be incorporated into the hemostatic compositions and then terminally sterilized prior to use to ensure a sterile composition.
In fact, when thrombin is used in conventional hemostatic compositions, nonsterilized thrombin is added after sterilization of hemostatic composition.
It would be desirable if a sterile hemostatic composition containing active sterile thrombin was available to the surgeon at the point of use without need for preparation, e.g. without having to add thrombin prior to use. The compositions of the present invention fulfill that need.
SUMMARY OF THE INVENTION
The present invention is directed to sterilized hemostatic compositions comprising a continuous, biocompatible liquid phase, a solid phase comprising porous or non-porous particles of a biocompatible polymer suitable for use in hemostasis and which are substantially insoluble in the liquid phase, and sterile thrombin.
The continuous liquid phase comprises the solid particulate phase and sterile thrombin substantially homogenously dispersed there through. The ratio of the liquid phase, the solid particulate phase and thrombin is effective to provide the composition with hemostatic properties, both prior to and after sterilization. Sterile compositions of the present invention may be prepared well in advance of the time of use while maintaining thrombin enzymatic activity even after being subjected to sterilizing radiation. The present invention also includes methods of making the hemostatic compositions .
DETAILED DESCRIPTION OF THE INVENTION
Sterilized compositions of the present invention contain solid, porous or non-porous particles of a biocompatible polymer suitable for use in hemostasis, a biocompatible liquid and sterile thrombin as its three primary components.
Particles, liquid and thrombin are combined and mixed under conditions effective to provide a substantially homogeneous hemostatic composition comprising a continuous liquid phase comprising the thrombin and having the solid polymer particles homogenously dispersed there through. The amount and average diameter of particles contained in the composition and the relative amounts of the solid, liquid and thrombin is effective to provide the composition with hemostatic and physical properties, as described herein below.
Compositions of the present invention may be prepared and sterilized by ionizing irradiation well in advance of the time of their intended use, while maintaining thrombin enzymatic activity effective to improve hemostasis of the composition when compared to a similar composition containing no thrombin or where the thrombin activity has been substantially diminished such that it no longer enhances hemostasis.
This is particularly surprising given that it is known in the art that thrombin is denatured when exposed to irradiation of the type used to sterilize conventional hemostatic compositions containing, for example, gelatin powder. Denaturing causes the thrombin to lose its enzymatic activity. The compositions further may include additives to facilitate the preparation of the composition, enhance physical and mechanical properties, enhance the hemostatic properties of the composition or provide antimicrobial properties.
As used herein, "continuous" and "discontinuous" are used in the ordinary meaning of those words in the context of standard nomenclature used to define and describe dispersions.
As used herein, "substantially homogenous" denotes that physical state of the compositions or pastes where the solid particles are uniformly dispersed throughout the continuous liquid phase such that the ratio of solid:liquid and the density of any portion or cross-section of the composition or paste are substantially the same.
As used herein, "sterile" means substantially free of living germs and/or microorganisms and as further recognized and described by governmental standards pertaining to compositions and medical devices described and claimed herein.
As used herein, "hemostatic", or "hemostatic properties", means the ability to stop or minimize bleeding, as one skilled in the art of hemostasis would understand those terms to mean, as further exemplified in the examples of the specification.
A variety of biocompatible natural, semi-synthetic or synthetic polymers may be used to prepare the solid particles used in compositions of the present invention. The polymer selected must be substantially insoluble in the liquid chosen for the particular composition. Preferably, water-insoluble biodegradable polymers that provide mechanical, chemical and/or biological hemostatic activity are used. Polyners that may be used include, without limitation, proteins and polysaccharides.
Polysaccharides that may be used include oxidized cellulose, chitosan, chitin, alginate, oxidized alginate and oxidized starch. The biocompatible polymer used to prepare the particles preferably is a cross-linked or denatured protein, such as gelatin, collagen, fibrinogen or fibronectin.
A preferred gelatin powder is a partially cross-linked gelatin powder prepared by milling gelatin sponge into particles having an average diameter of from about microns to about 1200 microns, more preferably from about 100 microns to about microns, as determined by laser diffraction.
Sterile compositions of the present invention comprise a continuous liquid phase in which the sterile thrombin and solid particles are dispersed.
Depending upon the particular medical device and use thereof, the liquid may be aqueous or non-aqueous. Preferably, the liquid phase is aqueous. Aqueous liquids may include, without limitation, biocompatible aqueous solutions, such as calcium chloride and saline. More preferably, the liquid phase comprises saline. The liquid phase and solid particulate phase are present in relative amounts effective to provide a composition, for example a paste, or slurry, suitable for use in providing hemostasis. hl certain embodiments, the weight ratio of solid particles to liquid generally is from about 1:1 to about 1:12, or from about 1:3 to about 1:8 or even about 1:5.
Compositions of the present invention include compositions described herein that are sterile, in that they have been irradiated with a level of, e.g.
ionizing irradiation.
Such irradiation may include e-beam or gamma irradiation. The level of irradiation and conditions of sterilization, including the time that the compositions are irradiated, are those that provide sterile compositions, as defined herein. Once having the benefit of this disclosure, one skilled in the art will be able to readily determine the level of irradiation necessary to provide sterile compositions.
As noted herein, thrombin, in an aqueous solution, has been found to lose all procoagulant activity when exposed to sterilization irradiation. In contrast, sterile thrombin contained in compositions of the present invention retain enzymatic activity sufficient to provide hemostatic properties to compositions of the present invention after being subjected to irradiation sufficient to provide sterilized compositions disclosed herein. Sterile thrombin in compositions of the present invention may lose only about 20 percent of its original enzymatic activity prior to sterilization. In certain embodiments of the present invention, the sterile thrombin exhibited a loss of enzymatic activity of not more than about 40% of its original enzymatic activity prior to sterilization, while maintaining all of its hemostatic activity after sterilization, when formulated in compositions according to this invention. While bovine thrombin is exemplified herein, human-derived thrombin, as described in U.S. Patent No.
5,143,838, also may be used in compositions of the present invention. The discovery that thrombin will maintain activity after being exposed to sterilizing radiation as described above is particularly surprising given the previous teachings of the art that would strongly suggest that if thrombin were to be used in hemostatic compositions it should be added after sterilization of the composition, not prior to sterilization.
The hemostatic compositions may further comprise effective amounts of one or more additives or compounds including, but not limited to, antimicrobial agents, surfactants, antioxidants, humectants, wetting agents, lubricants, thickeners, diluents, irradiation stabilizers, e.g. radical scavengers, plasticizers, and stabilizers. For example, glycerol may be added to enhance the extrudability or inj ectability of the composition. When utilized, glycerol may be present in the compositions at from about 0% to about 20% by weight, based on the weight of the liquid phase.
Preferably, the composition may comprise from about 1% to about 10% by weight of glycerol, based on the weight of the liquid phase. More preferably, the compositions may comprise from about 1% to about 5% by weight of glycerol, based on the weight of the liquid phase.
In addition, quaternary amines may be used to provide enhanced properties to the compositions. For example, benzalkonium chloride, Polybrene or Onamer M
may be used at levels up to about 1 percent by weight, based on the weight of the liquid phase. Preferably, benzalkonium chloride is used at levels of from about 0.001% to about 0.01 % by weight, based on the weight of the liquid phase. More preferably, the compositions may comprise from about 0.002 to about 0.006% by weight benzalkonium chloride, based on the weight of the liquid phase. It is believed that the quaternary amines may serve multiple functions, acting as an antimicrobial agent, a foaming agent, a radical scavenger and as a heparin neutralizer.
Such hemostatic compositions may further comprise heparin neutralizers, additional procoagulants or hemostatic agents, such as fibrinogen, fibrin, Factor Xa, or Factor VIIa. By "effective amount", it is meant that amount necessary to provide to the compositions those properties for which the additive is being added. The effective amount also is limited by the maximum amount that may be added without causing detrimental biological affects.
Medical devices in which the hemostatic compositions of the present invention may be utilized include any device currently being used to apply a flowable or injectable hemostatic paste or slurry to a site, or wound, requiring hemostasis. The site requiring hemostasis may be the result of an injury or a surgical procedure.
Examples of devices or applicators include syringes such as Becton Dickinson or Monoject luer syringes. Other devices are disclosed in detail in United States Patent No.
6,045,570, the contents of which are incorporated by reference in their entirety.
In one embodiment for making compositions of the invention, a substantially homogenous paste is prepared by mixing the particles with the liquid to form a uniform paste. The liquid includes the thrombin and may include effective amounts of other additives dissolved therein as described above. Mixing may be accomplished by extrusion or by mixing in a confined space under conditions effective to provide a uniform dispersion of the solid particles in the liquid phase.
Alternately, a mixer, e.g. a double planetary mixer, may be utilized in making compositions of the present invention. The liquid containing the thrombin is added to the mixer. The liquid may include effective amounts of additives dissolved therein prior to addition of particles to the solution. For example, a saline solution containing thrombin, glycerol and benzalkonium chloride may be prepared and then added to the mixer. The solid particles are added to the mixer over time with continuous mixing until all ingredients have been added. The mixing is continued until such time as a substantially homogenous composition is formed containing the solid particles uniformly dispersed throughout the continuous liquid phase.
The hemostatic compositions prepared as above are sterilized to provide sterile compositions comprising sterile thrombin. In some embodiments the compositions are transferred into a medical device as described above and the device containing the hemostatic composition is sterilized, preferably by ionizing radiation. More preferably, sterilization is by gamma irradiation as exemplified herein.
While the following examples demonstrate certain embodiments of the invention, they are not to be interpreted as limiting the scope of the invention, but rather as contributing to a complete description of the invention.

Exam lp a 1:
Two vials of lyophilized Bovine thrombin (20,000 units Thrombogen JJMn were reconstituted in 20 ml of saline to provide a working solution of 1,000 units/ml.
Clotting activity was measured in an ira vitro test as described in Example 2.
One vial of this material was stored at 4-8°C and the clotting activity measured at day l, day 8 and day 30, respectively. The second vial was sterilized by gamma irradiation (25kGy) and the clotting activity measured as above. The unsterilized and sterilized samples were designated samples la and lb, respectively. Both sterilized and unsterilized samples were stored at 4-8 °C between measurements.
Another 2 vials of 20,000 units of lyophilized bovine thrombin were reconstituted in saline containing 0.005% benzalkonium chloride and 5%
glycerol. One vial was stored at. 4-8°C and the clotting activity was measured at day 0, day 1, day 8 and day 30. The second vial was sterilized by gamma irradiation (25kGy) and the clotting activity measured as above. In between measurements both the sterilized and unsterilized samples were stored at 4-8 °C. The unsterilized and sterilized samples were designated samples 1 c and 1 d, respectively.
Several samples of gelatin paste containing the thrombin noted above were prepared by mixing 1 gram of Surgifoam gelatin powder with 5 ml of thrombin solution. The resulting paste was loaded into a lOcc syringe. Samples were then either sterilized at 25kGy followed by storage at 4-8°C, or stored unsterilized at 4-8°C.
Samples so prepared are designated and identified below.
Sample le = 1 g Surgifoam~ powder plus 5 ml of sample la; Sterilized Sample 1 f =1 g Surgifoam~ powder plus 5 ml of sample 1 c; Unsterilized Sample lg =1 g Surgifoam~ powder plus 5 ml of sample 1c; Sterilized Example 2:
Measurement of Thrombin activity by an ih ritro coagulation test in a Fibrometer instrument (BBL) Method: Serial dilutions of test sample containing thrombin were prepared in Veronal buffer pH 7.2. 0.2 ml of pooled normal plasma (Citrol Level 1 control plasma-Dade Diagnostics) was warmed to 37°C in the fibrometer incubator block.
0.1 ml of pre-warmed sample dilution was added to the plasma and the timer started simultaneously. The time to clot formation was recorded. All samples were tested in duplicate and an average clotting time calculated. Data was graphed as the logy dilution vs. loglo clotting time and a regression analysis performed. Freshly prepared thrombin was considered to have 100% activity and all other samples were calculated as a percentage of the activity relative to the freshly prepared thrombin.
Results are presented in Table 1 and Table 2.

Effect of Storage time on Thrombin Activity:
Stabilization by Formulated Gelatin Paste Storage Solution (Stored at 6C) Percent Loss in Thrombin Activity Time 0 Day 1 Day 8 Day 30 la 0 0 53.3 90.8 1 c 0 NA 41.1 82.9 if 0 0 0.8 0 Effect of Gamma Irradiation on Thrombin Activity:
Stabilization by Formulated Gelatin paste Media for Sterilized Thrombin * Samples (5m1/g gelatin powder- 25 kGy Dose) Loss in Thrombin Activity Day 6 lb 100 1 d 96.0 1 a 72.6 1 g 79.2 Ih vivo Hemostasis Performance of Pre-filled Thrombin/Gelatin Paste TIME: SAMPLE Number of CompressionsTime to Hemostasis (rains aecs) Day 0: if 1 0:30 Day42: if 1 0:30 Day 42: if 1 0:30 Day 42: 1g 1 0:30 Day 42: lg 1 0:30 Example 3: Sterilization of frozen Thrombin by Gelatin paste ~ne vial of 20,000 units of lyophilized bovine thrombin (Thrombogen JJMl~
was reconstituted in saline containing 0.005% BAK and 5% glycerol. 1 gram of Surgifoam~' powder was mixed with 5 ml of thrombin-containing saline solution . The resulting paste was loaded into a 10 ml syringe. The sample were frozen at -20°C and sterilized by gamma irradiation at a dose of 25kG. Thrombin clotting activity was measures as described in Example 2. It was noted that only 42 percent of thrombin activity was lost due to sterilization.

Claims (13)

1. A sterile hemostatic composition, comprising:
a continuous, biocompatible liquid phase comprising sterile thrombin; and a solid phase comprising particles of a biocompatible polymer suitable for use in hemostasis and which is substantially insoluble in said liquid phase, said continuous liquid phase comprising said solid phase and said sterile thrombin substantially homogenously dispersed there through, wherein the ratio of said liquid phase and said solid phase is effective to provide said composition with hemostatic properties and said sterile thrombin comprises enzymatic activity.
2. The sterile hemostatic composition of claim 1 wherein said liquid phase comprises saline.
3. The sterile hemostatic composition of claim 2 wherein said biocompatible polymer is selected from the group consisting of proteins and polysaccharides.
4. The sterile hemostatic composition of claim 3 wherein said protein is selected from the group consisting of gelatin, collagen, fibrinogen and fibronectin.
5. The sterile hemostatic composition of claim 4 wherein said protein comprises gelatin.
6. The sterile hemostatic composition of claim 1 wherein said sterile thrombin has lost not more than about 20 percent of the enzymatic activity it possessed prior to sterilization.
7. The sterile hemostatic composition of claim 1 wherein said sterile thrombin has lost not more than about 40 percent of the enzymatic activity it possessed prior to sterilization.
8. A method for making a sterile hemostatic composition, comprising:
providing a biocompatible liquid having thrombin dissolved therein, combining said liquid comprising said thrombin with particles of a biocompatible polymer suitable for use in hemostasis and which is substantially insoluble in said liquid, mixing said liquid comprising said thrombin and said particles under conditions effective to form a continuous liquid phase comprising said thrombin and said particles substantially homogenously dispersed there through, thereby forming a substantially homogeneous hemostatic composition; and irradiating said substantially homogeneous hemostatic composition with an amount of ionizing radiation and for a time effective to provide a sterile, substantially homogeneous hemostatic composition, wherein the ratio of said continuous liquid phase and said particles is effective to provide said composition with hemostatic properties and wherein said thrombin maintains at least a portion of its enzymatic activity.
9. The method of claim 8 wherein said liquid phase comprises saline.
10. The method of claim 9 wherein said biocompatible polymer is selected from the group consisting of proteins and polysaccharides.

10. The method of claim 9 wherein said protein is selected from the group consisting of gelatin, collagen, fibrinogen and fibronectin.
11. The method of claim 10 wherein said protein comprises gelatin.
12. The method of claim 8 wherein said sterile thrombin has lost not more than about 20 percent of the enzymatic activity it possessed prior to sterilization.
13. The method of claim 1 wherein said sterile thrombin has lost not more than about 20 percent of the enzymatic activity it possessed prior to sterilization.
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Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7094874B2 (en) 2000-05-26 2006-08-22 Bristol-Myers Squibb Co. Soluble CTLA4 mutant molecules
US7927626B2 (en) 2003-08-07 2011-04-19 Ethicon, Inc. Process of making flowable hemostatic compositions and devices containing such compositions
US8440225B2 (en) * 2003-08-07 2013-05-14 Ethicon, Inc. Process of making flowable hemostatic compositions and devices containing such compositions
US20060019868A1 (en) * 2004-01-30 2006-01-26 Pendharkar Sanyog M Hemostatic compositions and devices
CN1856283A (en) * 2003-09-23 2006-11-01 奥斯治疗有限公司 Bioabsorbable putty-like hemostatic implants
US7955616B2 (en) * 2003-09-23 2011-06-07 Orthocon, Inc. Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects
EP2462957B1 (en) * 2003-09-23 2019-04-24 Abyrx, Inc. Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects
US7109163B2 (en) 2004-01-30 2006-09-19 Ethicon, Inc. Hemostatic compositions and devices
DE102005017845A1 (en) * 2005-04-18 2006-10-19 Lohmann & Rauscher Gmbh & Co. Kg Autosterile, antiseptic collagen preparations, their use and methods of preparation
SE530659C2 (en) * 2005-12-22 2008-08-05 Delaval Holding Ab Washing device and method for cleaning milk-related equipment
GB0623607D0 (en) 2006-11-27 2007-01-03 Haemostatix Ltd Tissue adhesive
WO2009109194A2 (en) 2008-02-29 2009-09-11 Ferrosan A/S Device for promotion of hemostasis and/or wound healing
WO2009123903A1 (en) 2008-04-03 2009-10-08 Zymogenetics, Inc. Hemostatic microspheres
WO2010136588A2 (en) * 2009-05-28 2010-12-02 Profibrix B.V. Dry powder fibrin sealant
WO2011115828A1 (en) * 2010-03-13 2011-09-22 Devon Anderson Absorbent bioabsorbable composite surgical biomaterial
CN103037845B (en) 2010-06-01 2015-11-25 巴克斯特国际公司 For the preparation of the method for dry, stable hemostatic composition
US9084728B2 (en) 2010-06-01 2015-07-21 Baxter International Inc. Process for making dry and stable hemostatic compositions
JP6289096B2 (en) * 2010-06-01 2018-03-07 バクスター・インターナショナル・インコーポレイテッドＢａｘｔｅｒ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃｏｒｐ０Ｒａｔｅｄ Process for making a dry and stable hemostatic composition
US20130108671A1 (en) * 2011-10-27 2013-05-02 Baxter Healthcare S.A. Hemostatic compositions
GB201201751D0 (en) 2012-02-01 2012-03-14 Haemostatix Ltd Haemostatic wound dressing
JP6241624B2 (en) 2012-03-06 2017-12-06 フェロサン メディカル デバイシーズ エイ／エス Pressurized container containing hemostatic paste
JP6394916B2 (en) * 2012-06-12 2018-09-26 フェロサン メディカル デバイシーズ エイ／エス Dry hemostatic composition
US20160015792A1 (en) * 2013-03-07 2016-01-21 Profibrix Bv Powder formulation comprising thrombin and fibrinogen
US9040093B2 (en) 2013-03-13 2015-05-26 Orthovita, Inc. Bone graft materials containing calcium phosphate and chitosan
AU2014283170B2 (en) 2013-06-21 2017-11-02 Ferrosan Medical Devices A/S Vacuum expanded dry composition and syringe for retaining same
CA2928963C (en) 2013-12-11 2020-10-27 Ferrosan Medical Devices A/S Dry composition comprising an extrusion enhancer
WO2015089626A1 (en) 2013-12-16 2015-06-25 The University Of British Columbia Self-fueled particles for propulsion through flowing aqueous fluids
JP6726852B2 (en) 2014-10-13 2020-07-22 フェッローサン メディカル ディバイス エー／エス Dry composition for use in hemostasis and wound healing
JP6747650B2 (en) 2014-12-24 2020-08-26 フェロサン メディカル デバイシーズ エイ／エス Syringe for holding and mixing the first substance and the second substance
CZ307805B6 (en) * 2015-06-25 2019-05-22 Ing Medical S.R.O. Device for functionalizing fibrous structures in medicine and its operation
CZ308361B6 (en) * 2015-06-25 2020-06-24 Ing Medical S.R.O. A system for applying an active substance to an encapsulated carrier and a method for its activity
CA2986981A1 (en) 2015-07-03 2017-01-12 Ferrosan Medical Devices A/S Syringe for mixing two components and for retaining a vacuum in a storage condition
DK3496770T3 (en) 2016-08-12 2021-06-21 Biomup France Sas Hemostatic flowable material
KR101989054B1 (en) * 2017-11-28 2019-06-13 (주)다림티센 Hemostatic agent and container containing the same
JP7395113B2 (en) 2018-05-09 2023-12-11 フェロサン メディカル デバイシーズ エイ／エス Method of preparing a hemostatic composition
CN110732037B (en) 2018-07-20 2023-05-26 广州倍绣生物技术有限公司 Hemostatic paste and preparation method thereof
IL261190A (en) * 2018-08-16 2019-01-31 Omrix Biopharmaceuticals Ltd Stable liquid thrombin compositions

Family Cites Families (207)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2899362A (en) 1959-08-11 Hemostatic sponges and method of
US2465357A (en) 1944-08-14 1949-03-29 Upjohn Co Therapeutic sponge and method of making
US2507244A (en) * 1947-04-14 1950-05-09 Upjohn Co Surgical gelatin dusting powder and process for preparing same
CH264752A (en) 1947-06-03 1949-10-31 Hoffmann La Roche Process for the manufacture of carriers for pharmaceuticals.
US3089815A (en) 1951-10-11 1963-05-14 Lieb Hans Injectable pharmaceutical preparation, and a method of making same
NL302091A (en) 1962-12-20
US3743140A (en) * 1970-12-21 1973-07-03 Diehl Mateer G Co Filler apparatus with hopper and rotary feed mechanism for dispensing controlled volumes of materials
SE420565B (en) 1974-06-06 1981-10-19 Pharmacia Ab AID FOR INTRAVASCULAR ADMINISTRATION FOR USE IN CONNECTION WITH INTRAVASCULAR ADMINISTRATION OF A SOLUTION OR SUSPENSION OF A DIAGNOSTIC AGENT
US4002173A (en) 1974-07-23 1977-01-11 International Paper Company Diester crosslinked polyglucan hydrogels and reticulated sponges thereof
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
US4013078A (en) 1974-11-25 1977-03-22 Feild James Rodney Intervertebral protector means
JPS51125156U (en) 1975-03-31 1976-10-09
US4006220A (en) 1975-06-04 1977-02-01 Gottlieb Sheldon K Compositions and methods useful for repairing depressed cutaneous scars
US4164559A (en) 1977-09-21 1979-08-14 Cornell Research Foundation, Inc. Collagen drug delivery device
DE2843963A1 (en) 1978-10-09 1980-04-24 Merck Patent Gmbh BODY-RESORBABLE SHAPED MATERIAL BASED ON COLLAGEN AND THEIR USE IN MEDICINE
US4265233A (en) 1978-04-12 1981-05-05 Unitika Ltd. Material for wound healing
US4179400A (en) 1978-05-09 1979-12-18 W. R. Grace & Co. Process for preparing catalytic solutions of sulfonium salts
AT359652B (en) 1979-02-15 1980-11-25 Immuno Ag METHOD FOR PRODUCING A TISSUE ADHESIVE
AT359653B (en) 1979-02-15 1980-11-25 Immuno Ag METHOD FOR PRODUCING A TISSUE ADHESIVE
DE3036033A1 (en) 1980-09-24 1982-05-06 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen POWDERED WOUND TREATMENT AND METHOD FOR THE PRODUCTION THEREOF
US4300494A (en) 1979-09-26 1981-11-17 Shell Oil Company Thermal insulated intake ports
US4292972A (en) 1980-07-09 1981-10-06 E. R. Squibb & Sons, Inc. Lyophilized hydrocolloio foam
DE3105624A1 (en) 1981-02-16 1982-09-02 Hormon-Chemie München GmbH, 8000 München MATERIAL FOR SEALING AND HEALING Wounds
DE3267499D1 (en) 1981-03-18 1986-01-02 Fujirebio Kk Support material for use in serological testing and process for the production thereof
US4424208A (en) 1982-01-11 1984-01-03 Collagen Corporation Collagen implant material and method for augmenting soft tissue
DE3360633D1 (en) 1982-02-12 1985-10-03 Unitika Ltd Anti-cancer device
US4482386A (en) 1982-03-26 1984-11-13 Warner-Lambert Company Method of conditioning a water swellable hydrocolloid
US4543332A (en) 1982-03-29 1985-09-24 Miles Laboratories, Inc. Method for the preparation of spherical microorganism cell aggregates
US4540410A (en) 1982-11-16 1985-09-10 Serono Pharmaceutical Partners Lyophilized compositions, preparation and use thereof
JPS59113889A (en) 1982-12-17 1984-06-30 Sumitomo Chem Co Ltd Preparation of immobilized enzyme or immobilized microbial cell
EP0132983B2 (en) 1983-07-14 1991-06-12 Hitachi Chemical Co., Ltd. Production of gelatin spherical gels and their use
JPS60100516A (en) 1983-11-04 1985-06-04 Takeda Chem Ind Ltd Preparation of sustained release microcapsule
US4515637A (en) 1983-11-16 1985-05-07 Seton Company Collagen-thrombin compositions
AT389815B (en) 1984-03-09 1990-02-12 Immuno Ag METHOD FOR INACTIVATING VARIABLE FILTERABLE DISEASERS IN BLOOD PRODUCTS
US4600574A (en) 1984-03-21 1986-07-15 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Method of producing a tissue adhesive
US4837285A (en) 1984-03-27 1989-06-06 Medimatrix Collagen matrix beads for soft tissue repair
SE456346B (en) 1984-07-23 1988-09-26 Pharmacia Ab GEL TO PREVENT ADHESION BETWEEN BODY TISSUE AND SET FOR ITS PREPARATION
JPS6144825A (en) 1984-08-09 1986-03-04 Unitika Ltd Hemostatic agent
GB8422950D0 (en) 1984-09-11 1984-10-17 Warne K J Hydrogel
JPS61122222A (en) 1984-11-19 1986-06-10 Koken:Kk Hemostatic agent composed of collagen or gelatin and protamine
US5178883A (en) 1984-11-29 1993-01-12 Regents Of The University Of Minnesota Method for promoting hair growth
US5165938A (en) 1984-11-29 1992-11-24 Regents Of The University Of Minnesota Wound healing agents derived from platelets
US4600533A (en) 1984-12-24 1986-07-15 Collagen Corporation Collagen membranes for medical use
US5007916A (en) 1985-08-22 1991-04-16 Johnson & Johnson Medical, Inc. Method and material for prevention of surgical adhesions
US4696812A (en) 1985-10-28 1987-09-29 Warner-Lambert Company Thrombin preparations
IE59361B1 (en) 1986-01-24 1994-02-09 Akzo Nv Pharmaceutical preparation for obtaining a highly viscous hydrogel or suspension
JPS62228009A (en) 1986-03-29 1987-10-06 Nitto Electric Ind Co Ltd Member for external use
IL78826A (en) 1986-05-19 1991-05-12 Yissum Res Dev Co Precursor composition for the preparation of a biodegradable implant for the sustained release of an active material and such implants prepared therefrom
US4946870A (en) 1986-06-06 1990-08-07 Union Carbide Chemicals And Plastics Company Inc. Delivery systems for pharmaceutical or therapeutic actives
US5300494A (en) 1986-06-06 1994-04-05 Union Carbide Chemicals & Plastics Technology Corporation Delivery systems for quaternary and related compounds
US4832686A (en) 1986-06-24 1989-05-23 Anderson Mark E Method for administering interleukin-2
US4803075A (en) 1986-06-25 1989-02-07 Collagen Corporation Injectable implant composition having improved intrudability
US4743229A (en) 1986-09-29 1988-05-10 Collagen Corporation Collagen/mineral mixing device and method
US4965203A (en) 1987-01-28 1990-10-23 Warner-Lambert Company Purified thrombin preparations
CA1305069C (en) 1987-03-11 1992-07-14 John Cornell Wound dressings in sheet or gelled paste form
US4885161A (en) 1987-03-11 1989-12-05 Medi-Tech International Corporation Wound dressings in gelled paste form
US5080893A (en) 1988-05-31 1992-01-14 University Of Florida Method for preventing surgical adhesions using a dilute solution of polymer
US5017229A (en) 1990-06-25 1991-05-21 Genzyme Corporation Water insoluble derivatives of hyaluronic acid
ES2064439T3 (en) 1988-05-02 1995-02-01 Project Hear SURGICAL ADHESIVE MATERIAL.
US4936835A (en) 1988-05-26 1990-06-26 Haaga John R Medical needle with bioabsorbable tip
US5350573A (en) 1988-05-31 1994-09-27 University Of Florida Research Foundation, Inc. Method and composition for preventing surgical adhesions
US5140016A (en) 1988-05-31 1992-08-18 University Of Florida Method and composition for preventing surgical adhesions using a dilute solution of polymer
US5447966A (en) 1988-07-19 1995-09-05 United States Surgical Corporation Treating bioabsorbable surgical articles by coating with glycerine, polalkyleneoxide block copolymer and gelatin
US4925677A (en) 1988-08-31 1990-05-15 Theratech, Inc. Biodegradable hydrogel matrices for the controlled release of pharmacologically active agents
US5041292A (en) 1988-08-31 1991-08-20 Theratech, Inc. Biodegradable hydrogel matrices for the controlled release of pharmacologically active agents
US5135751A (en) 1988-11-16 1992-08-04 Mediventures Incorporated Composition for reducing postsurgical adhesions
US5126141A (en) 1988-11-16 1992-06-30 Mediventures Incorporated Composition and method for post-surgical adhesion reduction with thermo-irreversible gels of polyoxyalkylene polymers and ionic polysaccharides
US5162430A (en) 1988-11-21 1992-11-10 Collagen Corporation Collagen-polymer conjugates
US5510418A (en) 1988-11-21 1996-04-23 Collagen Corporation Glycosaminoglycan-synthetic polymer conjugates
US5614587A (en) 1988-11-21 1997-03-25 Collagen Corporation Collagen-based bioadhesive compositions
US4891359A (en) * 1988-12-08 1990-01-02 Johnson & Johnson Patient Care, Inc. Hemostatic collagen paste composition
DE3843126C3 (en) * 1988-12-22 1994-10-06 Octapharma Ag Process for the production of a high-purity thrombin concentrate
JPH02171207A (en) * 1988-12-24 1990-07-02 Ngk Insulators Ltd Ceramic injection-molded body and its molding method
DE3903672C1 (en) 1989-02-08 1990-02-01 Lohmann Gmbh & Co Kg
KR910007847B1 (en) 1989-06-10 1991-10-02 한국과학기술원 New sponge-like microporous
EP0493387B1 (en) 1989-08-10 1993-10-20 W.L. Gore & Associates, Inc. A medical dispensing system for tissue adhesive components
US5196185A (en) 1989-09-11 1993-03-23 Micro-Collagen Pharmaceutics, Ltd. Collagen-based wound dressing and method for applying same
US5061274A (en) 1989-12-04 1991-10-29 Kensey Nash Corporation Plug device for sealing openings and method of use
US5281528A (en) 1989-12-18 1994-01-25 Warner-Lambert Company Process for purified thromboplastin for ultra-pure thrombin preparation
US5733572A (en) 1989-12-22 1998-03-31 Imarx Pharmaceutical Corp. Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles
US5219328A (en) 1990-01-03 1993-06-15 Cryolife, Inc. Fibrin sealant delivery method
US5134229A (en) 1990-01-12 1992-07-28 Johnson & Johnson Medical, Inc. Process for preparing a neutralized oxidized cellulose product and its method of use
JPH0813750B2 (en) 1990-03-01 1996-02-14 持田製薬株式会社 Oral thrombin formulation
US5306501A (en) 1990-05-01 1994-04-26 Mediventures, Inc. Drug delivery by injection with thermoreversible gels containing polyoxyalkylene copolymers
US5595735A (en) * 1990-05-23 1997-01-21 Johnson & Johnson Medical, Inc. Hemostatic thrombin paste composition
US5634943A (en) 1990-07-12 1997-06-03 University Of Miami Injectable polyethylene oxide gel implant and method for production
US5292362A (en) * 1990-07-27 1994-03-08 The Trustees Of Columbia University In The City Of New York Tissue bonding and sealing composition and method of using the same
US5209776A (en) 1990-07-27 1993-05-11 The Trustees Of Columbia University In The City Of New York Tissue bonding and sealing composition and method of using the same
US5108421A (en) 1990-10-01 1992-04-28 Quinton Instrument Company Insertion assembly and method of inserting a vessel plug into the body of a patient
US5192300A (en) 1990-10-01 1993-03-09 Quinton Instrument Company Insertion assembly and method of inserting a vessel plug into the body of a patient
NO302481B1 (en) 1990-10-16 1998-03-09 Takeda Chemical Industries Ltd Polymer for an extended release preparation, as well as an extended release preparation
US5129882A (en) 1990-12-27 1992-07-14 Novoste Corporation Wound clotting device and method of using same
US5690675A (en) 1991-02-13 1997-11-25 Fusion Medical Technologies, Inc. Methods for sealing of staples and other fasteners in tissue
US5605938A (en) 1991-05-31 1997-02-25 Gliatech, Inc. Methods and compositions for inhibition of cell invasion and fibrosis using dextran sulfate
AU654574B2 (en) 1991-06-14 1994-11-10 Amgen, Inc. Collagen film drug delivery for proteins
NL9101051A (en) 1991-06-18 1993-01-18 Ashridge Ag CLOSING DEVICE FOR A VESSEL OR THE LIKE.
US5292632A (en) 1991-09-24 1994-03-08 Eastman Kodak Company High tabularity high chloride emulsions with inherently stable grain faces
AT398079B (en) 1991-11-04 1994-09-26 Immuno Ag PREPARATION WITH THROMBINE ACTIVITY AND METHOD FOR THEIR PRODUCTION
DK0632820T3 (en) 1992-02-28 2000-10-02 Collagen Corp Highly concentrated, homogenized collagen compositions
ATE269371T1 (en) 1992-02-28 2004-07-15 Cohesion Tech Inc INJECTABLE CERAMIC COMPOUNDS AND METHOD FOR THEIR PRODUCTION AND USE
US5468505A (en) 1992-02-28 1995-11-21 Board Of Regents, The University Of Texas System Local delivery of fibrinolysis enhancing agents
US5204382A (en) 1992-02-28 1993-04-20 Collagen Corporation Injectable ceramic compositions and methods for their preparation and use
US5384333A (en) 1992-03-17 1995-01-24 University Of Miami Biodegradable injectable drug delivery polymer
CA2134071C (en) 1992-04-23 1999-04-27 Sew Wah Tay Apparatus and method for sealing vascular punctures
IL105529A0 (en) 1992-05-01 1993-08-18 Amgen Inc Collagen-containing sponges as drug delivery for proteins
JPH05308969A (en) 1992-05-13 1993-11-22 Japan Vilene Co Ltd Enzyme holder and its production
AU4406793A (en) 1992-06-04 1993-12-30 Clover Consolidated, Limited Water-soluble polymeric carriers for drug delivery
US5385606A (en) 1992-07-06 1995-01-31 Kowanko; Nicholas Adhesive composition and method
US5413571A (en) 1992-07-16 1995-05-09 Sherwood Medical Company Device for sealing hemostatic incisions
US5428022A (en) 1992-07-29 1995-06-27 Collagen Corporation Composition of low type III content human placental collagen
US5514379A (en) 1992-08-07 1996-05-07 The General Hospital Corporation Hydrogel compositions and methods of use
DE4227681C2 (en) 1992-08-21 1995-05-18 Becker & Co Naturinwerk Wound covering material based on collagen fibers and process for its production
CA2149221C (en) 1992-11-12 2005-02-08 Neville Alleyne Cardiac protection device
US5667839A (en) 1993-01-28 1997-09-16 Collagen Corporation Human recombinant collagen in the milk of transgenic animals
WO1994023788A1 (en) 1993-04-20 1994-10-27 Medchem Products, Inc. Apparatus and method for applying a particulate hemostatic agent to living tissue
EP0702959B1 (en) 1993-05-31 2001-08-08 Kaken Pharmaceutical Co., Ltd. Cross-linked gelatin gel preparation containing basic fibroblast growth factor
JPH0790241A (en) 1993-09-22 1995-04-04 Menicon Co Ltd Temporary adhesive for eye lens material
EP0726749B1 (en) 1993-11-03 2004-08-11 Clarion Pharmaceuticals, Inc. Hemostatic patch
FR2715309B1 (en) 1994-01-24 1996-08-02 Imedex Adhesive composition, for surgical use, based on collagen modified by oxidative cutting and not crosslinked.
US5674275A (en) 1994-04-06 1997-10-07 Graphic Controls Corporation Polyacrylate and polymethacrylate ester based hydrogel adhesives
US5531759A (en) 1994-04-29 1996-07-02 Kensey Nash Corporation System for closing a percutaneous puncture formed by a trocar to prevent tissue at the puncture from herniating
JP3107726B2 (en) 1994-05-13 2000-11-13 株式会社クラレ Water-swellable polymer gel
DE69530553T2 (en) 1994-05-13 2004-03-25 KURARAY CO., LTD, Kurashiki MEDICAL POLYMER GEL
GB9415739D0 (en) 1994-07-30 1994-09-21 Scimat Ltd Gel wound dressing
US5599735A (en) 1994-08-01 1997-02-04 Texas Instruments Incorporated Method for doped shallow junction formation using direct gas-phase doping
US5516532A (en) 1994-08-05 1996-05-14 Children's Medical Center Corporation Injectable non-immunogenic cartilage and bone preparation
US5931165A (en) 1994-09-06 1999-08-03 Fusion Medical Technologies, Inc. Films having improved characteristics and methods for their preparation and use
AU1287895A (en) 1994-10-03 1996-04-26 Otogen Corporation Differentially biodegradable biomedical implants
FR2726571B1 (en) 1994-11-03 1997-08-08 Izoret Georges BIOLOGICAL GLUE, PREPARATION METHOD AND APPLICATION DEVICE FOR BIOLOGICAL GLUE, AND HARDENERS FOR BIOLOGICAL GLUE
US5698213A (en) 1995-03-06 1997-12-16 Ethicon, Inc. Hydrogels of absorbable polyoxaesters
US5580923A (en) 1995-03-14 1996-12-03 Collagen Corporation Anti-adhesion films and compositions for medical use
US5677284A (en) 1995-06-06 1997-10-14 Regen Biologics, Inc. Charged collagen particle-based delivery matrix
US6129761A (en) 1995-06-07 2000-10-10 Reprogenesis, Inc. Injectable hydrogel compositions
US5752974A (en) 1995-12-18 1998-05-19 Collagen Corporation Injectable or implantable biomaterials for filling or blocking lumens and voids of the body
US6458889B1 (en) 1995-12-18 2002-10-01 Cohesion Technologies, Inc. Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use
PT876165E (en) 1995-12-18 2006-10-31 Angiotech Biomaterials Corp COMPOSITIONS OF RETICULATED POLYMERS AND PROCESSES FOR THEIR USE
US5748318A (en) 1996-01-23 1998-05-05 Brown University Research Foundation Optical stress generator and detector
US5782917A (en) 1996-02-26 1998-07-21 Sunmed, Inc. Intramedullary bone plug
CA2251475C (en) 1996-04-04 2006-09-05 Immuno Aktiengesellschaft Hemostatic sponge based on collagen
CA2251129A1 (en) 1996-05-03 1997-11-13 Innogenetics N.V. New medicaments containing gelatin cross-linked with oxidized polysaccharides
FR2749759B1 (en) 1996-06-17 1999-11-26 Adir USE OF STRONTIUM SALTS FOR THE PRODUCTION OF PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF ARTHROSIS
US5902832A (en) 1996-08-20 1999-05-11 Menlo Care, Inc. Method of synthesizing swollen hydrogel for sphincter augmentation
US6063061A (en) * 1996-08-27 2000-05-16 Fusion Medical Technologies, Inc. Fragmented polymeric compositions and methods for their use
US6066325A (en) 1996-08-27 2000-05-23 Fusion Medical Technologies, Inc. Fragmented polymeric compositions and methods for their use
US6706690B2 (en) * 1999-06-10 2004-03-16 Baxter Healthcare Corporation Hemoactive compositions and methods for their manufacture and use
US7435425B2 (en) 2001-07-17 2008-10-14 Baxter International, Inc. Dry hemostatic compositions and methods for their preparation
US8303981B2 (en) 1996-08-27 2012-11-06 Baxter International Inc. Fragmented polymeric compositions and methods for their use
US7871637B2 (en) 1996-08-27 2011-01-18 Baxter International Inc. Dry hemostatic compositions and methods for their preparation
US7320962B2 (en) 1996-08-27 2008-01-22 Baxter International Inc. Hemoactive compositions and methods for their manufacture and use
AU4648697A (en) * 1996-09-23 1998-04-14 Chandrashekar Pathak Methods and devices for preparing protein concentrates
BR9700855A (en) 1997-01-02 1998-12-15 Univ Minas Gerais Process for production of growth factor of recombinant bean virus 58058 (begf) and recombinant begf protein
JP2001508689A (en) * 1997-01-16 2001-07-03 コヘージョン コーポレイション Lyophilized collagen-based biomaterials, their preparation process and use
US6045570A (en) * 1997-02-11 2000-04-04 Biointerventional Corporation Biological sealant mixture and system for use in percutaneous occlusion of puncture sites and tracts in the human body and method
US6120751A (en) * 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
EP0986408B1 (en) 1997-06-03 2005-05-11 Innogenetics N.V. New medicaments based on polymers composed of methacrylamide-modified gelatin
US5908054A (en) 1997-06-16 1999-06-01 Fusion Medical Technologies, Inc. Fluid dispersion and delivery assembly and method
US6869938B1 (en) 1997-06-17 2005-03-22 Fziomed, Inc. Compositions of polyacids and polyethers and methods for their use in reducing adhesions
AU7977298A (en) 1997-06-18 1999-01-04 Cohesion Technologies, Inc. Compositions containing thrombin and microfibrillar collagen, and methods for preparation and use thereof
DE69831964T2 (en) 1997-09-16 2006-07-27 Integra Lifesciences Corp. COMPOSITION FOR PROMOTING THE GROWTH OF DURAL OR MENINGEAL TISSUE CONTAINING COLLAGEN
US5997895A (en) 1997-09-16 1999-12-07 Integra Lifesciences Corporation Dural/meningeal repair product using collagen matrix
US6179872B1 (en) 1998-03-17 2001-01-30 Tissue Engineering Biopolymer matt for use in tissue repair and reconstruction
FR2784296B1 (en) * 1998-09-18 2001-01-05 Imedex Biomateriaux DEVICE FOR FORMULATING AND DELIVERING A MIXTURE, PARTICULARLY FOR THE SURGICAL APPLICATION OF THIS MIXTURE
US6110484A (en) 1998-11-24 2000-08-29 Cohesion Technologies, Inc. Collagen-polymer matrices with differential biodegradability
GB2344519B (en) 1998-12-07 2004-05-19 Johnson & Johnson Medical Ltd Sterile therapeutic compositions
JP2000229882A (en) 1998-12-10 2000-08-22 Sankyo Co Ltd Modified cyclodextrin-containing thrombin aqueous liquid preparation
US6454787B1 (en) 1998-12-11 2002-09-24 C. R. Bard, Inc. Collagen hemostatic foam
US6328229B1 (en) 1998-12-18 2001-12-11 Cohesion Technologies, Inc. Low volume mixing spray head for mixing and dispensing of two reactive fluid components
US6312725B1 (en) 1999-04-16 2001-11-06 Cohesion Technologies, Inc. Rapid gelling biocompatible polymer composition
US6221109B1 (en) 1999-09-15 2001-04-24 Ed. Geistlich Söhne AG fur Chemische Industrie Method of protecting spinal area
US6312474B1 (en) 1999-09-15 2001-11-06 Bio-Vascular, Inc. Resorbable implant materials
PT1220693E (en) 1999-10-15 2005-02-28 Inst Genetics Llc FORMULATIONS FOR OSTEOGENIC PROTEIN LIBERATION
US6432415B1 (en) 1999-12-17 2002-08-13 Axrix Laboratories, Inc. Pharmaceutical gel and aerosol formulations and methods to administer the same to skin and mucosal surfaces
US6566345B2 (en) * 2000-04-28 2003-05-20 Fziomed, Inc. Polyacid/polyalkylene oxide foams and gels and methods for their delivery
DE10012732A1 (en) 2000-03-18 2001-09-20 Aventis Behring Gmbh Thrombin composition, for use as hemostatic or as a component of fibrin glues, comprises non-covalently bonded inhibitor for stabilization
US20030012687A1 (en) 2000-03-23 2003-01-16 Macphee Martin J. Methods of sterilizing biological materials
CN1114728C (en) 2000-04-21 2003-07-16 中国石油化工集团公司 Staltic fibre and its manufacture method
AU2001259177A1 (en) * 2000-04-28 2001-11-12 Fziomed, Inc. Polyacid/polyalkylene oxide foams and gels and methods for their delivery
AU2001266926A1 (en) 2000-06-16 2002-01-02 University Of Medicine And Dentistry Of New Jersey Hemostatic compositions, devices and methods
US7094428B2 (en) 2000-06-16 2006-08-22 The University Of Medicine And Dentistry Of New Jersey Hemostatic compositions, devices and methods
AT412445B (en) 2000-06-20 2005-03-25 Biering Wolfgang LIQUID COLLAGE HEMOSTATIC
CA2422852C (en) 2000-09-18 2012-06-26 Organogenesis Inc. Methods for treating a patient using a bioengineered flat sheet graft prostheses
JP2002104996A (en) 2000-09-25 2002-04-10 Mochida Pharmaceut Co Ltd Coloring matter-containing hemostatic composition
EP1209708B1 (en) 2000-11-24 2007-01-17 Sony Deutschland GmbH Hybrid solar cells with thermal deposited semiconductive oxide layer
EP1359947A2 (en) 2001-01-25 2003-11-12 Nycomed Pharma AS A suspension comprising fibrinogen, thrombin and alcohol and a method of coating a carrier with the same
WO2002087636A1 (en) † 2001-03-12 2002-11-07 Sub-Q, Inc. Methods for sterilizing cross-linked gelatin compositions
US8187625B2 (en) * 2001-03-12 2012-05-29 Boston Scientific Scimed, Inc. Cross-linked gelatin composition comprising a wetting agent
US6682695B2 (en) 2001-03-23 2004-01-27 Clearant, Inc. Methods for sterilizing biological materials by multiple rates
DE10131474A1 (en) 2001-06-29 2003-05-28 Bosch Gmbh Robert Electrical machine
AU2002300450B2 (en) 2001-08-10 2007-04-05 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Collagen Carrier of Therapeutic Genetic Material, and Method
EP2289566A1 (en) 2001-12-21 2011-03-02 Ferrosan Medical Devices A/S Medical device comprising a haemostatic agent and haemostatic kit comprising the medical device
AU2004245086B2 (en) 2003-06-05 2008-06-26 Baxter Healthcare S.A. Compositions for repairing and regenerating human dura mater
US8834864B2 (en) 2003-06-05 2014-09-16 Baxter International Inc. Methods for repairing and regenerating human dura mater
US7927626B2 (en) 2003-08-07 2011-04-19 Ethicon, Inc. Process of making flowable hemostatic compositions and devices containing such compositions
US20060019868A1 (en) * 2004-01-30 2006-01-26 Pendharkar Sanyog M Hemostatic compositions and devices
EP1682196A2 (en) 2003-11-10 2006-07-26 Angiotech International Ag Medical implants and anti-scarring agents
US7109163B2 (en) 2004-01-30 2006-09-19 Ethicon, Inc. Hemostatic compositions and devices
AR054637A1 (en) 2004-01-30 2007-07-11 Ferrosan As AEROSOLS AND HEMOSTATIC COMPOSITIONS
WO2006031358A2 (en) 2004-08-13 2006-03-23 Hyperbranch Medical Technology, Inc. Dendritic polymers, crosslinked gels, and their uses as ophthalmic sealants and lenses
US20080091277A1 (en) 2004-08-13 2008-04-17 Kai Deusch Surgical prosthesis having biodegradable and nonbiodegradable regions
ES2367583T3 (en) 2005-05-04 2011-11-10 Suprapolix B.V. HYDROGELS WITH HYDROGEN LINKS.
WO2007001926A2 (en) 2005-06-24 2007-01-04 Hyperbranch Medical Technology, Inc. Low-swelling hydrogel sealants for wound repair
CN101454030B (en) 2006-05-31 2013-06-26 巴克斯特国际公司 Method for directed cell in-growth and controlled tissue regeneration in spinal surgery
TWI436793B (en) 2006-08-02 2014-05-11 Baxter Int Rapidly acting dry sealant and methods for use and manufacture
JP2011500237A (en) 2007-10-30 2011-01-06 バクスター・インターナショナル・インコーポレイテッド Use of regenerative biofunctional collagen biomatrix to treat visceral or cavity wall defects
US9039783B2 (en) 2009-05-18 2015-05-26 Baxter International, Inc. Method for the improvement of mesh implant biocompatibility
PT2442835E (en) 2009-06-16 2015-03-23 Baxter Healthcare Sa Hemostatic sponge
US9687445B2 (en) 2012-04-12 2017-06-27 Lts Lohmann Therapie-Systeme Ag Oral film containing opiate enteric-release beads

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