CA2329809A1 - Compositions comprising hemostatic compounds and bioabsorbable polymers - Google Patents
Compositions comprising hemostatic compounds and bioabsorbable polymers Download PDFInfo
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- CA2329809A1 CA2329809A1 CA002329809A CA2329809A CA2329809A1 CA 2329809 A1 CA2329809 A1 CA 2329809A1 CA 002329809 A CA002329809 A CA 002329809A CA 2329809 A CA2329809 A CA 2329809A CA 2329809 A1 CA2329809 A1 CA 2329809A1
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- composition
- hemostatic
- fibrinogen
- thrombin
- fibrous
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
Abstract
Solid, fibrous bioabsorbable hemostatic compositions containing a bioabsorbable polymer and a hemostatic compound, methods for making the hemostatic compositions, and methods for using the hemostatic compositions are disclosed.
Description
WO 99/5679$ PCT/US99/09$91 COMPOSTTIONS COMPRISING HEMOSTATIC COMPOUNDS
AND BIOABSORBABLE POLYMERS
BACKGROUND OF THE INVENTION
1 o This invention relates to hemostatic compositions useful in the stemming or prevention of blood loss from surgical or traumatic wounds.
A hemorrhage of a blood vessel, body tissue, organ or bone can result in blood loss leading to hypovolemic shock and death. However, despite continued advances in trauma care, a significant number of trauma victims suffer fatal or severe hemorrhage every year. Many of these fatalities could be prevented if adequate means existed for on site control of blood loss. Hemophiliacs and patients receiving anticoagulant medication (e.g., during and/or after heart surgery) are also at high risk for rapid blood loss.
The use of fibrin as a coagulating substance for stopping bleeding and for sealing wounds has been widely accepted. Generally, such biological adhesives or "fibrin glues" are based on a two component system of fibrinogen and thrombin which when mixed form a fibrin coagulum by the cleavage of fibrinogen through the action of thrombin to form fibrin monomers that spontaneously polymerize to form a three dimensional network of fibrin. For example, TisseeITM is a two-component kit containing a fluid thrombin component including calcium chloride and a somewhat more viscous fibrinogen component including factor XIII, fibronectin, aprotinin and plasminogen. The two components are delivered deep frozen in two separate syringes, or as two lyophilized powders with corresponding aprotinin and calcium solutions as solvents. Using this method, the fibrin glue consolidates when the two components are combined due to fibrin monomer aggregation. The setting rate is dependent on the thrombin concentration and varies from a few seconds (high thrombin concentration) to a couple of minutes (low thrombin concentration).
The major disadvantage of these preparations is that the water-like fluidity of the components renders them difficult to handle and administer.
Although various efforts have been made to facilitate the administration of these compositions, for example, by the development of double-syringe applicators as described in U.S. Patent No. 4,359,049, or a spray system as described in U.S.
Patent No. 4,427,651, the basic problem of low viscosity remains.
Wadstrom, U.S. Patent No. 5,631,011 describes a method of increasing the viscosity of fibrin glue compositions by adding a biocompatible polymer capable of fom-ling a viscous aqueous solution. The components of this system are provided in deep freeze solutions or as lyophilized powders which are diluted prior to use with aqueous solutions. The primary route of administration taught by Wadstrom is by a two component preparation. Thus, while Wadstrom emphasizes the advantages of increasing the viscosity of the solution over prior "water-like" fibrin glues, the components of this system still require additional preparation at the time of use. Wadstrom further teaches that compositions having a high viscosity are to be avoided because fibrin polymerization and adhesion to the tissues would be inhibited.
One currently used alternative to fibrin glue, is a biodegradable collagen patch ("TAF" patch). For example, Zimmerman and Schiele, U.S. Patent 4,453,939, describe collagen carriers in the form of a foam, web or film that is coated with a mixture of blood-clotting components including fibrinogen and thrombin. To prevent reaction of the blood-clotting components prior to use, they are provided as a suspension in an organic solvent which is applied to the collagen by brushing, spraying or dipping. However, difficulties in achieving optimum timing for the fixing procedure have been reported using this method resulting in inconsistent attachment and stability of the active components onto the collagen carrier. Moreover, penetration of the active components beyond the surface of the collagen carrier is not possible using this method, thereby limiting the concentration of blood-clotting components available to the surface of the device. Another problem with the TAF patches is that the collagen fleece/foam used does not provide sufficient mechanical support once wet, preventing application of manual pressure to assist in stopping blood flow or repositioning of the patch once it has been applied to the wound. Further, surgeons have 1o reported that the inflexibility of the TAF patch prevents them from easily conforming to the contours of the site to which they are applied. Still another problem with TAF patches is that they require refrigeration prohibiting use outside a clinic or hospital setting.
WO 96/17633 describes tissue sealants including a fibrin bandage. In the method used for generating the bandage, the active components are lyophilized in separate layers which are supported by an occlusive backing. Therefore, the active components are not homogeneously mixed throughout the bandage.
Accordingly, there is a need for hemostatic compositions that are sturdy enough to withstand manual pressure and which are less complicated to use, especially in emergency situations such as life-threatening traumas wherein stemming blood flow as fast as possible can be critical.
SUMMARY OF THE INVENTION
In one aspect, the invention features a hemostatic, biocompatible composition in the form of a fibrous solid that is bioabsorbable. The composition contains a bioabsorbable polymer and one or more hemostatic compounds. Preferably, the hemostatic compound is thrombin, more preferably, the composition contains thrombin and a calcium salt, and most preferably also includes fibrinogen. A "hemostatic compound or composition," as used herein, is a substance or composition that, upon application to a wound reduces or stops blood loss by promoting blood clot formation. By the term "fibrous" as used herein is meant a composition comprising natural or synthetic fibers. By "fiber"
is meant a unit of matter, either natural or manufactured, that forms the basic element of fabrics and other textile structures. A fiber is characterized by having a length at least 100 times its diameter or width.
The bioabsorbable polymers contained within the hemostatic composition of the invention include polyanionic polysaccharides, alginic acid, chitin, chitosan, fibrin, polyglycolide, polylactide, polycaprolactone, dextran and copolymers thereof. The term "polymer," as used herein refers to a molecule made by the repetitive bonding of at least two, and preferably more than two, repeating monomeric smaller units (e.g., monosaccharide, amino acid, nucleotide, alkene, or organic acid units). Accordingly, the term copolymer refers to a polymer formed by combination of two or more copolymerized monomeric or polymeric species. The term "bioabsorbable," as used herein, refers to the ability of a tissue-compatible material to degrade in the body after implantation into nontoxic products which are eliminated from the body or metabolized (Barrows, "Synthetic Bioabsorbable Polymers," p. 243, In: High Performance from Biomaterials -A comprehensive Guide to Medical and Pharmaceutical Applications, Michael Szycher, ed., Technomic Publishing, 2o Lancaster, PA, 1991 ). Generally, the concentration of bioabsorbable polymer used in the hemostatic compositions of the invention is in the range of 0. 1 to 50 mg/cm2; preferably the concentration of bioabsorbable polymer is in the range of 0. 1 to 30 mg/cm2 ; and more preferably the concentration of the bioabsorbable polymer ranges from 0. 1 to 10 mg/cm2 .
In one preferred embodiment, the bioabsorbable polymer is a polyanionic polysaccharide. A "polyanionic polysaccharide" (PAS) as the term is used herein, is a polyaccharide, including non-modified as well as chemical derivatives thereof, that contains more than one negatively charged group (e.g., carboxyl groups at pH values above about 4.0) and includes salts thereof, such as sodium or potassium salts, and alkaline earth metal salts such a calcium or magnesium salts. Preferred polyanionic polysaccharides contained in the hemostatic composition of the invention include, but are not limited to, hyaluronic acid (HA), carboxymethylcellulose (CMC carboxymethylarnylose (CMA), chondroitin-6-sulfate, dermatin sulfate, dermatin-6-sulfate and combinations thereof.
Most preferably, the polyanionic polysaccharide is HA, CMC or CMA
which is in the form of a water-insoluble derivative. A "polyanionic polysaccharide derivative," as the term is used herein, is one or more polyanionic polysaccharides (PAS) that are chemically modified from the native form. Such modifications can include the addition of functional groups (e.g., substituted amide groups, ester linkages, and amino groups); reactions that increase the water insolubility of the PAS by covalently cross-linking the PAS
y 5 molecules; and reactions that increase the water-insolubility of the PAS
by noncovalent interactions. Additionally, the hemostatic composition can include two or more polyanionic polysaccharides or their water-insoluble derivatives, e.g.. HA and CMC or HA and CMA.
In another preferred embodiment, the polyanionic polysaccharide is combined with one or more hydrophobic bioabsorbable polymers or copolymers. As used herein, "hydrophobic," refers to compounds or compositions which lack an affinity for water. Preferably, the hydrophobic bioabsorbable polymer is chosen from the group consisting of polyglycolide, polylactide (D, L or DL), polydioxanones, polyestercarbonates, polyhydroxyalkonates, polycaprolactone (polylactones), and copolymers thereof.
More preferably, polyglycolide, polylactide, or copolymers of polyglycolide-caprolactone, polyglycolide-polylactide, or polylactide-polycaprolactone are used in the composition of the invention. The concentration of hydrophobic bioabsorbable polymer used in combination with 3o the polyanionic polysaccharide is preferably in the range of 0. 1 to 50 mg/cm2 .
The thrombin used in preferred embodiments of this aspect of the invention can be of animal or human origin. For example, thrombin obtained from one mammalian species {e.g., bovine, pig, sheep) can be incorporated into compositions of the invention used to treat another mammalian species, for example, humans. More preferably, the thrombin used in the composition is from the same species for which the composition is intended to be used. The term "thrombin" as used herein includes natural thrombin molecules derived from animal or human plasma, and synthetic forms such as those produced by 1o recombinant DNA technology including functionally active analogs that effectively maintain clotting activity in an animal or human. Thrombin is present in the hemostatic composition of the invention in a concentration of 1 to 100 U/CMZ , and preferably between 10 to 50 U/cmz. A unit of thrombin, as used herein, is defined as the amount of thrombin required to clot a standardized 1 ml fibrinogen (~ 250 mg/ml) solution in 15 seconds.
The concentration of calcium chloride used in preferred embodiments of this aspect of the invention is sufficient to allow for activation of the thrombin.
Typically, the concentration of calcium will vary between 0.01 to 10 mg/cm2 .
The particular concentration of calcium used will depend on the specific purpose of the composition and can be readily determined by the skilled artisan using the teachings herein.
In other preferred embodiments of this aspect of the invention, the hemostatic composition includes fibrinogen. The fibrinogen can be of animal or human origin, and is preferably from the same species for which the composition is intended to be used. By the term "fibrinogen," as used herein, is meant to include natural fibrinogen molecules derived from animal or human plasma, and synthetic forms such as those produced by recombinant DNA
technology including functionally active analogs that effectively maintain clotting activity in an animal or human. The fibrinogen used in the compositions of the invention can be highly purified, can contain small amounts of clotting Factor XIII, or can be enriched with clotting Factor XllI. Typically, the amount of clottable fibrinogen is present in the hemostatic composition of the invention in a concentration between about 0.05 and 20 mg/cmz , preferably between about 1 and 20 mg/cm2, and more preferably between about 5 and 1 S mg/cm2.
Additional blood-clotting constituents and fibrinolysis inhibitors can also be included in the compositions of the invention. Examples include, but are not limited to, Factor XIII, fibronectin, plasminogen, aprotinin, alpha-2-antiplasmin, alpha-2-macroglobulin, alpha-1-antitrypsin, epsilon-aminocaproic acid or tranexamic acid, or a plasmin activator inhibitor, e.g., PAI-1 or PAI-2.
In a further embodiment, the hemostatic composition of the invention can also contain an amount of the agent protamine sulfate effective to neutralize heparin present in the local environment of the area of application. Protamine sulfate neutralizes heparin or vitamin K antagonists that are present in the blood of certain patients who, for example, are undergoing parental therapy with heparin.
The compositions of the invention can further include a drug. The particular drug used is a matter of choice depending on the intended use of the composition. Preferred drugs include, but are not limited to, growth factors, growth-factor inhibitors, antibodies, non-steroidal anti-inflammatory drugs, antibiotics, and cytostatics.
The hemostatic composition of the invention typically has a mass/area (M/A) between about 15 to 100 mg/cm2 preferably a M/A between about 20 to 60 mg/cm2, more preferably a M/A between about 30 to 40 mg/cm2 . The size and shape of the composition will vary depending on the particular use. For example, in certain preferred embodiments the hemostatic composition can be supplied in a variety of standard rectangular or circular sizes, such as those commonly used in first-aid kits, triage, and surgery, and which can be further cut and sized to the particular area being treated. Alternatively, the hemostatic composition can be provided in a variety of other shapes which are useful for packing into body cavities, including, but not limited to spherical, conical, cuboidal or cylindrical shapes.
In further related embodiments, the hemostatic composition is contained within a sealed, waterproof, sterile package which facilitates removal of the compositions without contamination. Preferred waterproof packaging materials include, for example, aluminum foil, plastic, or other conventional material that is easily sterilized. Sterilization can be accomplished, for example, by subjecting the packaged composition to radiation, for example, gamma radiation or E-beam, or by treatment with ethylene oxide.
In another aspect, the invention features a method of making a solid, fibrous, bioabsorbable hemostatic composition which includes the steps of combining a bioabsorbable polymer and one or more hemostatic compounds in the presence of a non-aqueous solvent and subjecting the combination to a paper-making process to produce a solid, bioabsorbable hemostatic composition.
In one preferred embodiment of this aspect of the invention, the method involves precipitating the components of the hemostatic composition either separately or together into a non-aqueous solvent, admixing the precipitated components under conditions sufficient to form a fibrous pulp, and then collecting, pressing and drying the fibrous pulp to produce a solid, bioabsorbable hemostatic composition.
Examples of organic solvents which can be used in the method of the invention include straight-chain or branched C~-CS alcohols, especially n-propanol, isopropanol, n-butanol, isobutanol and ethanol; ketones, for example, acetone or methyl ethyl ketone; aliphatic or cycloaliphatic ethers, for example dimethyl ether or diethyl ether, tetrahydrofuran or dioxane; esters, for example, ethyl acetate; nitrites, for example, acetonitrile; and aliphatic halogenated hydrocarbons, for example, carbon tetrachloride, methylene chloride and chloroform.
In preferred embodiments of the method of the invention, admixing of the components occurs under high shear conditions to evenly disperse the materials in the organic solvent. One preferred method of collecting the fibrous pulp uses forii-iing fabric. The term "forming fabric" refers to a material used during paper formation that permits the drainage of the pulp -solution while retaining the fibers, provides mechanical support, imparts surface characteristics during pressing and drying, and is released from the dried paper product. The forming fabric can be a variety of materials including, but not limited to a Teflon or stainless steel mesh screen, and preferably is a polyester woven fabric.
In other preferred embodiments, the fibrous pulp is collected onto the forming fabric under vacuum conditions; the wet pulp collected is subjected to heat compression; and air dried at room temperature, or preferably under heated conditions, for example, between 80 to 140°F, and most preferably is dried at 100 to 135°F.
In related embodiments of this aspect of the invention, the methods of the invention can produce a hemostatic composition in which the hemostatic compounds are evenly dispersed throughout the composition, or supplied as a gradient, for example, by collecting fibrous pulps containing a range of desired concentrations of the hemostatic compound or compounds one after the other prior to the steps of pressing and drying. Alternatively, the methods of the invention can be used to produce a multilayered hemostatic composition. For example, bilayer compositions containing one layer of bioabsorbable polymer and another layer containing one or more hemostatic compositions can be produced by collecting a fibrous pulp of the bioabsorbable polymer after collection of the fibrous pulp of the hemostatic compound and then combining the pulps in layers prior to the pressing and drying steps. Trilayer compositions can also be produced, for example, having hemostatic compounds on both sides of a core containing a bioabsorbable polymer.
In still another aspect, the invention includes a method of inhibiting or stopping blood loss from a wound by applying to the wound a solid hemostatic composition containing a bioabsorbable polymer and one or more hemostatic compounds. Preferably, the composition is maintained in contact with the wound preferably with light pressure (e.g., manual) for a period of time sufficient for blood clotting to occur at the interface between the composition and the wound and for bleeding to be substantially arrested. Generally, the hemostatic composition is maintained in contact with the wound surface for a period of about 20 seconds to 10 minutes, preferably about 20 seconds to 5 minutes, and more preferably about 20 seconds to 2 minutes. The composition can be applied directly to the wound alone, or can be held in place by means of a dry sterile material such as gauze. Depending on the location of the wound, a bandage, including an elasticized bandage can be wrapped around the patch so as to provide pressure to the wound site.
Preferred embodiments of this aspect of the invention include use of the hemostatic composition for topical treatment to inhibit or stop bleeding of wounds due to trauma or surgery. In additional preferred embodiments, the method of the invention uses the hemostatic composition to inhibit or stop bleeding of a parenchyma) organ, such as the liver, kidney, spleen, pancreas or lungs. Alternatively, the methods include inhibiting or stopping bleeding or fluid loss during surgery including, but not limited to, abdominal, vascular, urological, gynecological, thyroidal, neurosurgery, tissue transplant, and dental surgery.
In further embodiments, the hemostatic composition can also be provided for use to anastomose or fuse ends of a blood vessel or other body lumen that has been severed, for example, during surgery. In this embodiment, the hemostatic composition is provided in a form that is easily fit to the ends of a vascular prosthesis. In cases where the vascular prosthesis is synthetic, such as a Dacron graft, the hemostatic composition can be provided in a form (e.g., cylindrical) sized to easily fit over the ends of the graft. Accordingly, also provided are kits that contain a vascular prosthesis and a hemostatic composition of the invention designed for fitting with the ends of the prosthesis.
Alternatively, in cases wherein pre-sizing is not possible (e.g., natural grafts) the hemostatic composition can be provided in a form that is easily wrapped around the prosthesis just prior to use.
Additionally, a hemostatic composition according to the invention which is intended for topical applications can be applied with an adhesive tape, or adhered to an adhesive backing in a Band-Aid form. The type of adhesive used can be any type of medically acceptable adhesive. Preferably the adhesive used is porous to areas which contact the skin to allow diffusion of oxygen.
A kit is also provided which according to the invention comprises any of the above described embodiments of the hemostatic composition. For example, the kit can contain multiple hemostatic compositions, preferably wherein each is provided in a separate, waterproof, sterile package. Additionally, a kit designed for emergency or military use can also contain disposable pre-sterilized instruments, such as scissors, scalpel, clamp, tourniquet, elastic or inelastic bandages, or the like.
An important advantage of the hemostatic composition of the present invention is that the mechanical integrity of the composition is maintained after contact with body fluids allowing application of manual pressure to promote stoppage of blood flow, and repositioning of the composition when necessary.
In further contrast to prior art compositions, the active components necessary to promote hemostasis are dispersed throughout the composition avoiding the problem of separation of different layers thereby allowing the compositions to be cut and sized to the particular wound being treated.
Accordingly, the hemostatic compositions of the invention provide a means for rapidly reducing bleeding in trauma victims and surgical patients without the time delay associated with solubilization and mixing of components.
The hemostatic compositions can be readily used by untrained individuals as well as medical personnel. These characteristics allow use of these compositions in field applications, such as in trauma packs for soldiers, rescue workers, ambulance/paramedic teams, firemen, and by emergency room personnel, and in first aid kits for the general public use. Thus, utilization of the hemostatic compositions of the invention will result in a reduction of fatalities due to trauma and also decrease the demand upon the available blood supply during instances of severe natural or man-made disasters.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although any method and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.
All publications mentioned hereunder are incorporated by reference. Unless mentioned otherwise, the techniques employed or contemplated herein are standard methodologies well known to one skilled in the art. The materials, methods and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following description and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
A process is described for producing a solid, fibrous hemostatic composition containing proteins including, but not limited to, thrombin, or a combination of thrombin and fibrinogen, and salts such as, but not limited to, calcium chloride in combination with one or more bioabsorbable polymers.
Materials Fibrinogen and thrombin for use in the invention can be readily obtained from a number of commercial sources (e.g., Sigma, CalBiochem, American Diagnostics, Inc.). Alternatively, these proteins can be derived from the plasma of any desirable species, or produced using recombinant DNA methods (e.g., Prunkard et al., Nature Biotechnology 14:867-871, 1996; Velander, WO
95/22249; Karges and Metzner, Seminars in Thrombosis and Hemostasis, 22:427-436, 1996; Lewis et al., Biochemistry 36:995-1002, 1997; Lai et al, J.
Biol. Chem. 269:24596-24601, 1994; Fischer et al., Thrombosis Res.
81:157-162, 1996; Lord et al., Blood Coagulation and Fibrinolysis 4:55-59, 1993; DiBella et al., J. Biol. Chem. 270:163-169, 1995; Roy et al., J. Biol.
Chem. 270:163-169, 1995).
Preferably, the fibrinogen and thrombin used are of bovine or human origin. When the composition is to be used in humans, the fibrinogen and 1 o thrombin are most preferably of human origin. Additionally, when the fibrinogen is derived from human plasma it is preferably subjected to heat inactivation methods, or even more preferably to solvent detergent methods, well known to those skilled in the art and intended to inactivate any viruses that might be present (e.g., see Radosevich et al., "Fibrin Sealant: Scientific rationale, production methods, properties, and current clinical use," Vox Sang 2:133-I43, 1997).
Bioabsorbable biopolymers for use in the composition of the invention can be obtained from a variety of standard commercial sources (e.g., Genzyme Corp., Aqualon, Birmingham Polymers, Deknatel). Water-insoluble polyanionic 2o polysaccharide compositions can be prepared by a number of methods for use in this invention. For example, derivatives can be generated via the formation of covalent intra- and inter-chain crosslinks as previously described (e.g., see Sparer et al., 1983, Chapter 6, pages 107-119, in Roseman et al., Controlled Release Delivery Systems, Marcel Dekker, Inc., New York; DeBelder et al., PCT
Publication No. WO 86/00912; Balazs et al., 1986 U.S. Patent No. 4,582,865;
Malson et al., 1986, PCT Publication No. WO/86/00079; and Prestwich et al., EP Publication No. 0416250A2, 1991 ). Water insoluble compositions which do not contain covalent cross-links between polyanionic polysaccharide molecules and compositions containing polyanionic polysaccharides can be formed using 3o the methods described in Hamilton et al., U.S. Patent No. 4,937,270, Burns et al., U.S. Patent No. 5,017,229, USSN 07/03,254, 07/833,973, and compositions containing combinations of polyanionic polysaccharides and hydrophobic , polymers or copolymers are described in USSN 08/318,987 (all of the above hereby incorporated by reference).
Preparation of Hemostatic Compositions Generally, compositions according to the invention are formed by precipitating thrombin (with or without biopolymers and calcium chloride) by injecting the aqueous solution using a syringe into a rapidly stirring non-aqueous solvent coagulation bath containing ethanol, isopropanol, butanol or a combination thereof In compositions containing a combination of thrombin and fibrinogen, a second aqueous solution containing fibrinogen (with or without biopolymers and calcium chloride) is also precipitated into fibers using a non-aqueous solvent in the same manner. The fibrous precipitates) is then washed with the non-aqueous solvent to purify and dewater.
The desired fibrous precipitate or combination of precipitates (e.g., thrombin and biopolymer; thrombin, fibrinogen and biopolymer;
thrombin/biopolymer; thrombin/biopolymer and fibrinogen; thrombin and fibrinogen/biopolymer; and thrombin/biopolymer and fibrinogen/biopolymer) are high shear mixed to form a fibrous pulp solution in the non-aqueous solvent.
The pulp solution is then collected, pressed and dried using existing paper-making technology, (see, e.g., Handbook for Puip & Paper Technologists, Smook, G. 2nd edition, Angus Wilde Publications Inc., 1994), and as described in the following examples. The resulting paper-like structure consists of dry thrombin, or thrombin and fibrinogen in combination with one or more biopolymers, and can additionally contain calcium and/or other agents as described herein. Since all of the precipitation, mixing and paper-making steps are in a non-aqueous solvent and not in water, the thrombin does not activate fibrinogen during processing. The resulting, solid, fibrous, dried composition can contain the hemostatic components distributed throughout the paper-like material. Alternatively, a paper-like composition can be generated which has a concentration gradient of the desirable hemostatic components, for example, by collecting fibrous pulps containing varying concentrations of the hemostatic components prior to compression and drying.
Upon activation by blood, body fluids, saline or water, the composition acts as a hemostatic patch.
In another variation of the invention, the proteins and salts can be added to a non-aqueous slurry containing the biopolymer. For example, commercially available lyophilized fibrinogen, thrombin and calcium chloride powders can be added to the bioabsorbable polymer (e.g., HA/CMC and/or PGA) fibers in ethanol. The mixture can then be collected, pressed and dried according to existing paper-making technology to form a paper-like structure with hemostatic components homogeneously dispersed throughout the thickness. This paper-like structure has superior mechanical properties compared to prior art materials.
Moreover, since all of the precipitation, mixing and paper-making steps are in a non-solvent and not in water, the thrombin does not activate fibrinogen during processing.
Bilayer compositions can also be made with one side containing the hemostatic agents and the other side being non-hemostatic and non-adhesiogenic. For example, the hemostatic side can contain fibrinogen, thrombin and calcium chloride and the non-adhesiogenic side can contain HA/CMC. Alternatively, the hemostatic side can further contain one or more bioabsorbable polymers as described herein, whereas the non-adhesiogenic side would contain a bioabsorbable polymer without the hemostatic components.
HA/CMC has been demonstrated to reduce post-surgical adhesion formation (e.g., Becker et al., British J. Surg. 82:Suppl. 1, 1995). Therefore, the side containing the hemostatic components will provide hemostasis, while the side containing the bioabsorbable polymer, e.g., HA/CMC, would prevent adhesions.
Each side of the bilayer composition can be marked for appropriate placement, e.g., by the addition of a biocompatible dye such as riboflavin to one of the bilayers.
The paper-like compositions generated according to the herein described methods can also be used alone or in combination with tri-layer laminated technology such as that described in USSN 08/318,987. Tri-layer composites can be made by laminating the hemostatic paper-like membrane to a hydrophobic bioabsorbable polymer core, such as polyglycolide, polylactide, polycaprolactone, or copolymers thereof. The tri-layer composition can have hemostatic components laminated on both sides of the core which would provide hemostatic activity to both surfaces while increasing the strength and in vivo residence time of the device with the addition of the core polymer.
Alternatively, the hemostatic components can be laminated to one side of the core while laminating a nonadhesiogenic material such as HA/CMC to the other side thereby producing a device with one hemostatic surface and one non-adhesiogenic surface.
Additional Components In addition to the hemostatic agents, the compositions of the invention can further contain components which promote wound healing and prevent 2o infection such as, but not limited to polypeptide growth factors, non-steroidal anti-inflammatory agents, antibiotics, and cytostatics. The concentrations) of the additional components will vary depending on the desired objective, and should be sufficient to accomplish the particular purpose for which they are used. The amount of each component can be readily determined by those skilled in the art, for example, by empirically testing various concentrations and selecting that which is effective for the intended purpose and the site of application.
Examples of polypeptide growth factors which are known to play a role in healing include, but are not limited to: platelet-derived growth factors (PDGFs); insulin-binding growth factor- I (IGF-1); insulin-binding growth factor-2 {IGF-2); epidermal growth factor (EGF); transforming growth factor-a (TGF-a), transforming growth factor-~i (TGF-(3); platelet factor 4 (PF-4);
fibroblast growth factor (FGF); and heparin binding growth factors one and two (HBGF-1 and HBGF-2). The growth factor, or mixture thereof, can be prepared by any method known to those skilled in the art, or can be purchased from a variety of commercial sources. The selection of the particular growth factors) used will depend on the desired application and can be readily determined by those skilled in the art.
The invention is described in more detail in the following examples.
These examples are given by way of illustration and are not intended to limit the invention except for as set forth in the claims.
Example 1 Thirty-seven milliliters of an aqueous fibrinogen solution (40 mg/ml) was injected using a syringe into approximately 700 ml of 95% ethanol while stirring. The fibrous precipitate that resulted was stored in ethanol overnight. A
portion of the ethanol was decanted and all of the fibrinogen precipitate ( 1.48 g) in 540 ml of 95% ethanol was high shear mixed at 4000 rpm for 30 seconds with a Ultra-Turrax T50 homogenizer. The resulting pulp solution was stored in 95% ethanol.
Forty milliliters of fibrinogen pulp solution was diluted with 200 ml of 95% ethanol. To this furnish solution was added 20 mg of thrombin powder and 80 mg calcium chloride. The sample was collected on forming fabric using a Millipore filter housing (dia. = 7.4 cm). The wet sample was pressed at 2 metric ton for I S seconds and air dried to produce an extremely thin membrane.
Example 2 One-hundred-twenty milliliters of fibrinogen pulp solution prepared as described in Example 1 was diluted with 200 ml of 95% ethanol. To this furnish solution was added 40 mg of thrombin powder, 160 mg calcium chloride and 20 ml of modified hyaluronic acid/carboxymethyl cellulose pulp solution obtained by precipitating carbodiin-iide modified HA/CMC (modified as described in U.S. Patent No. 5,017,229) into ethanol, and high shearing the resulting fibrous precipitate into a pulp-like ethanol slurry. The mixture was collected as described for Example 1 on standard forming fabric using a Millipore filter under vacuum assist, pressed at 2 metric ton for 15 seconds, and air dried. A
paper-like membrane resulted.
Example 3 Three milliliters of an aqueous fibrinogen solution (40 mg/ml) was injected with a syringe into 100 ml of 100% ethanol while stirring. The fibrous precipitate that resulted was collected on a polyester filter. A small sample of the dry material (~ 1 cm2 ) was placed in 30 ml of deionized water with 5 mg of thrombin and 100 mg of calcium chloride. The material formed a fibrin clot immediately.
Example 4 0.22 g of lyophilized fibrinogen powder was added to 65 ml of HA/CMC
pulp (0.22 g HA/CMC in 100% ethanol). Also added to this mixture was 28 mg of calcium chloride powder and 3.3 mg of thrombin powder. The mixture was diluted with and additional 340 ml of 100% ethanol and high shear blended with an Ultra-Turrax T50 with a G45F dispersing head for 45 seconds at 5,000 rpm.
The mixture was then collected on forming fabric using a Millipore filter housing (dia.= 7.4 cm). The wet sample pressed twice at 10 psi with a roll press and air dried. A paper-like membrane resulted similar to that produced in Example 8 discussed below.
Example 5 Sixty-five milliliters of HA/CMC pulp (0.22 g HA/CMC in 100%
ethanol) was diluted with 340 ml of 100% ethanol and collected on forming fabric using a Millipore filter housing (dia.= 7.4 cm). Then a solution containing 65 ml of HA/CMC pulp, 0.22 g of lyophilized fibrinogen powder, 29 mg of 3o calcium chloride and 3.8 mg of thrombin was diluted with 340 ml of 100%
ethanol and collected on top of the HA/CMC wet cake. The wet sample was pressed two times at 10 psi with a roll press and dried at 100°F with a drum dryer. A thick bi-layer paper-like membrane resulted that was enriched with active fibrinogen/thrombin dispersed throughout the layer on one side and with a nonadhesiogenic HA/CMC layer on the other side.
Example 6 0.67g of chopped PGA fibers (Deknatel, Inc.) were added to 400 ml of 100% ethanol. 0.64 g of fibrinogen, 22 mg of thrombin and 100 mg of calcium chloride were added to the ethanol slurry and collected on Teflon forming fabric using a Millipore filter housing (dia = 7.4). The wet sample was pressed once at 10 psi with a roll press and dried at 120-125°F with a drum dryer. A
thick paper-like membrane resulted with a M/A of 36.6 mg/cm2 . The hemostatic paper was very absorbent and formed a fibrin clot when immersed in water.
Example 7 2.0 g of PGA fibers (Deknatel, Inc.) were chopped into ~5-10 mm segments and added to 600 ml of ethanol. In a separate vessel, 2.6 g of lyophilized bovine fibrinogen (77% protein, 90% clottable), 67 mg of bovine thrombin, and 0.3 g of calcium chloride powder were added to 900 ml of 100%
ethanol and high shear blended with an Ultra-Turrax T50 with a G45G
dispersing head for 30 seconds at 5000 rpm. The materials were combined and collected on Teflon forming fabric in a 4.25 x 4.25 inch headbox. The material drained in approximately 10 seconds without vacuum assistance. The fibrous cake was pressed once at 10 psi with a roll press and dried at 125-135°F for minutes. An 11.3 cm x 11.4 cm soft paper resulted with a M/A of 31.8 mg/cm2.
Example 8 4I0 ml of HA/CMC pulp ( 1.8 g of HA/CMC in 100% ethanol) was 3o diluted with 590 of 100% ethanol, and 2.6 g of lyophilized bovine fibrinogen (77% protein, 90% clottable), 67 mg of bovine thrombin and 0.3 g of calcium chloride were added and high shear blended with an Ultra-Turrax T50 with a G45G dispersing head for 15 seconds at 5000 rpm. The mixture was then collected on Teflon forming fabric in a 4.25 x 4.25 inch headbox. The material -was drained for 60 seconds without vacuum assistance and for 135 seconds with vacuum assistance. The resulting fibrous cake was pressed once at 10 psi with a roll press and dried at 125-135°F for ~ 30 minutes. An I 1.2 x 12.8 cm paper resulted with a M/A of 31 mg/cm2 .
Example 9 Samples of materials produced according to Examples 4 and 8 were tested in a platelet aggregation assay as described by Wagner et al, J. Surg.
Res.
66:100-108 (1996) using Coulter Counter Model J.T. (Coutler, Corp.). Both of these materials reduced platelet count by 45% compared to 9.5%,13% and 23%
with Gelfoam~ (absorbable gelatin sponge, Upjohn) Avitene~ (microfibrillar collagen hemostat, Davol), and ActifoamTM (absorbable collagen hemostatic sponge, MedChem Products), respectively.
Example 10 A sample prepared according to the method described in Example 8 was evaluated for sealing/hemostatic properties in the rabbit vena cava model. The vena cava of 26 anesthetized, heparinized ( 150 ILT/kg), 4-5 kg New Zealand White rabbits was each punctured using a i6 gauge needle. A 1 cm2 piece of the sample from Example 8, Avitene~ , TachoComb~ or surgical gauze was applied for 20 seconds directly over the puncture with light finger pressure.
The pressure was removed after 20 seconds and the breakthrough bleeding was observed. In the case of no further bleeding, observation was continued for 10 min. to ensure hemostasis. In the case of breakthrough bleeding, another 1 cm2 piece was applied over the first piece for another 20 seconds with light finger pressure. In the case of continued bleeding, the applications continued until a total of 10 minutes had elapsed. The results of this study are set forth in Table I.
-Table 1. Hemostasis/Sealant Model Group Average No. ApplicationsAverage Time to Hemostasis Control Gauze 15.4 2.1 * 8/9 > 600 seconds (n=9) t Avitene~ (n=6) 1.5 0.2 49.0 16.4 seconds TachoComb~ (n=5)6.0 t 3.7* >361 seconds ~
HA/CMC/Fib/Thromb/C1.0 t 0.2 25.8 seconds a Paper (n=6) fi~taustically sigmricant from HA/CMC/Fig/Thromb/Ca paper (Anova p=0.00 i , Tukey-Kramer) fiStatistically significant from HA/CMC/Fib/Thromb/Ca paper (Anova p=0.0005, Tukey-Kramer) The results of this study demonstrate the statistically superior hemostatic activity of the HA/CMC/Fibrinogen/Thrombin paper produced according to the methods of the invention as compared to Avitene~ and TachoComb~J in heparinized animals. The time to hemostasis was reduced by 48% compared to Avitene~ and 14 times compared to TachoComb~. The results further demonstrate that the composition of the invention also required fewer applications than either Avitene~ or TachoComb~.
Example 11 The preparation described in Example 8 was evaluated for resealing properties in the rabbit vena cava puncture model described in Example 10. The test article was initially placed over the wound, and hemostasis was achieved within approximately 20 seconds. The wound was monitored for a further 10 minutes to ensure that complete hemostasis had occurred. The test composition was then removed from the vena cava in one piece using forceps, and bleeding reinitiated. The previously used test composition was then replaced onto the wound and hemostasis was again achieved within approximately 20 seconds.
TachoComb~ (collagen sponge coated with thin layers of fibrinogen and thrombin, Nycomed, Austria) and Avitene~ were also tested for repositioning and resealing qualities in this model. TachoComb~ could not be removed in one piece, and the collagen layer separated from the fibrinogen and thrombin layer.
1o Avitene~ could not be removed in one piece or repositioned on the wound.
The results of this study demonstrate that compositions of the invention have improved physico-mechanical properties over both TachoComb~ and Avitene~. Therefore, the compositions of the invention can be removed and repositioned during use without a decrease in hemostatic or sealing capabilities, a significant advantage over the prior art hemostatic compositions.
Example 12 The preparation described in Example 8 was also tested for the ability to function in the presence of excess amounts of blood in the rabbit vena cava puncture model. The vena cava was punctured with a 16 gauge needle, and blood was allowed to fill the abdominal cavity. A 1 cm2 piece of the hemostatic composition of Example 8 was blindly applied to the wound for 20 seconds with finger pressure, and the excess blood was removed. Hemostasis was achieved in one application within 20 seconds. In contrast, Avitene~ fell apart when inserted into the bloodfilled abdominal cavity.
Example 13 The hemostatic composition prepared in Example 8 was sterilized by gamma irradiation (2.SMRad) and evaluated in the rabbit vena cava puncture model. Hemostasis was achieved in all three animals tested with one application for 20 seconds.
3o Example 14 1.8 g of PGA fibers (Deknatel, Inc.) were chopped into 5-10 min segments and added to 400 ml of 100% ethanol. In a separate vessel, 2.5 g of lyophilized bovine fibrinogen (77% protein, 90% clottable), 67 mg of bovine thrombin, 0.3 g of calcium chloride and 140 ml of HA/CMC pulp (0.6 g of HA/CMC in 100% ethanol) were added to 1000 ml of 100% ethanol and high shear blended with an Ultra-Turrax TSO with a G4SG dispersing head for 1 S
seconds at 5000 rpm. The materials were combined, stiffed, and collected on Teflon forming fabric ( 1 SO gm) in a 4.24 x 4.25 inch headbox. The material was 1 o drained for 60 seconds without vacuum assistance. The resulting fibrous cake was pressed once at 10 psi with a roll press and dried at 12S-13S°F for ~ 1S
minutes. An 11.4 x 11.4 cm soft paper resulted with a M/A of 3S mg/cm2.
Example 1S
67 mg of bovine thrombin and 0.3 g of calcium chloride were added to 4S0 ml of 100% ethanol and high shear blended with an Ultra-Turrax T50 with a G4SG dispersing head for 15 seconds at 4000 rpm. 2.S g of lyophilized bovine fibrinogen (77% protein, 90% clottable) was added to the mixture and high shear blended with an Ultra-Turrax TSO with a G45G dispersing head for 1 S
seconds at 4000 rpm. 1.8 g of PGA fibers (Deknatel) were chopped into ~ 10 2o mm segments, added to 3S0 ml of 100% ethanol, and then added to the fibrinogen/thrombin/calcium chloride mixture.
140 ml of HA/CMC pulp (0.6 g of HA/CMC in 100% ethanol) was diluted with 860 ml of 100% ethanol and collected on Teflon forming fabric ( 1 SO gm) in a 4.24 x 4.25 inch headbox. The material was drained until the remaining ethanol level was z I inch above the settled HA/CMC material (~ 150 seconds).
The PGA/fibrinogen/thrombin/calcium chloride mixture was then slowly added over the HA/CMC material. The material was allowed to drain for 60 seconds with vacuum assistance. Two different layers could be differentiated in 3o the resulting fibrous cake. The cake was pressed once at 10 psi with a roll press and dried at 12S-132°F for ~ 20 minutes, An 11.2 cm x 11.2 cm bilayer paper resulted with a M/A of 31 mg/cm2 , and the HA/CMC layer for adhesion prevention and the PGA/fibrinogen/thrombin/calcium chloride layer for hemostasis could be distinguished visually.
Example 16 Samples of materials produced according to Example 6 were tested in a platelet aggregation assay as described by Wagner et al., supra, using Multisizer Model 0217 (Coulter Corp.}. These materials reduced the volume in the platelet 1o region (2-4.5pm) by 27% compared to 0% with TachoComb~ (Nycomed), Gelfoam ~ (Upjohn) and Novacol~ (Datascope), by 11 % with Avitene~
(Davol), and by 19% with ActifoarnTM (MedChem).
Example 17 1. 8 g of PGA fibers (Deknatel) were chopped into -5-10 mm segments and added to 300 ml of 100% ethanol. In a separate vessel, 121 mg (3630 U) of bovine thrombin and 0.3 g of calcium chloride were added to 700 ml of 100%
ethanol and high shear blended with an UltraTurrax T50 with a G45G dispersing head for 15 seconds at 5000 rpm. Seventy milliliters of HA/CMC pulp (0.3 g of HA/CMC in 100% ethanol) was added during the last 5 seconds of mixing. The 2o materials were combined, stirred, and collected on Teflon forming fabric ( pm) in a 4.25 x 4.25 inch headbox. The material drained in 20 seconds without vacuum assistance. The fibrous cake was pressed once at 10 psi with a roll press and dried at 125-145°F for ~10 min. An 11.2 x 11.2 cm soft paper resulted with a M/A of 17.9 mg/cm2.
Example 18 Samples produced according to Examples 7, 8 and 14 were evaluated for dry and wet mechanical properties and compared to Avitene~ and TachoComb~ . A 10 mm x 50 mm piece of each material was placed in the grips of Instron Model 4201. The initial gauge length was 25 nim. Each material was tested under dry conditions at the crosshead speed of 2 mm/min. To test wet strength, materials were placed in 30 ml of PBS, pH 7.2 at 37°C for 15 minutes and measurements were taken at 23°C at a crosshead speed of 5 mm/min.
immediately after removal from the PBS. Maximum load before the material breaks is indicative of the strength of the material. The results of this study WO 99!56798 PCT/US99/09891 -(Table I>] demonstrate that the hemostatic materials of the invention have statistically significant increased dry and wet strength over both Avitene~
and TachoComb~
Table II. Mechanical Properties of Hemostats Sample Type Dry Testing Max. Wet Testing Max. Load Load PGA/F/T/Ca 0.34 t 0.04# 0.5645 0.0782 (Ex. 7) HA/CMC/F/T/Ca 9.11 0.92" 1.8275 t 0.977"
(Ex. 8) PGA/HA:CMC/F/T/Ca6.86 t 0.57" 1.2738 0.2308"
(Ex. 14 TachoComb~ 1.83 t 0.18 0.5242 t 0.1099 Avitene~ 0.12 t 0.08 Nd *Sample fell apart and could not be tested "Difference from TachoComb~ and Avitene~ (Anova p=0.01, Tukey-Kramer) #Difference from Avitene~ (Anova p=0.02, Tukey-Kramer) Other Embodiments From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions. For example, components including but not limited to plasticizers, polyethylene glycol, glycerol, and albumin can also be included in the composition of the invention to provide additional stability, mechanical strength and flexibility.
AND BIOABSORBABLE POLYMERS
BACKGROUND OF THE INVENTION
1 o This invention relates to hemostatic compositions useful in the stemming or prevention of blood loss from surgical or traumatic wounds.
A hemorrhage of a blood vessel, body tissue, organ or bone can result in blood loss leading to hypovolemic shock and death. However, despite continued advances in trauma care, a significant number of trauma victims suffer fatal or severe hemorrhage every year. Many of these fatalities could be prevented if adequate means existed for on site control of blood loss. Hemophiliacs and patients receiving anticoagulant medication (e.g., during and/or after heart surgery) are also at high risk for rapid blood loss.
The use of fibrin as a coagulating substance for stopping bleeding and for sealing wounds has been widely accepted. Generally, such biological adhesives or "fibrin glues" are based on a two component system of fibrinogen and thrombin which when mixed form a fibrin coagulum by the cleavage of fibrinogen through the action of thrombin to form fibrin monomers that spontaneously polymerize to form a three dimensional network of fibrin. For example, TisseeITM is a two-component kit containing a fluid thrombin component including calcium chloride and a somewhat more viscous fibrinogen component including factor XIII, fibronectin, aprotinin and plasminogen. The two components are delivered deep frozen in two separate syringes, or as two lyophilized powders with corresponding aprotinin and calcium solutions as solvents. Using this method, the fibrin glue consolidates when the two components are combined due to fibrin monomer aggregation. The setting rate is dependent on the thrombin concentration and varies from a few seconds (high thrombin concentration) to a couple of minutes (low thrombin concentration).
The major disadvantage of these preparations is that the water-like fluidity of the components renders them difficult to handle and administer.
Although various efforts have been made to facilitate the administration of these compositions, for example, by the development of double-syringe applicators as described in U.S. Patent No. 4,359,049, or a spray system as described in U.S.
Patent No. 4,427,651, the basic problem of low viscosity remains.
Wadstrom, U.S. Patent No. 5,631,011 describes a method of increasing the viscosity of fibrin glue compositions by adding a biocompatible polymer capable of fom-ling a viscous aqueous solution. The components of this system are provided in deep freeze solutions or as lyophilized powders which are diluted prior to use with aqueous solutions. The primary route of administration taught by Wadstrom is by a two component preparation. Thus, while Wadstrom emphasizes the advantages of increasing the viscosity of the solution over prior "water-like" fibrin glues, the components of this system still require additional preparation at the time of use. Wadstrom further teaches that compositions having a high viscosity are to be avoided because fibrin polymerization and adhesion to the tissues would be inhibited.
One currently used alternative to fibrin glue, is a biodegradable collagen patch ("TAF" patch). For example, Zimmerman and Schiele, U.S. Patent 4,453,939, describe collagen carriers in the form of a foam, web or film that is coated with a mixture of blood-clotting components including fibrinogen and thrombin. To prevent reaction of the blood-clotting components prior to use, they are provided as a suspension in an organic solvent which is applied to the collagen by brushing, spraying or dipping. However, difficulties in achieving optimum timing for the fixing procedure have been reported using this method resulting in inconsistent attachment and stability of the active components onto the collagen carrier. Moreover, penetration of the active components beyond the surface of the collagen carrier is not possible using this method, thereby limiting the concentration of blood-clotting components available to the surface of the device. Another problem with the TAF patches is that the collagen fleece/foam used does not provide sufficient mechanical support once wet, preventing application of manual pressure to assist in stopping blood flow or repositioning of the patch once it has been applied to the wound. Further, surgeons have 1o reported that the inflexibility of the TAF patch prevents them from easily conforming to the contours of the site to which they are applied. Still another problem with TAF patches is that they require refrigeration prohibiting use outside a clinic or hospital setting.
WO 96/17633 describes tissue sealants including a fibrin bandage. In the method used for generating the bandage, the active components are lyophilized in separate layers which are supported by an occlusive backing. Therefore, the active components are not homogeneously mixed throughout the bandage.
Accordingly, there is a need for hemostatic compositions that are sturdy enough to withstand manual pressure and which are less complicated to use, especially in emergency situations such as life-threatening traumas wherein stemming blood flow as fast as possible can be critical.
SUMMARY OF THE INVENTION
In one aspect, the invention features a hemostatic, biocompatible composition in the form of a fibrous solid that is bioabsorbable. The composition contains a bioabsorbable polymer and one or more hemostatic compounds. Preferably, the hemostatic compound is thrombin, more preferably, the composition contains thrombin and a calcium salt, and most preferably also includes fibrinogen. A "hemostatic compound or composition," as used herein, is a substance or composition that, upon application to a wound reduces or stops blood loss by promoting blood clot formation. By the term "fibrous" as used herein is meant a composition comprising natural or synthetic fibers. By "fiber"
is meant a unit of matter, either natural or manufactured, that forms the basic element of fabrics and other textile structures. A fiber is characterized by having a length at least 100 times its diameter or width.
The bioabsorbable polymers contained within the hemostatic composition of the invention include polyanionic polysaccharides, alginic acid, chitin, chitosan, fibrin, polyglycolide, polylactide, polycaprolactone, dextran and copolymers thereof. The term "polymer," as used herein refers to a molecule made by the repetitive bonding of at least two, and preferably more than two, repeating monomeric smaller units (e.g., monosaccharide, amino acid, nucleotide, alkene, or organic acid units). Accordingly, the term copolymer refers to a polymer formed by combination of two or more copolymerized monomeric or polymeric species. The term "bioabsorbable," as used herein, refers to the ability of a tissue-compatible material to degrade in the body after implantation into nontoxic products which are eliminated from the body or metabolized (Barrows, "Synthetic Bioabsorbable Polymers," p. 243, In: High Performance from Biomaterials -A comprehensive Guide to Medical and Pharmaceutical Applications, Michael Szycher, ed., Technomic Publishing, 2o Lancaster, PA, 1991 ). Generally, the concentration of bioabsorbable polymer used in the hemostatic compositions of the invention is in the range of 0. 1 to 50 mg/cm2; preferably the concentration of bioabsorbable polymer is in the range of 0. 1 to 30 mg/cm2 ; and more preferably the concentration of the bioabsorbable polymer ranges from 0. 1 to 10 mg/cm2 .
In one preferred embodiment, the bioabsorbable polymer is a polyanionic polysaccharide. A "polyanionic polysaccharide" (PAS) as the term is used herein, is a polyaccharide, including non-modified as well as chemical derivatives thereof, that contains more than one negatively charged group (e.g., carboxyl groups at pH values above about 4.0) and includes salts thereof, such as sodium or potassium salts, and alkaline earth metal salts such a calcium or magnesium salts. Preferred polyanionic polysaccharides contained in the hemostatic composition of the invention include, but are not limited to, hyaluronic acid (HA), carboxymethylcellulose (CMC carboxymethylarnylose (CMA), chondroitin-6-sulfate, dermatin sulfate, dermatin-6-sulfate and combinations thereof.
Most preferably, the polyanionic polysaccharide is HA, CMC or CMA
which is in the form of a water-insoluble derivative. A "polyanionic polysaccharide derivative," as the term is used herein, is one or more polyanionic polysaccharides (PAS) that are chemically modified from the native form. Such modifications can include the addition of functional groups (e.g., substituted amide groups, ester linkages, and amino groups); reactions that increase the water insolubility of the PAS by covalently cross-linking the PAS
y 5 molecules; and reactions that increase the water-insolubility of the PAS
by noncovalent interactions. Additionally, the hemostatic composition can include two or more polyanionic polysaccharides or their water-insoluble derivatives, e.g.. HA and CMC or HA and CMA.
In another preferred embodiment, the polyanionic polysaccharide is combined with one or more hydrophobic bioabsorbable polymers or copolymers. As used herein, "hydrophobic," refers to compounds or compositions which lack an affinity for water. Preferably, the hydrophobic bioabsorbable polymer is chosen from the group consisting of polyglycolide, polylactide (D, L or DL), polydioxanones, polyestercarbonates, polyhydroxyalkonates, polycaprolactone (polylactones), and copolymers thereof.
More preferably, polyglycolide, polylactide, or copolymers of polyglycolide-caprolactone, polyglycolide-polylactide, or polylactide-polycaprolactone are used in the composition of the invention. The concentration of hydrophobic bioabsorbable polymer used in combination with 3o the polyanionic polysaccharide is preferably in the range of 0. 1 to 50 mg/cm2 .
The thrombin used in preferred embodiments of this aspect of the invention can be of animal or human origin. For example, thrombin obtained from one mammalian species {e.g., bovine, pig, sheep) can be incorporated into compositions of the invention used to treat another mammalian species, for example, humans. More preferably, the thrombin used in the composition is from the same species for which the composition is intended to be used. The term "thrombin" as used herein includes natural thrombin molecules derived from animal or human plasma, and synthetic forms such as those produced by 1o recombinant DNA technology including functionally active analogs that effectively maintain clotting activity in an animal or human. Thrombin is present in the hemostatic composition of the invention in a concentration of 1 to 100 U/CMZ , and preferably between 10 to 50 U/cmz. A unit of thrombin, as used herein, is defined as the amount of thrombin required to clot a standardized 1 ml fibrinogen (~ 250 mg/ml) solution in 15 seconds.
The concentration of calcium chloride used in preferred embodiments of this aspect of the invention is sufficient to allow for activation of the thrombin.
Typically, the concentration of calcium will vary between 0.01 to 10 mg/cm2 .
The particular concentration of calcium used will depend on the specific purpose of the composition and can be readily determined by the skilled artisan using the teachings herein.
In other preferred embodiments of this aspect of the invention, the hemostatic composition includes fibrinogen. The fibrinogen can be of animal or human origin, and is preferably from the same species for which the composition is intended to be used. By the term "fibrinogen," as used herein, is meant to include natural fibrinogen molecules derived from animal or human plasma, and synthetic forms such as those produced by recombinant DNA
technology including functionally active analogs that effectively maintain clotting activity in an animal or human. The fibrinogen used in the compositions of the invention can be highly purified, can contain small amounts of clotting Factor XIII, or can be enriched with clotting Factor XllI. Typically, the amount of clottable fibrinogen is present in the hemostatic composition of the invention in a concentration between about 0.05 and 20 mg/cmz , preferably between about 1 and 20 mg/cm2, and more preferably between about 5 and 1 S mg/cm2.
Additional blood-clotting constituents and fibrinolysis inhibitors can also be included in the compositions of the invention. Examples include, but are not limited to, Factor XIII, fibronectin, plasminogen, aprotinin, alpha-2-antiplasmin, alpha-2-macroglobulin, alpha-1-antitrypsin, epsilon-aminocaproic acid or tranexamic acid, or a plasmin activator inhibitor, e.g., PAI-1 or PAI-2.
In a further embodiment, the hemostatic composition of the invention can also contain an amount of the agent protamine sulfate effective to neutralize heparin present in the local environment of the area of application. Protamine sulfate neutralizes heparin or vitamin K antagonists that are present in the blood of certain patients who, for example, are undergoing parental therapy with heparin.
The compositions of the invention can further include a drug. The particular drug used is a matter of choice depending on the intended use of the composition. Preferred drugs include, but are not limited to, growth factors, growth-factor inhibitors, antibodies, non-steroidal anti-inflammatory drugs, antibiotics, and cytostatics.
The hemostatic composition of the invention typically has a mass/area (M/A) between about 15 to 100 mg/cm2 preferably a M/A between about 20 to 60 mg/cm2, more preferably a M/A between about 30 to 40 mg/cm2 . The size and shape of the composition will vary depending on the particular use. For example, in certain preferred embodiments the hemostatic composition can be supplied in a variety of standard rectangular or circular sizes, such as those commonly used in first-aid kits, triage, and surgery, and which can be further cut and sized to the particular area being treated. Alternatively, the hemostatic composition can be provided in a variety of other shapes which are useful for packing into body cavities, including, but not limited to spherical, conical, cuboidal or cylindrical shapes.
In further related embodiments, the hemostatic composition is contained within a sealed, waterproof, sterile package which facilitates removal of the compositions without contamination. Preferred waterproof packaging materials include, for example, aluminum foil, plastic, or other conventional material that is easily sterilized. Sterilization can be accomplished, for example, by subjecting the packaged composition to radiation, for example, gamma radiation or E-beam, or by treatment with ethylene oxide.
In another aspect, the invention features a method of making a solid, fibrous, bioabsorbable hemostatic composition which includes the steps of combining a bioabsorbable polymer and one or more hemostatic compounds in the presence of a non-aqueous solvent and subjecting the combination to a paper-making process to produce a solid, bioabsorbable hemostatic composition.
In one preferred embodiment of this aspect of the invention, the method involves precipitating the components of the hemostatic composition either separately or together into a non-aqueous solvent, admixing the precipitated components under conditions sufficient to form a fibrous pulp, and then collecting, pressing and drying the fibrous pulp to produce a solid, bioabsorbable hemostatic composition.
Examples of organic solvents which can be used in the method of the invention include straight-chain or branched C~-CS alcohols, especially n-propanol, isopropanol, n-butanol, isobutanol and ethanol; ketones, for example, acetone or methyl ethyl ketone; aliphatic or cycloaliphatic ethers, for example dimethyl ether or diethyl ether, tetrahydrofuran or dioxane; esters, for example, ethyl acetate; nitrites, for example, acetonitrile; and aliphatic halogenated hydrocarbons, for example, carbon tetrachloride, methylene chloride and chloroform.
In preferred embodiments of the method of the invention, admixing of the components occurs under high shear conditions to evenly disperse the materials in the organic solvent. One preferred method of collecting the fibrous pulp uses forii-iing fabric. The term "forming fabric" refers to a material used during paper formation that permits the drainage of the pulp -solution while retaining the fibers, provides mechanical support, imparts surface characteristics during pressing and drying, and is released from the dried paper product. The forming fabric can be a variety of materials including, but not limited to a Teflon or stainless steel mesh screen, and preferably is a polyester woven fabric.
In other preferred embodiments, the fibrous pulp is collected onto the forming fabric under vacuum conditions; the wet pulp collected is subjected to heat compression; and air dried at room temperature, or preferably under heated conditions, for example, between 80 to 140°F, and most preferably is dried at 100 to 135°F.
In related embodiments of this aspect of the invention, the methods of the invention can produce a hemostatic composition in which the hemostatic compounds are evenly dispersed throughout the composition, or supplied as a gradient, for example, by collecting fibrous pulps containing a range of desired concentrations of the hemostatic compound or compounds one after the other prior to the steps of pressing and drying. Alternatively, the methods of the invention can be used to produce a multilayered hemostatic composition. For example, bilayer compositions containing one layer of bioabsorbable polymer and another layer containing one or more hemostatic compositions can be produced by collecting a fibrous pulp of the bioabsorbable polymer after collection of the fibrous pulp of the hemostatic compound and then combining the pulps in layers prior to the pressing and drying steps. Trilayer compositions can also be produced, for example, having hemostatic compounds on both sides of a core containing a bioabsorbable polymer.
In still another aspect, the invention includes a method of inhibiting or stopping blood loss from a wound by applying to the wound a solid hemostatic composition containing a bioabsorbable polymer and one or more hemostatic compounds. Preferably, the composition is maintained in contact with the wound preferably with light pressure (e.g., manual) for a period of time sufficient for blood clotting to occur at the interface between the composition and the wound and for bleeding to be substantially arrested. Generally, the hemostatic composition is maintained in contact with the wound surface for a period of about 20 seconds to 10 minutes, preferably about 20 seconds to 5 minutes, and more preferably about 20 seconds to 2 minutes. The composition can be applied directly to the wound alone, or can be held in place by means of a dry sterile material such as gauze. Depending on the location of the wound, a bandage, including an elasticized bandage can be wrapped around the patch so as to provide pressure to the wound site.
Preferred embodiments of this aspect of the invention include use of the hemostatic composition for topical treatment to inhibit or stop bleeding of wounds due to trauma or surgery. In additional preferred embodiments, the method of the invention uses the hemostatic composition to inhibit or stop bleeding of a parenchyma) organ, such as the liver, kidney, spleen, pancreas or lungs. Alternatively, the methods include inhibiting or stopping bleeding or fluid loss during surgery including, but not limited to, abdominal, vascular, urological, gynecological, thyroidal, neurosurgery, tissue transplant, and dental surgery.
In further embodiments, the hemostatic composition can also be provided for use to anastomose or fuse ends of a blood vessel or other body lumen that has been severed, for example, during surgery. In this embodiment, the hemostatic composition is provided in a form that is easily fit to the ends of a vascular prosthesis. In cases where the vascular prosthesis is synthetic, such as a Dacron graft, the hemostatic composition can be provided in a form (e.g., cylindrical) sized to easily fit over the ends of the graft. Accordingly, also provided are kits that contain a vascular prosthesis and a hemostatic composition of the invention designed for fitting with the ends of the prosthesis.
Alternatively, in cases wherein pre-sizing is not possible (e.g., natural grafts) the hemostatic composition can be provided in a form that is easily wrapped around the prosthesis just prior to use.
Additionally, a hemostatic composition according to the invention which is intended for topical applications can be applied with an adhesive tape, or adhered to an adhesive backing in a Band-Aid form. The type of adhesive used can be any type of medically acceptable adhesive. Preferably the adhesive used is porous to areas which contact the skin to allow diffusion of oxygen.
A kit is also provided which according to the invention comprises any of the above described embodiments of the hemostatic composition. For example, the kit can contain multiple hemostatic compositions, preferably wherein each is provided in a separate, waterproof, sterile package. Additionally, a kit designed for emergency or military use can also contain disposable pre-sterilized instruments, such as scissors, scalpel, clamp, tourniquet, elastic or inelastic bandages, or the like.
An important advantage of the hemostatic composition of the present invention is that the mechanical integrity of the composition is maintained after contact with body fluids allowing application of manual pressure to promote stoppage of blood flow, and repositioning of the composition when necessary.
In further contrast to prior art compositions, the active components necessary to promote hemostasis are dispersed throughout the composition avoiding the problem of separation of different layers thereby allowing the compositions to be cut and sized to the particular wound being treated.
Accordingly, the hemostatic compositions of the invention provide a means for rapidly reducing bleeding in trauma victims and surgical patients without the time delay associated with solubilization and mixing of components.
The hemostatic compositions can be readily used by untrained individuals as well as medical personnel. These characteristics allow use of these compositions in field applications, such as in trauma packs for soldiers, rescue workers, ambulance/paramedic teams, firemen, and by emergency room personnel, and in first aid kits for the general public use. Thus, utilization of the hemostatic compositions of the invention will result in a reduction of fatalities due to trauma and also decrease the demand upon the available blood supply during instances of severe natural or man-made disasters.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although any method and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.
All publications mentioned hereunder are incorporated by reference. Unless mentioned otherwise, the techniques employed or contemplated herein are standard methodologies well known to one skilled in the art. The materials, methods and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following description and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
A process is described for producing a solid, fibrous hemostatic composition containing proteins including, but not limited to, thrombin, or a combination of thrombin and fibrinogen, and salts such as, but not limited to, calcium chloride in combination with one or more bioabsorbable polymers.
Materials Fibrinogen and thrombin for use in the invention can be readily obtained from a number of commercial sources (e.g., Sigma, CalBiochem, American Diagnostics, Inc.). Alternatively, these proteins can be derived from the plasma of any desirable species, or produced using recombinant DNA methods (e.g., Prunkard et al., Nature Biotechnology 14:867-871, 1996; Velander, WO
95/22249; Karges and Metzner, Seminars in Thrombosis and Hemostasis, 22:427-436, 1996; Lewis et al., Biochemistry 36:995-1002, 1997; Lai et al, J.
Biol. Chem. 269:24596-24601, 1994; Fischer et al., Thrombosis Res.
81:157-162, 1996; Lord et al., Blood Coagulation and Fibrinolysis 4:55-59, 1993; DiBella et al., J. Biol. Chem. 270:163-169, 1995; Roy et al., J. Biol.
Chem. 270:163-169, 1995).
Preferably, the fibrinogen and thrombin used are of bovine or human origin. When the composition is to be used in humans, the fibrinogen and 1 o thrombin are most preferably of human origin. Additionally, when the fibrinogen is derived from human plasma it is preferably subjected to heat inactivation methods, or even more preferably to solvent detergent methods, well known to those skilled in the art and intended to inactivate any viruses that might be present (e.g., see Radosevich et al., "Fibrin Sealant: Scientific rationale, production methods, properties, and current clinical use," Vox Sang 2:133-I43, 1997).
Bioabsorbable biopolymers for use in the composition of the invention can be obtained from a variety of standard commercial sources (e.g., Genzyme Corp., Aqualon, Birmingham Polymers, Deknatel). Water-insoluble polyanionic 2o polysaccharide compositions can be prepared by a number of methods for use in this invention. For example, derivatives can be generated via the formation of covalent intra- and inter-chain crosslinks as previously described (e.g., see Sparer et al., 1983, Chapter 6, pages 107-119, in Roseman et al., Controlled Release Delivery Systems, Marcel Dekker, Inc., New York; DeBelder et al., PCT
Publication No. WO 86/00912; Balazs et al., 1986 U.S. Patent No. 4,582,865;
Malson et al., 1986, PCT Publication No. WO/86/00079; and Prestwich et al., EP Publication No. 0416250A2, 1991 ). Water insoluble compositions which do not contain covalent cross-links between polyanionic polysaccharide molecules and compositions containing polyanionic polysaccharides can be formed using 3o the methods described in Hamilton et al., U.S. Patent No. 4,937,270, Burns et al., U.S. Patent No. 5,017,229, USSN 07/03,254, 07/833,973, and compositions containing combinations of polyanionic polysaccharides and hydrophobic , polymers or copolymers are described in USSN 08/318,987 (all of the above hereby incorporated by reference).
Preparation of Hemostatic Compositions Generally, compositions according to the invention are formed by precipitating thrombin (with or without biopolymers and calcium chloride) by injecting the aqueous solution using a syringe into a rapidly stirring non-aqueous solvent coagulation bath containing ethanol, isopropanol, butanol or a combination thereof In compositions containing a combination of thrombin and fibrinogen, a second aqueous solution containing fibrinogen (with or without biopolymers and calcium chloride) is also precipitated into fibers using a non-aqueous solvent in the same manner. The fibrous precipitates) is then washed with the non-aqueous solvent to purify and dewater.
The desired fibrous precipitate or combination of precipitates (e.g., thrombin and biopolymer; thrombin, fibrinogen and biopolymer;
thrombin/biopolymer; thrombin/biopolymer and fibrinogen; thrombin and fibrinogen/biopolymer; and thrombin/biopolymer and fibrinogen/biopolymer) are high shear mixed to form a fibrous pulp solution in the non-aqueous solvent.
The pulp solution is then collected, pressed and dried using existing paper-making technology, (see, e.g., Handbook for Puip & Paper Technologists, Smook, G. 2nd edition, Angus Wilde Publications Inc., 1994), and as described in the following examples. The resulting paper-like structure consists of dry thrombin, or thrombin and fibrinogen in combination with one or more biopolymers, and can additionally contain calcium and/or other agents as described herein. Since all of the precipitation, mixing and paper-making steps are in a non-aqueous solvent and not in water, the thrombin does not activate fibrinogen during processing. The resulting, solid, fibrous, dried composition can contain the hemostatic components distributed throughout the paper-like material. Alternatively, a paper-like composition can be generated which has a concentration gradient of the desirable hemostatic components, for example, by collecting fibrous pulps containing varying concentrations of the hemostatic components prior to compression and drying.
Upon activation by blood, body fluids, saline or water, the composition acts as a hemostatic patch.
In another variation of the invention, the proteins and salts can be added to a non-aqueous slurry containing the biopolymer. For example, commercially available lyophilized fibrinogen, thrombin and calcium chloride powders can be added to the bioabsorbable polymer (e.g., HA/CMC and/or PGA) fibers in ethanol. The mixture can then be collected, pressed and dried according to existing paper-making technology to form a paper-like structure with hemostatic components homogeneously dispersed throughout the thickness. This paper-like structure has superior mechanical properties compared to prior art materials.
Moreover, since all of the precipitation, mixing and paper-making steps are in a non-solvent and not in water, the thrombin does not activate fibrinogen during processing.
Bilayer compositions can also be made with one side containing the hemostatic agents and the other side being non-hemostatic and non-adhesiogenic. For example, the hemostatic side can contain fibrinogen, thrombin and calcium chloride and the non-adhesiogenic side can contain HA/CMC. Alternatively, the hemostatic side can further contain one or more bioabsorbable polymers as described herein, whereas the non-adhesiogenic side would contain a bioabsorbable polymer without the hemostatic components.
HA/CMC has been demonstrated to reduce post-surgical adhesion formation (e.g., Becker et al., British J. Surg. 82:Suppl. 1, 1995). Therefore, the side containing the hemostatic components will provide hemostasis, while the side containing the bioabsorbable polymer, e.g., HA/CMC, would prevent adhesions.
Each side of the bilayer composition can be marked for appropriate placement, e.g., by the addition of a biocompatible dye such as riboflavin to one of the bilayers.
The paper-like compositions generated according to the herein described methods can also be used alone or in combination with tri-layer laminated technology such as that described in USSN 08/318,987. Tri-layer composites can be made by laminating the hemostatic paper-like membrane to a hydrophobic bioabsorbable polymer core, such as polyglycolide, polylactide, polycaprolactone, or copolymers thereof. The tri-layer composition can have hemostatic components laminated on both sides of the core which would provide hemostatic activity to both surfaces while increasing the strength and in vivo residence time of the device with the addition of the core polymer.
Alternatively, the hemostatic components can be laminated to one side of the core while laminating a nonadhesiogenic material such as HA/CMC to the other side thereby producing a device with one hemostatic surface and one non-adhesiogenic surface.
Additional Components In addition to the hemostatic agents, the compositions of the invention can further contain components which promote wound healing and prevent 2o infection such as, but not limited to polypeptide growth factors, non-steroidal anti-inflammatory agents, antibiotics, and cytostatics. The concentrations) of the additional components will vary depending on the desired objective, and should be sufficient to accomplish the particular purpose for which they are used. The amount of each component can be readily determined by those skilled in the art, for example, by empirically testing various concentrations and selecting that which is effective for the intended purpose and the site of application.
Examples of polypeptide growth factors which are known to play a role in healing include, but are not limited to: platelet-derived growth factors (PDGFs); insulin-binding growth factor- I (IGF-1); insulin-binding growth factor-2 {IGF-2); epidermal growth factor (EGF); transforming growth factor-a (TGF-a), transforming growth factor-~i (TGF-(3); platelet factor 4 (PF-4);
fibroblast growth factor (FGF); and heparin binding growth factors one and two (HBGF-1 and HBGF-2). The growth factor, or mixture thereof, can be prepared by any method known to those skilled in the art, or can be purchased from a variety of commercial sources. The selection of the particular growth factors) used will depend on the desired application and can be readily determined by those skilled in the art.
The invention is described in more detail in the following examples.
These examples are given by way of illustration and are not intended to limit the invention except for as set forth in the claims.
Example 1 Thirty-seven milliliters of an aqueous fibrinogen solution (40 mg/ml) was injected using a syringe into approximately 700 ml of 95% ethanol while stirring. The fibrous precipitate that resulted was stored in ethanol overnight. A
portion of the ethanol was decanted and all of the fibrinogen precipitate ( 1.48 g) in 540 ml of 95% ethanol was high shear mixed at 4000 rpm for 30 seconds with a Ultra-Turrax T50 homogenizer. The resulting pulp solution was stored in 95% ethanol.
Forty milliliters of fibrinogen pulp solution was diluted with 200 ml of 95% ethanol. To this furnish solution was added 20 mg of thrombin powder and 80 mg calcium chloride. The sample was collected on forming fabric using a Millipore filter housing (dia. = 7.4 cm). The wet sample was pressed at 2 metric ton for I S seconds and air dried to produce an extremely thin membrane.
Example 2 One-hundred-twenty milliliters of fibrinogen pulp solution prepared as described in Example 1 was diluted with 200 ml of 95% ethanol. To this furnish solution was added 40 mg of thrombin powder, 160 mg calcium chloride and 20 ml of modified hyaluronic acid/carboxymethyl cellulose pulp solution obtained by precipitating carbodiin-iide modified HA/CMC (modified as described in U.S. Patent No. 5,017,229) into ethanol, and high shearing the resulting fibrous precipitate into a pulp-like ethanol slurry. The mixture was collected as described for Example 1 on standard forming fabric using a Millipore filter under vacuum assist, pressed at 2 metric ton for 15 seconds, and air dried. A
paper-like membrane resulted.
Example 3 Three milliliters of an aqueous fibrinogen solution (40 mg/ml) was injected with a syringe into 100 ml of 100% ethanol while stirring. The fibrous precipitate that resulted was collected on a polyester filter. A small sample of the dry material (~ 1 cm2 ) was placed in 30 ml of deionized water with 5 mg of thrombin and 100 mg of calcium chloride. The material formed a fibrin clot immediately.
Example 4 0.22 g of lyophilized fibrinogen powder was added to 65 ml of HA/CMC
pulp (0.22 g HA/CMC in 100% ethanol). Also added to this mixture was 28 mg of calcium chloride powder and 3.3 mg of thrombin powder. The mixture was diluted with and additional 340 ml of 100% ethanol and high shear blended with an Ultra-Turrax T50 with a G45F dispersing head for 45 seconds at 5,000 rpm.
The mixture was then collected on forming fabric using a Millipore filter housing (dia.= 7.4 cm). The wet sample pressed twice at 10 psi with a roll press and air dried. A paper-like membrane resulted similar to that produced in Example 8 discussed below.
Example 5 Sixty-five milliliters of HA/CMC pulp (0.22 g HA/CMC in 100%
ethanol) was diluted with 340 ml of 100% ethanol and collected on forming fabric using a Millipore filter housing (dia.= 7.4 cm). Then a solution containing 65 ml of HA/CMC pulp, 0.22 g of lyophilized fibrinogen powder, 29 mg of 3o calcium chloride and 3.8 mg of thrombin was diluted with 340 ml of 100%
ethanol and collected on top of the HA/CMC wet cake. The wet sample was pressed two times at 10 psi with a roll press and dried at 100°F with a drum dryer. A thick bi-layer paper-like membrane resulted that was enriched with active fibrinogen/thrombin dispersed throughout the layer on one side and with a nonadhesiogenic HA/CMC layer on the other side.
Example 6 0.67g of chopped PGA fibers (Deknatel, Inc.) were added to 400 ml of 100% ethanol. 0.64 g of fibrinogen, 22 mg of thrombin and 100 mg of calcium chloride were added to the ethanol slurry and collected on Teflon forming fabric using a Millipore filter housing (dia = 7.4). The wet sample was pressed once at 10 psi with a roll press and dried at 120-125°F with a drum dryer. A
thick paper-like membrane resulted with a M/A of 36.6 mg/cm2 . The hemostatic paper was very absorbent and formed a fibrin clot when immersed in water.
Example 7 2.0 g of PGA fibers (Deknatel, Inc.) were chopped into ~5-10 mm segments and added to 600 ml of ethanol. In a separate vessel, 2.6 g of lyophilized bovine fibrinogen (77% protein, 90% clottable), 67 mg of bovine thrombin, and 0.3 g of calcium chloride powder were added to 900 ml of 100%
ethanol and high shear blended with an Ultra-Turrax T50 with a G45G
dispersing head for 30 seconds at 5000 rpm. The materials were combined and collected on Teflon forming fabric in a 4.25 x 4.25 inch headbox. The material drained in approximately 10 seconds without vacuum assistance. The fibrous cake was pressed once at 10 psi with a roll press and dried at 125-135°F for minutes. An 11.3 cm x 11.4 cm soft paper resulted with a M/A of 31.8 mg/cm2.
Example 8 4I0 ml of HA/CMC pulp ( 1.8 g of HA/CMC in 100% ethanol) was 3o diluted with 590 of 100% ethanol, and 2.6 g of lyophilized bovine fibrinogen (77% protein, 90% clottable), 67 mg of bovine thrombin and 0.3 g of calcium chloride were added and high shear blended with an Ultra-Turrax T50 with a G45G dispersing head for 15 seconds at 5000 rpm. The mixture was then collected on Teflon forming fabric in a 4.25 x 4.25 inch headbox. The material -was drained for 60 seconds without vacuum assistance and for 135 seconds with vacuum assistance. The resulting fibrous cake was pressed once at 10 psi with a roll press and dried at 125-135°F for ~ 30 minutes. An I 1.2 x 12.8 cm paper resulted with a M/A of 31 mg/cm2 .
Example 9 Samples of materials produced according to Examples 4 and 8 were tested in a platelet aggregation assay as described by Wagner et al, J. Surg.
Res.
66:100-108 (1996) using Coulter Counter Model J.T. (Coutler, Corp.). Both of these materials reduced platelet count by 45% compared to 9.5%,13% and 23%
with Gelfoam~ (absorbable gelatin sponge, Upjohn) Avitene~ (microfibrillar collagen hemostat, Davol), and ActifoamTM (absorbable collagen hemostatic sponge, MedChem Products), respectively.
Example 10 A sample prepared according to the method described in Example 8 was evaluated for sealing/hemostatic properties in the rabbit vena cava model. The vena cava of 26 anesthetized, heparinized ( 150 ILT/kg), 4-5 kg New Zealand White rabbits was each punctured using a i6 gauge needle. A 1 cm2 piece of the sample from Example 8, Avitene~ , TachoComb~ or surgical gauze was applied for 20 seconds directly over the puncture with light finger pressure.
The pressure was removed after 20 seconds and the breakthrough bleeding was observed. In the case of no further bleeding, observation was continued for 10 min. to ensure hemostasis. In the case of breakthrough bleeding, another 1 cm2 piece was applied over the first piece for another 20 seconds with light finger pressure. In the case of continued bleeding, the applications continued until a total of 10 minutes had elapsed. The results of this study are set forth in Table I.
-Table 1. Hemostasis/Sealant Model Group Average No. ApplicationsAverage Time to Hemostasis Control Gauze 15.4 2.1 * 8/9 > 600 seconds (n=9) t Avitene~ (n=6) 1.5 0.2 49.0 16.4 seconds TachoComb~ (n=5)6.0 t 3.7* >361 seconds ~
HA/CMC/Fib/Thromb/C1.0 t 0.2 25.8 seconds a Paper (n=6) fi~taustically sigmricant from HA/CMC/Fig/Thromb/Ca paper (Anova p=0.00 i , Tukey-Kramer) fiStatistically significant from HA/CMC/Fib/Thromb/Ca paper (Anova p=0.0005, Tukey-Kramer) The results of this study demonstrate the statistically superior hemostatic activity of the HA/CMC/Fibrinogen/Thrombin paper produced according to the methods of the invention as compared to Avitene~ and TachoComb~J in heparinized animals. The time to hemostasis was reduced by 48% compared to Avitene~ and 14 times compared to TachoComb~. The results further demonstrate that the composition of the invention also required fewer applications than either Avitene~ or TachoComb~.
Example 11 The preparation described in Example 8 was evaluated for resealing properties in the rabbit vena cava puncture model described in Example 10. The test article was initially placed over the wound, and hemostasis was achieved within approximately 20 seconds. The wound was monitored for a further 10 minutes to ensure that complete hemostasis had occurred. The test composition was then removed from the vena cava in one piece using forceps, and bleeding reinitiated. The previously used test composition was then replaced onto the wound and hemostasis was again achieved within approximately 20 seconds.
TachoComb~ (collagen sponge coated with thin layers of fibrinogen and thrombin, Nycomed, Austria) and Avitene~ were also tested for repositioning and resealing qualities in this model. TachoComb~ could not be removed in one piece, and the collagen layer separated from the fibrinogen and thrombin layer.
1o Avitene~ could not be removed in one piece or repositioned on the wound.
The results of this study demonstrate that compositions of the invention have improved physico-mechanical properties over both TachoComb~ and Avitene~. Therefore, the compositions of the invention can be removed and repositioned during use without a decrease in hemostatic or sealing capabilities, a significant advantage over the prior art hemostatic compositions.
Example 12 The preparation described in Example 8 was also tested for the ability to function in the presence of excess amounts of blood in the rabbit vena cava puncture model. The vena cava was punctured with a 16 gauge needle, and blood was allowed to fill the abdominal cavity. A 1 cm2 piece of the hemostatic composition of Example 8 was blindly applied to the wound for 20 seconds with finger pressure, and the excess blood was removed. Hemostasis was achieved in one application within 20 seconds. In contrast, Avitene~ fell apart when inserted into the bloodfilled abdominal cavity.
Example 13 The hemostatic composition prepared in Example 8 was sterilized by gamma irradiation (2.SMRad) and evaluated in the rabbit vena cava puncture model. Hemostasis was achieved in all three animals tested with one application for 20 seconds.
3o Example 14 1.8 g of PGA fibers (Deknatel, Inc.) were chopped into 5-10 min segments and added to 400 ml of 100% ethanol. In a separate vessel, 2.5 g of lyophilized bovine fibrinogen (77% protein, 90% clottable), 67 mg of bovine thrombin, 0.3 g of calcium chloride and 140 ml of HA/CMC pulp (0.6 g of HA/CMC in 100% ethanol) were added to 1000 ml of 100% ethanol and high shear blended with an Ultra-Turrax TSO with a G4SG dispersing head for 1 S
seconds at 5000 rpm. The materials were combined, stiffed, and collected on Teflon forming fabric ( 1 SO gm) in a 4.24 x 4.25 inch headbox. The material was 1 o drained for 60 seconds without vacuum assistance. The resulting fibrous cake was pressed once at 10 psi with a roll press and dried at 12S-13S°F for ~ 1S
minutes. An 11.4 x 11.4 cm soft paper resulted with a M/A of 3S mg/cm2.
Example 1S
67 mg of bovine thrombin and 0.3 g of calcium chloride were added to 4S0 ml of 100% ethanol and high shear blended with an Ultra-Turrax T50 with a G4SG dispersing head for 15 seconds at 4000 rpm. 2.S g of lyophilized bovine fibrinogen (77% protein, 90% clottable) was added to the mixture and high shear blended with an Ultra-Turrax TSO with a G45G dispersing head for 1 S
seconds at 4000 rpm. 1.8 g of PGA fibers (Deknatel) were chopped into ~ 10 2o mm segments, added to 3S0 ml of 100% ethanol, and then added to the fibrinogen/thrombin/calcium chloride mixture.
140 ml of HA/CMC pulp (0.6 g of HA/CMC in 100% ethanol) was diluted with 860 ml of 100% ethanol and collected on Teflon forming fabric ( 1 SO gm) in a 4.24 x 4.25 inch headbox. The material was drained until the remaining ethanol level was z I inch above the settled HA/CMC material (~ 150 seconds).
The PGA/fibrinogen/thrombin/calcium chloride mixture was then slowly added over the HA/CMC material. The material was allowed to drain for 60 seconds with vacuum assistance. Two different layers could be differentiated in 3o the resulting fibrous cake. The cake was pressed once at 10 psi with a roll press and dried at 12S-132°F for ~ 20 minutes, An 11.2 cm x 11.2 cm bilayer paper resulted with a M/A of 31 mg/cm2 , and the HA/CMC layer for adhesion prevention and the PGA/fibrinogen/thrombin/calcium chloride layer for hemostasis could be distinguished visually.
Example 16 Samples of materials produced according to Example 6 were tested in a platelet aggregation assay as described by Wagner et al., supra, using Multisizer Model 0217 (Coulter Corp.}. These materials reduced the volume in the platelet 1o region (2-4.5pm) by 27% compared to 0% with TachoComb~ (Nycomed), Gelfoam ~ (Upjohn) and Novacol~ (Datascope), by 11 % with Avitene~
(Davol), and by 19% with ActifoarnTM (MedChem).
Example 17 1. 8 g of PGA fibers (Deknatel) were chopped into -5-10 mm segments and added to 300 ml of 100% ethanol. In a separate vessel, 121 mg (3630 U) of bovine thrombin and 0.3 g of calcium chloride were added to 700 ml of 100%
ethanol and high shear blended with an UltraTurrax T50 with a G45G dispersing head for 15 seconds at 5000 rpm. Seventy milliliters of HA/CMC pulp (0.3 g of HA/CMC in 100% ethanol) was added during the last 5 seconds of mixing. The 2o materials were combined, stirred, and collected on Teflon forming fabric ( pm) in a 4.25 x 4.25 inch headbox. The material drained in 20 seconds without vacuum assistance. The fibrous cake was pressed once at 10 psi with a roll press and dried at 125-145°F for ~10 min. An 11.2 x 11.2 cm soft paper resulted with a M/A of 17.9 mg/cm2.
Example 18 Samples produced according to Examples 7, 8 and 14 were evaluated for dry and wet mechanical properties and compared to Avitene~ and TachoComb~ . A 10 mm x 50 mm piece of each material was placed in the grips of Instron Model 4201. The initial gauge length was 25 nim. Each material was tested under dry conditions at the crosshead speed of 2 mm/min. To test wet strength, materials were placed in 30 ml of PBS, pH 7.2 at 37°C for 15 minutes and measurements were taken at 23°C at a crosshead speed of 5 mm/min.
immediately after removal from the PBS. Maximum load before the material breaks is indicative of the strength of the material. The results of this study WO 99!56798 PCT/US99/09891 -(Table I>] demonstrate that the hemostatic materials of the invention have statistically significant increased dry and wet strength over both Avitene~
and TachoComb~
Table II. Mechanical Properties of Hemostats Sample Type Dry Testing Max. Wet Testing Max. Load Load PGA/F/T/Ca 0.34 t 0.04# 0.5645 0.0782 (Ex. 7) HA/CMC/F/T/Ca 9.11 0.92" 1.8275 t 0.977"
(Ex. 8) PGA/HA:CMC/F/T/Ca6.86 t 0.57" 1.2738 0.2308"
(Ex. 14 TachoComb~ 1.83 t 0.18 0.5242 t 0.1099 Avitene~ 0.12 t 0.08 Nd *Sample fell apart and could not be tested "Difference from TachoComb~ and Avitene~ (Anova p=0.01, Tukey-Kramer) #Difference from Avitene~ (Anova p=0.02, Tukey-Kramer) Other Embodiments From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions. For example, components including but not limited to plasticizers, polyethylene glycol, glycerol, and albumin can also be included in the composition of the invention to provide additional stability, mechanical strength and flexibility.
Claims (44)
1. A solid, fibrous, bioabsorbable hemostatic composition comprising a bioabsorbable polymer and a hemostatic compound, wherein the hemostatic compound is dispersed throughout the hemostatic composition.
2. The composition of claim 1 wherein the bioabsorbable polymer is selected from the group consisting of polyanionic polysaccharides, alginie-acid, chitin, chitosan, fibrin, polyglycolide, polylactide, polycaprolactone, dextran and copolymers thereof.
3. The composition of claim 1 wherein the bioabsorbable polymer is a polyanionic polysaccharide.
4. The composition of claim 3 wherein the polyanionic polysaccharide is in the form of a water-insoluble derivative.
5. The composition of claims 3 or 4 wherein the polyanionic polysaccharide is selected from the group consisting of carboxymethylcellulose, carboxymethylamylose, and hyaluronic acid.
6. The composition of claims 3 or 4 wherein the hemostatic composition comprises two or more polyanionic polysaccharides.
7. The composition of claim 3 or 4 further comprising a hydrophobic bioabsorbable polymer.
8. The composition of claim 7 wherein the hydrophobic bioabsorbable polymer is selected from the group consisting of polyglycolide, polylactide, polydioxanones, polyestercarbonates, polyhydroxyalkonates, polylactones and copolymers thereof.
9. The composition of claim 1 wherein the hemostatic compound is thrombin.
10. The composition of claim 9 wherein the thrombin is present at a concentration between about I and 100 U/cm2.
11. The composition of claim I wherein the hemostatic compound is fibrinogen.
12. The composition of claim 11 wherein the fibrinogen is present in a concentration between about 0.05 and 20 mg/cm2.
13. The composition of claims 9 or 11 further comprising a calcium salt.
14. The composition of claim 13 wherein the calcium salt is calcium chloride.
15. The composition of claim 13 wherein the calcium salt is present in a concentration between 0.01 and 10 mg/cm2.
16. The composition of claim 9 further comprising fibrinogen.
17. The composition of claim 14 wherein the fibrinogen is present in a concentration between about 0.05 and 20 mg/cm2.
18. The composition of claim 1 further comprising Factor XIII, fibronectin, plasminogen, aprotinin, alpha-2-antiplasmin, 1pha-2-macroglobulin, alpha-1-antitrypsin, epsilon-aminocaproic acid, tranexamic acid, a plasmin activator inhibitor, or a combination thereof.
19. The composition of claim 1 further comprising protamine sulfate.
20. The composition of claim 1 further comprising a drug.
21. The composition of claim 20 wherein the drug is selected from the group consisting of growth factors, growth factor inhibitors, antibodies, non-steroidal anti-inflammatory agents, antibiotics and cytokines.
22. The composition of claim 1 having a mass/area between about 15 and 50 mg/cm2.
23. The composition of claim 1 wherein the composition is provided in a waterproof, sterile package.
24. The composition of claim 1 further comprising a medically acceptable adhesive backing.
25. The composition of claim 1 wherein the composition is formed to fit over the ends of a vascular prosthesis.
26. A kit comprising the hemostatic composition of claim 1.
27. The composition of claim 1 wherein the hemostatic compound is dispersed evenly throughout the composition.
28. The composition of claim 1 wherein the hemostatic compound is present as a gradient.
29. The composition of claim 1 further comprising a non-adhesiogenic layer.
30. A method for making a solid, fibrous, bioabsorbable hemostatic composition comprising the steps of a) admixing a bioabsorbable polymer and a hemostatic compound in the presence of a non-aqueous solvent to form a fibrous pulp; and b) subjecting the fibrous pulp to a paper-making process.
31. The method of claim 30 wherein the non-aqueous solvent is selected from the group consisting of straight-chain or branched C1-C5 alcohols, ketones, aliphatic ethers, cycloaliphatic ethers, esters, nitriles, and aliphatic halogenated hydrocarbons.
32. The method of claim 31 wherein the non-aqueous solvent is an alcohol.
33. The method of claim 32 wherein the alcohol is ethanol.
34. The method of claim 32 wherein the alcohol is 95% to 100%
ethanol.
ethanol.
35. The method of claim 30 wherein the bioabsorbable polymer and hemostatic compound are admixed under high shear conditions.
36. The method of claim 30 wherein the paper-making process includes the steps a) collecting the fibrous pulp from the non-aqueous solvent;
b) pressing the collected fibrous pulp; and c) drying the pressed pulp.
b) pressing the collected fibrous pulp; and c) drying the pressed pulp.
37. The method of claim 36 wherein the fibrous pulp is collected onto a forming fabric.
38. The method of claim 37 wherein the forming fabric is selected from the group consisting of Teflon mesh, stainless steel mesh and polyester fabric.
39. The method of claim 37 wherein the forming fabric is a polyester fabric.
40. The method of claim 36 wherein the collected fibrous pulp is subjected to heat compression.
41. A method for inhibiting or stopping blood loss from a wound comprising contacting the wound with a solid, fibrous, biodegradeable hemostatic composition comprising a bioabsorbable polymer and a hemostatic compound for a period of time sufficient to promote blood clotting to occur.
42. The method of claim 41 further comprising applying manual pressure hemostatic composition after contact with the wound.
43. The method of claim 41 wherein the wound is caused by accidental trauma.
44. The method of claim 41 wherein the wound is due to a surgical procedure.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/074,146 US6056970A (en) | 1998-05-07 | 1998-05-07 | Compositions comprising hemostatic compounds and bioabsorbable polymers |
| US09/074,146 | 1998-05-07 | ||
| PCT/US1999/009891 WO1999056798A1 (en) | 1998-05-07 | 1999-05-06 | Compositions comprising hemostatic compounds and bioabsorbable polymers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2329809A1 true CA2329809A1 (en) | 1999-11-11 |
Family
ID=22117992
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002329809A Abandoned CA2329809A1 (en) | 1998-05-07 | 1999-05-06 | Compositions comprising hemostatic compounds and bioabsorbable polymers |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US6056970A (en) |
| EP (1) | EP1075288A1 (en) |
| JP (1) | JP2002513645A (en) |
| AU (1) | AU3788299A (en) |
| CA (1) | CA2329809A1 (en) |
| WO (1) | WO1999056798A1 (en) |
Families Citing this family (174)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6528483B2 (en) | 1995-06-07 | 2003-03-04 | André Beaulieu | Method of producing concentrated non-buffered solutions of fibronectin |
| FR2766716B1 (en) | 1997-08-01 | 2000-02-18 | Cogent Sarl | COMPOSITE PROSTHESIS FOR PREVENTION OF POST-SURGICAL ADHESIONS AND PROCESS FOR OBTAINING SAME |
| JP3578627B2 (en) * | 1998-05-15 | 2004-10-20 | 株式会社ホギメディカル | Tissue sealant that promotes wound healing |
| WO1999066797A1 (en) | 1998-06-22 | 1999-12-29 | Worden Charles E | Enriched platelet wound healant |
| BE1012536A3 (en) | 1998-11-04 | 2000-12-05 | Baxter Int | Element with a layer fibrin its preparation and use. |
| CA2350628A1 (en) * | 1998-11-12 | 2000-05-18 | Polymer Biosciences, Inc. | Hemostatic polymer useful for rapid blood coagulation and hemostasis |
| AU774118B2 (en) * | 1999-02-12 | 2004-06-17 | Baxter Healthcare Sa | A method for producing a preparation based on fibrinogen and fibronectin as well as protein compositions obtainable according to this method |
| AU3862900A (en) | 1999-03-01 | 2000-09-21 | Uab Research Foundation | Porous tissue scaffolding materials and uses thereof |
| EP2305324B1 (en) * | 1999-03-25 | 2014-09-17 | Metabolix, Inc. | Medical devices and applications of polyhydroxyalkanoate polymers |
| JP2003500170A (en) * | 1999-06-01 | 2003-01-07 | ブリストル−マイヤーズ スクイブ カンパニー | Prevention of postoperative adhesion using fibrin monomer sealant |
| US7371408B1 (en) * | 1999-06-07 | 2008-05-13 | Wright Medical Technology, Inc. | Bone graft substitute composition |
| JP2003508425A (en) * | 1999-08-30 | 2003-03-04 | テファ， インコーポレイテッド | Washable disposable polymer products |
| US6262020B1 (en) * | 2000-02-15 | 2001-07-17 | Alphamed Pharmaceuticals Corp. | Topical wound therapeutic compositions |
| CA2416126C (en) | 2000-07-28 | 2011-07-05 | Anika Therapeutics, Inc. | Bioabsorbable composites of derivatized hyaluronic acid |
| US20040013715A1 (en) * | 2001-09-12 | 2004-01-22 | Gary Wnek | Treatment for high pressure bleeding |
| US7326412B2 (en) * | 2000-10-13 | 2008-02-05 | Baxter International Inc. | Fibrinogen plus a non-plasmin-acting fibrinolysis inhibitor for the reduction or prevention of adhesion formation |
| US6800245B1 (en) * | 2000-11-28 | 2004-10-05 | Vita Special Purpose Corporation | Sterile polymerizable systems and kits and methods of their manufacture and use |
| US7041657B2 (en) | 2001-02-12 | 2006-05-09 | Marine Polymer Technologies Inc. | Compositions and methods for modulation of vascular structure and/or function |
| WO2002083188A2 (en) * | 2001-04-16 | 2002-10-24 | Cassidy James J | Dense/porous structures for use as bone substitutes |
| US6685956B2 (en) | 2001-05-16 | 2004-02-03 | The Research Foundation At State University Of New York | Biodegradable and/or bioabsorbable fibrous articles and methods for using the articles for medical applications |
| AU2002320182B2 (en) * | 2001-06-29 | 2008-02-21 | Cook Biotech Incorporated | Porous sponge matrix medical devices and methods |
| IL144446A0 (en) * | 2001-07-19 | 2002-05-23 | Prochon Biotech Ltd | Plasma protein matrices and methods for their preparation |
| US7371409B2 (en) | 2001-09-06 | 2008-05-13 | Wright Medical Technology, Inc. | Bone graft substitute composition |
| WO2003057274A2 (en) * | 2001-12-28 | 2003-07-17 | Genzyme Corporation | Bioresorbable foam packing device and use thereof |
| EP1469865A4 (en) * | 2001-12-31 | 2010-04-14 | Crosslink D Inc | Hemostatic compositions and methods for controlling bleeding |
| WO2003065877A2 (en) * | 2002-02-04 | 2003-08-14 | Damage Control Surgical Technologies, Inc. | Method and apparatus for improved hemostasis and damage control operations |
| ATE490745T1 (en) | 2002-03-29 | 2010-12-15 | Wright Medical Tech Inc | BONE TRANSPLANT REPLACEMENT COMPOSITION |
| US7291179B2 (en) | 2002-06-24 | 2007-11-06 | Wright Medical Technology, Inc. | Bone graft substitute composition |
| US6652887B1 (en) | 2002-06-24 | 2003-11-25 | Wright Medical Technology, Inc. | Bone graft substitute composition |
| WO2004043503A1 (en) * | 2002-11-14 | 2004-05-27 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | Thrombin-carrying bioabsorbable synthetic nonwoven fabric |
| US6896809B2 (en) * | 2002-12-20 | 2005-05-24 | Providence Health System - Oregon | Methods for purifying chitosan |
| WO2004060172A1 (en) * | 2002-12-31 | 2004-07-22 | Marine Polymer Technologies, Inc. | Hemostatic compositions and uses therefor |
| JP4769578B2 (en) * | 2003-01-20 | 2011-09-07 | 一般財団法人化学及血清療法研究所 | Hemostasis material |
| US7943810B2 (en) | 2003-02-04 | 2011-05-17 | Buckman Robert F | Method and apparatus for hemostasis |
| US7507257B2 (en) * | 2003-02-04 | 2009-03-24 | Wright Medical Technology, Inc. | Injectable resorbable bone graft material, powder for forming same and methods relating thereto for treating bone defects |
| US7452374B2 (en) * | 2003-04-24 | 2008-11-18 | Maquet Cardiovascular, Llc | AV grafts with rapid post-operative self-sealing capabilities |
| WO2004101002A2 (en) | 2003-05-08 | 2004-11-25 | Tepha, Inc. | Polyhydroxyalkanoate medical textiles and fibers |
| US20040243044A1 (en) * | 2003-06-02 | 2004-12-02 | Penegor Stephen A. | Hemostatic wound dressing |
| EP1651273B1 (en) * | 2003-07-08 | 2012-08-29 | Tepha, Inc. | Poly-4-hydroxybutyrate matrices for sustained drug delivery |
| JP2007503221A (en) * | 2003-08-22 | 2007-02-22 | テファ， インコーポレイテッド | Polyhydroxyalkanoate nerve regeneration device |
| CN101897989B (en) * | 2004-02-23 | 2013-11-13 | 洛马林达大学医学中心 | Hemostatic agent for topical and internal use |
| EP1727569A1 (en) * | 2004-03-11 | 2006-12-06 | Medtrade Products Ltd. | Compositions of alpha and beta chitosan and methods of preparing them |
| CN101068555B (en) * | 2004-03-17 | 2011-07-06 | 根茨美公司 | Anti-adhesion spraying |
| JPWO2005113030A1 (en) * | 2004-05-21 | 2008-07-31 | 財団法人化学及血清療法研究所 | Tissue closure agent |
| CA2571057A1 (en) * | 2004-06-30 | 2006-01-12 | James V. Sitzmann | Medical devices for minimally invasive surgeries and other internal procedures |
| EP1778305B1 (en) * | 2004-08-03 | 2010-07-07 | Tepha, Inc. | Non-curling polyhydroxyalkanoate sutures |
| EP1791496B1 (en) * | 2004-08-31 | 2019-07-31 | C.R. Bard, Inc. | Self-sealing ptfe graft with kink resistance |
| US9801982B2 (en) | 2004-09-28 | 2017-10-31 | Atrium Medical Corporation | Implantable barrier device |
| US9012506B2 (en) | 2004-09-28 | 2015-04-21 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
| EP1811933B1 (en) | 2004-09-28 | 2016-03-23 | Atrium Medical Corporation | Barrier layer |
| US8367099B2 (en) | 2004-09-28 | 2013-02-05 | Atrium Medical Corporation | Perforated fatty acid films |
| US9000040B2 (en) | 2004-09-28 | 2015-04-07 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
| US8312836B2 (en) * | 2004-09-28 | 2012-11-20 | Atrium Medical Corporation | Method and apparatus for application of a fresh coating on a medical device |
| US20060088596A1 (en) | 2004-09-28 | 2006-04-27 | Atrium Medical Corporation | Solubilizing a drug for use in a coating |
| US9358318B2 (en) * | 2004-10-20 | 2016-06-07 | Ethicon, Inc. | Method of making a reinforced absorbable multilayered hemostatic wound dressing |
| CA2584698C (en) * | 2004-10-20 | 2014-02-25 | Ethicon, Inc. | A reinforced absorbable multilayered hemostatic wound dressing and method of making |
| US7250550B2 (en) * | 2004-10-22 | 2007-07-31 | Wright Medical Technology, Inc. | Synthetic bone substitute material |
| US8029563B2 (en) | 2004-11-29 | 2011-10-04 | Gore Enterprise Holdings, Inc. | Implantable devices with reduced needle puncture site leakage |
| CA2596283C (en) * | 2005-01-28 | 2011-11-01 | Tepha, Inc. | Embolization using poly-4-hydroxybutyrate particles |
| WO2006099137A1 (en) * | 2005-03-10 | 2006-09-21 | Uab Research Foundation | Endothelial predecessor cell seeded wound healing scaffold |
| PT1890641T (en) * | 2005-06-17 | 2017-05-30 | Bard Inc C R | Vascular graft with kink resistance after clamping |
| US8025903B2 (en) * | 2005-09-09 | 2011-09-27 | Wright Medical Technology, Inc. | Composite bone graft substitute cement and articles produced therefrom |
| CN103349793B (en) | 2005-09-09 | 2016-02-10 | 阿格诺沃斯健康关爱公司 | Composite bone graft substitute cement and the goods obtained by it |
| US9278161B2 (en) | 2005-09-28 | 2016-03-08 | Atrium Medical Corporation | Tissue-separating fatty acid adhesion barrier |
| US9427423B2 (en) | 2009-03-10 | 2016-08-30 | Atrium Medical Corporation | Fatty-acid based particles |
| CA2626030A1 (en) | 2005-10-15 | 2007-04-26 | Atrium Medical Corporation | Hydrophobic cross-linked gels for bioabsorbable drug carrier coatings |
| JP2009514597A (en) | 2005-11-04 | 2009-04-09 | ライフサイエンス・プラス・インコーポレイテッド | Bioabsorbable hemostatic gauze |
| US20070104769A1 (en) * | 2005-11-04 | 2007-05-10 | Lifescience Plus, Inc. | Bioabsorbable hemostatic gauze |
| CA2626598A1 (en) | 2005-11-09 | 2007-05-18 | C.R. Bard Inc. | Grafts and stent grafts having a radiopaque marker |
| FR2894831B1 (en) * | 2005-12-16 | 2008-02-15 | Lab Francais Du Fractionnement | THROMBIN FREE BIOLOGICAL GLUE AND USE THEREOF AS MEDICAMENT. |
| US8277837B2 (en) | 2006-01-11 | 2012-10-02 | Entegrion, Inc. | Hemostatic textile |
| US9532943B2 (en) * | 2010-12-20 | 2017-01-03 | Cormatrix Cardiovascular, Inc. | Drug eluting patch for the treatment of localized tissue disease or defect |
| CA2573472A1 (en) * | 2006-01-23 | 2007-07-23 | Tyco Healthcare Group Lp | Biodegradable hemostatic compositions |
| US20070248653A1 (en) * | 2006-04-20 | 2007-10-25 | Cochrum Kent C | Hemostatic compositions and methods for controlling bleeding |
| EP2022276A4 (en) * | 2006-05-18 | 2012-06-13 | Gustavo Larsen | Methods for making a multicomponent hemostatic dressing |
| US20080033332A1 (en) * | 2006-08-04 | 2008-02-07 | Macphee Martin | Solid dressing for treating wounded tissue |
| US9198749B2 (en) | 2006-10-12 | 2015-12-01 | C. R. Bard, Inc. | Vascular grafts with multiple channels and methods for making |
| WO2008057328A2 (en) | 2006-11-06 | 2008-05-15 | Atrium Medical Corporation | Tissue separating device with reinforced support for anchoring mechanisms |
| US9492596B2 (en) | 2006-11-06 | 2016-11-15 | Atrium Medical Corporation | Barrier layer with underlying medical device and one or more reinforcing support structures |
| US7943683B2 (en) * | 2006-12-01 | 2011-05-17 | Tepha, Inc. | Medical devices containing oriented films of poly-4-hydroxybutyrate and copolymers |
| US20080138387A1 (en) * | 2006-12-07 | 2008-06-12 | Machiraju Venkat R | Hemostatic sponge and article |
| US9289196B2 (en) * | 2006-12-12 | 2016-03-22 | Cook Medical Technologies Llc | Hemostatic substance with a coating |
| US20100239560A1 (en) * | 2007-04-20 | 2010-09-23 | Jens Hassingboe | Multi component non-woven |
| NZ580803A (en) * | 2007-04-27 | 2012-03-30 | Endo Pharmaceuticals Solutions | Implant device release agents and methods of using same |
| US20090004455A1 (en) * | 2007-06-27 | 2009-01-01 | Philippe Gravagna | Reinforced composite implant |
| US9011894B2 (en) * | 2007-06-29 | 2015-04-21 | Carbylan Therapeutics, Inc. | Sterile hyaluronic acid polymer compositions and related methods |
| WO2009020612A1 (en) * | 2007-08-06 | 2009-02-12 | Stb Lifesaving Technologies, Inc. | Methods and dressing for sealing internal injuries |
| US9308068B2 (en) | 2007-12-03 | 2016-04-12 | Sofradim Production | Implant for parastomal hernia |
| CA2716872C (en) | 2008-02-29 | 2015-02-10 | Ferrosan Medical Devices A/S | Device for promotion of hemostasis and/or wound healing |
| JP5539959B2 (en) * | 2008-04-11 | 2014-07-02 | ヴァージニア コモンウェルス ユニバーシティ | Drugs and bandages with electrospun dextran fibers |
| US9242026B2 (en) | 2008-06-27 | 2016-01-26 | Sofradim Production | Biosynthetic implant for soft tissue repair |
| TWI488662B (en) * | 2008-12-11 | 2015-06-21 | Baxter Int | Preparations based on fibrinogen and sulfated polysaccharides |
| US9433700B2 (en) | 2009-04-27 | 2016-09-06 | Medibeacon Inc. | Tissue sealant compositions, vascular closure devices, and uses thereof |
| ITPI20090066A1 (en) * | 2009-05-26 | 2010-11-27 | Consiglio Nazionale Ricerche | METHOD TO PRODUCE A DEVICE APPLICABLE TO BIOLOGICAL FABRICS, IN PARTICULAR A PATCH TO TREAT DAMAGED FABRICS, AND DEVICE OBTAINED WITH THIS METHOD |
| JP5820807B2 (en) * | 2009-05-28 | 2015-11-24 | プロフィブリックス ビー．ヴイ． | Fibrin sealant |
| WO2010143711A1 (en) * | 2009-06-11 | 2010-12-16 | 一般財団法人化学及血清療法研究所 | Wound-covering material |
| WO2011014432A1 (en) | 2009-07-30 | 2011-02-03 | Carbylan Biosurgery, Inc. | Modified hyaluronic acid polymer compositions and related methods |
| US20110038910A1 (en) | 2009-08-11 | 2011-02-17 | Atrium Medical Corporation | Anti-infective antimicrobial-containing biomaterials |
| EP2471902B9 (en) * | 2009-08-25 | 2018-12-19 | Servicio Andaluz De Salud | Production of artificial tissues by means of tissue engineering using agarose-fibrin biomaterials |
| FR2949688B1 (en) | 2009-09-04 | 2012-08-24 | Sofradim Production | FABRIC WITH PICOTS COATED WITH A BIORESORBABLE MICROPOROUS LAYER |
| US10065030B2 (en) | 2010-02-23 | 2018-09-04 | Viaderm Llc | Vacuum assisted percutaneous appliance |
| US8551531B2 (en) | 2010-04-12 | 2013-10-08 | The Curators Of The University Of Missouri | Pentablock polymers |
| EP2593141B1 (en) | 2010-07-16 | 2018-07-04 | Atrium Medical Corporation | Composition and methods for altering the rate of hydrolysis of cured oil-based materials |
| WO2012011429A1 (en) * | 2010-07-20 | 2012-01-26 | 一般財団法人化学及血清療法研究所 | Sheet preparation for tissue adhesion |
| FR2972626B1 (en) | 2011-03-16 | 2014-04-11 | Sofradim Production | PROSTHETIC COMPRISING A THREE-DIMENSIONAL KNIT AND ADJUSTED |
| FR2977789B1 (en) | 2011-07-13 | 2013-07-19 | Sofradim Production | PROSTHETIC FOR UMBILIC HERNIA |
| FR2977790B1 (en) | 2011-07-13 | 2013-07-19 | Sofradim Production | PROSTHETIC FOR UMBILIC HERNIA |
| EP2556842A1 (en) | 2011-08-11 | 2013-02-13 | Bioftalmik, S.L. | Composition in the form of film comprising fibrinogen and a fibrinogen activator and the applications thereof |
| WO2013046058A2 (en) | 2011-09-30 | 2013-04-04 | Sofradim Production | Reversible stiffening of light weight mesh |
| US20130108550A1 (en) | 2011-10-26 | 2013-05-02 | Abbott Cardiovasculr Systems, Inc. | Bioabsorbable Co-Filler for Cerebrovascular Aneurysms |
| AR088531A1 (en) | 2011-10-27 | 2014-06-18 | Baxter Int | HEMOSTATIC COMPOSITIONS |
| US20140275287A1 (en) | 2011-11-01 | 2014-09-18 | Abyrx, Inc. | Compositions and Methods for Hemostasis |
| US9056092B2 (en) * | 2011-12-02 | 2015-06-16 | Ethicon, Inc. | Hemostatic bioabsorbable device with polyethylene glycol binder |
| FR2985170B1 (en) | 2011-12-29 | 2014-01-24 | Sofradim Production | PROSTHESIS FOR INGUINAL HERNIA |
| FR2985271B1 (en) | 2011-12-29 | 2014-01-24 | Sofradim Production | KNITTED PICOTS |
| DE102012002209A1 (en) * | 2012-02-07 | 2013-08-08 | Carl Freudenberg Kg | Biodegradable nonwoven for medical purposes |
| IN2014DN09624A (en) * | 2012-05-14 | 2015-07-31 | Teijin Ltd | |
| PL2851095T3 (en) * | 2012-05-14 | 2022-01-10 | Teijin Limited | Sheet molding and hemostatic material |
| US9168178B2 (en) | 2012-05-22 | 2015-10-27 | Covidien Lp | Energy-delivery system and method for controlling blood loss from wounds |
| CN104349797B (en) * | 2012-06-12 | 2017-10-27 | 弗罗桑医疗设备公司 | Dry hemostatic composition |
| US9867880B2 (en) | 2012-06-13 | 2018-01-16 | Atrium Medical Corporation | Cured oil-hydrogel biomaterial compositions for controlled drug delivery |
| FR2994185B1 (en) | 2012-08-02 | 2015-07-31 | Sofradim Production | PROCESS FOR THE PREPARATION OF A POROUS CHITOSAN LAYER |
| FR2995778B1 (en) | 2012-09-25 | 2015-06-26 | Sofradim Production | ABDOMINAL WALL REINFORCING PROSTHESIS AND METHOD FOR MANUFACTURING THE SAME |
| FR2995779B1 (en) | 2012-09-25 | 2015-09-25 | Sofradim Production | PROSTHETIC COMPRISING A TREILLIS AND A MEANS OF CONSOLIDATION |
| FR2995788B1 (en) | 2012-09-25 | 2014-09-26 | Sofradim Production | HEMOSTATIC PATCH AND PREPARATION METHOD |
| US10159555B2 (en) | 2012-09-28 | 2018-12-25 | Sofradim Production | Packaging for a hernia repair device |
| CN105007841A (en) * | 2012-12-31 | 2015-10-28 | 乔治·D.·福卢什 | Lyophilized fibrin sealant for high volume hemorrhage |
| US9040093B2 (en) | 2013-03-13 | 2015-05-26 | Orthovita, Inc. | Bone graft materials containing calcium phosphate and chitosan |
| EP2988771B1 (en) * | 2013-04-22 | 2018-12-19 | Sealantium Medical Ltd. | Fibrinogen-based tissue adhesive patches |
| US11071805B2 (en) * | 2013-04-22 | 2021-07-27 | Sealantium Medical Ltd. | Fibrinogen-based tissue adhesive patches |
| JP2016520141A (en) | 2013-05-16 | 2016-07-11 | ザ・キュレイターズ・オブ・ザ・ユニバーシティー・オブ・ミズーリＴｈｅ Ｃｕｒａｔｏｒｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｍｉｓｓｏｕｒｉ | Pentablock polymer, manufacturing method, and drug filling |
| FR3006578B1 (en) | 2013-06-07 | 2015-05-29 | Sofradim Production | PROSTHESIS BASED ON TEXTILE FOR LAPAROSCOPIC PATHWAY |
| FR3006581B1 (en) | 2013-06-07 | 2016-07-22 | Sofradim Production | PROSTHESIS BASED ON TEXTILE FOR LAPAROSCOPIC PATHWAY |
| US9724078B2 (en) | 2013-06-21 | 2017-08-08 | Ferrosan Medical Devices A/S | Vacuum expanded dry composition and syringe for retaining same |
| US9814560B2 (en) | 2013-12-05 | 2017-11-14 | W. L. Gore & Associates, Inc. | Tapered implantable device and methods for making such devices |
| CA2928963C (en) | 2013-12-11 | 2020-10-27 | Ferrosan Medical Devices A/S | Dry composition comprising an extrusion enhancer |
| US10625066B2 (en) | 2014-05-23 | 2020-04-21 | Viaderm, Llc | Vacuum assisted percutaneous appliance |
| US10500303B2 (en) | 2014-08-15 | 2019-12-10 | Tepha, Inc. | Self-retaining sutures of poly-4-hydroxybutyrate and copolymers thereof |
| EP3000489B1 (en) | 2014-09-24 | 2017-04-05 | Sofradim Production | Method for preparing an anti-adhesion barrier film |
| EP3000432B1 (en) | 2014-09-29 | 2022-05-04 | Sofradim Production | Textile-based prosthesis for treatment of inguinal hernia |
| EP3000433B1 (en) | 2014-09-29 | 2022-09-21 | Sofradim Production | Device for introducing a prosthesis for hernia treatment into an incision and flexible textile based prosthesis |
| AU2015333206B2 (en) | 2014-10-13 | 2019-07-11 | Ferrosan Medical Devices A/S. | Dry composition for use in haemostasis and wound healing |
| EP3029189B1 (en) | 2014-12-05 | 2021-08-11 | Sofradim Production | Prosthetic porous knit, method of making same and hernia prosthesis |
| CA2969429C (en) | 2014-12-11 | 2020-10-27 | Tepha, Inc. | Methods of orienting multifilament yarn and monofilaments of poly-4-hydroxybutyrate and copolymers thereof |
| US10626521B2 (en) | 2014-12-11 | 2020-04-21 | Tepha, Inc. | Methods of manufacturing mesh sutures from poly-4-hydroxybutyrate and copolymers thereof |
| RU2705905C2 (en) | 2014-12-24 | 2019-11-12 | Ферросан Медикал Дивайсиз А/С | Syringe for holding and mixing first and second substances |
| WO2016112026A1 (en) * | 2015-01-06 | 2016-07-14 | St. Teresa Medical, Inc. | Hemostatic products |
| EP3059255B1 (en) | 2015-02-17 | 2020-05-13 | Sofradim Production | Method for preparing a chitosan-based matrix comprising a fiber reinforcement member |
| US11027047B2 (en) | 2015-03-31 | 2021-06-08 | The University Of North Carolina At Chapel Hill | Delivery vehicles for stem cells and uses thereof |
| EP3085337B1 (en) | 2015-04-24 | 2022-09-14 | Sofradim Production | Prosthesis for supporting a breast structure |
| EP3302619A1 (en) | 2015-06-05 | 2018-04-11 | W. L. Gore & Associates, Inc. | A low bleed implantable prosthesis with a taper |
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Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4442655A (en) * | 1981-06-25 | 1984-04-17 | Serapharm Michael Stroetmann | Fibrinogen-containing dry preparation, manufacture and use thereof |
| DE3214337C2 (en) * | 1982-04-19 | 1984-04-26 | Serapharm - Michael Stroetmann, 4400 Münster | Resorbable flat material for sealing and healing wounds and processes for their manufacture |
| NZ205863A (en) * | 1982-10-18 | 1985-09-13 | Johnson & Johnson Prod Inc | Absorbable haemostatic material containing lactide and glycolide homopolymers and copolymers |
| JPS6144825A (en) * | 1984-08-09 | 1986-03-04 | Unitika Ltd | Hemostatic agent |
| CS253042B1 (en) * | 1985-09-25 | 1987-10-15 | Maxmilian Mozisek | Haemostatical material |
| DE3708916A1 (en) * | 1987-03-19 | 1988-09-29 | Boehringer Ingelheim Kg | METHOD FOR CLEANING RESORBABLE POLYESTERS |
| CA2033046C (en) * | 1990-01-12 | 1999-08-03 | Lowell Saferstein | Process for preparing a neutralized oxidized cellulose product and its method of use |
| SE9101853D0 (en) * | 1991-06-17 | 1991-06-17 | Jonas Wadstroem | IMPROVED TISSUE ASHESIVE |
| AU1086795A (en) * | 1993-11-03 | 1995-05-23 | Clarion Pharmaceuticals, Inc. | Hemostatic patch |
| US6294202B1 (en) * | 1994-10-06 | 2001-09-25 | Genzyme Corporation | Compositions containing polyanionic polysaccharides and hydrophobic bioabsorbable polymers |
| WO1996017633A1 (en) * | 1994-12-07 | 1996-06-13 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| WO1997028832A1 (en) * | 1996-02-06 | 1997-08-14 | New Generation Medical Corporation | Composition for sealing wounds |
-
1998
- 1998-05-07 US US09/074,146 patent/US6056970A/en not_active Expired - Fee Related
-
1999
- 1999-05-06 WO PCT/US1999/009891 patent/WO1999056798A1/en not_active Application Discontinuation
- 1999-05-06 CA CA002329809A patent/CA2329809A1/en not_active Abandoned
- 1999-05-06 AU AU37882/99A patent/AU3788299A/en not_active Abandoned
- 1999-05-06 EP EP99920366A patent/EP1075288A1/en not_active Withdrawn
- 1999-05-06 JP JP2000546822A patent/JP2002513645A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP1075288A1 (en) | 2001-02-14 |
| JP2002513645A (en) | 2002-05-14 |
| WO1999056798A1 (en) | 1999-11-11 |
| AU3788299A (en) | 1999-11-23 |
| US6056970A (en) | 2000-05-02 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Discontinued |