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    patent summary: "bioabsorbable hemostatic device with polyethylene glycol binder". The present invention relates to a hemostatic pad comprising a bioabsorbable scaffolding material; a lyophilized thrombin powder, a lyophilized fibrinogen powder and a meltable binder powder with all powders disposed in the bioabsorbable framework material. a castable binder such as peg binds lyophilized thrombin powder and lyophilized fibrinogen powder to bioabsorbable framework material for improved friability, wettability and performance in one use, such as hemostatic treatment or sealing at a wound site.
    公开号:BR112014013337B1
    申请号:R112014013337-9
    申请日:2012-11-28
    公开日:2019-10-15
    发明作者:Aaron D. Pesnell；Gerard Llanos
    申请人:Ethicon, Inc.；
    IPC主号:
    专利说明:

    Descriptive Report of the Invention Patent for HEMOSTATIC COMPRESSES AND ITS MANUFACTURING METHOD.
    FIELD OF THE INVENTION [001] The present invention relates, in general, to agents and devices for the promotion of hemostasis and tissue sealing and, more particularly, to hemostatic compresses that comprise bioabsorbable frameworks that transport lyophilized proteins that promote hemostasis , such as fibrinogen and thrombin.
    BACKGROUND [002] Blood is a liquid tissue that includes red blood cells, leukocytes, corpuscles and platelets dispersed in a liquid phase. The liquid phase is the plasma, which includes acids, lipids, dissolved electrolytes and proteins. A specific protein suspended in the liquid phase is fibrinogen. When bleeding occurs, fibrinogen reacts with water and thrombin (an enzyme) to form fibrin, which is insoluble in the blood and polymerizes to form clots.
    [003] In a wide variety of circumstances, animals, including humans, may experience bleeding due to injury or during surgical procedures. In some circumstances, bleeding is relatively small, and normal blood clotting functions, in addition to simple first aid actions, are all that is needed. In other circumstances, substantial bleeding may occur. These situations generally require specialized equipment and materials, as well as trained personnel to administer the appropriate assistance.
    [004] In an effort to deal with the problems described above, materials have been developed to control excessive bleeding. Topical bioabsorbable hemostatic agents (tahs) are widely used in surgical applications. The agents
    Petition 870190007047, of 23/01/2019, p. 5/19
    2/24 topical bioabsorbable hemostats cover products based on various woven or non-woven materials or sponges, typically produced from at least partially resorbable materials, ranging from natural to synthetic polymers and combinations thereof, including lactide-glycolide-based copolymers such as polyglactin 910, oxidized cellulose (OC), oxidized regenerated cellulose (ORC), gelatin, collagen, chitin, chitosan, etc. To improve hemostatic performance, frameworks based on the materials mentioned above can be combined with biologically derived coagulation factors, such as thrombin and / or fibrinogen.
    [005] Numerous hemostatic formulations currently available on the market or in development use lyophilized fibrinogen, often in combination with lyophilized thrombin, with hemostatic formulations applied in the form of dry powder, semi-liquid paste, liquid formula, or optionally placed on a support framework such as a framework of bioabsorbable tissue.
    [006] For hemostatic bandages or compresses containing lyophilized thrombin and fibrinogen in bioabsorbable frameworks, there is a need to improve the performance and properties of the device, with the particularly necessary improvements being related to the improved wettability of the compresses, leading to faster reconstitution lyophilized proteins, and faster hemostasis; reduced friability, that is, reduced spreading of active powders during handling and / or cutting the compresses; and improved tissue adhesion and wound sealing properties.
    [007] U.S. patent #No. 7,320,962 entitled Hemoactive compositions and methods for their manufacture and use features a dry hemoactive material to inhibit bleeding or release an agent, comprising: a biologically crosslinked polymer
    3/24 compatible that forms a hydrogel when exposed to blood; and a biologically compatible non-cross-linked polymer that solubilizes when exposed to blood: the cross-linked polymer being dispersed in a dry matrix of the non-cross-linking polymer. The reference also presents a plasticizer present at least in the non-crosslinked polymer and teaches that the plasticizer is selected from the group consisting of polyethylene glycol, sorbitol and glycerol.
    [008] U.S. patent #No. 6,706,690 entitled Hemoactive compositions and methods for their manufacture and use presents a dry material that forms a hydrogel when exposed to blood, and said material comprises: a biologically compatible cross-linked polymer that forms a hydrogel when exposed to blood; and a biologically compatible non-crosslinked polymer that dissolves when exposed to blood; a plasticizer present in the biologically compatible non-crosslinked polymer; and since the crosslinked polymer is dispersed in a dry matrix of the non-crosslinked polymer, the biologically compatible non-crosslinked polymer dissolves in 15 minutes or less when exposed to blood. The reference also shows a plasticizer present in the non-crosslinked polymer from 1% by weight to 20% by weight of the material, and teaches that the plasticizer is selected from the group consisting of polyethylene glycol, sorbitol and glycerol.
    [009] U.S. patent application #No. 2011 / 0071499A1 titled FREE-STANDING BIODEGRADABLE PATCH, features a device that comprises: a film that comprises a mixture of solid fibrinogen and solid thrombin, the film being independently supportive and configured to form a fibrin bandage upon exposure to moisture and also teaches that the film additionally comprises a plasticizer. It additionally features the device on which the film comprises
    4/24 about 5 to about 30 weight percent polyethylene glycol.
    [0010] U.S. patent application #No. 2009 / 0053288A1 entitled Hemostatic woven fabric presents a woven material that has a modified interlaced weave pattern, which also comprises a hemostatic agent. The reference also presents the woven material which also comprises a preservative selected from the group consisting of glycerol, propanediol, polyoxy ethylene glycol (PEG), trehalose, and combinations thereof.
    [0011] U.S. patent application #No. 2007 / 0160653A1 entitled Hemostatic textile presents a hemostatic textile, which comprises: a material comprising glass fibers and one or more secondary fibers selected from the group consisting of silk fibers; polyester fibers; nylon fibers; ceramic fibers; raw or regenerated bamboo fibers; cotton fibers; rayon fibers; linen fibers; lactide and / or glycolide polymers; lactide / glycolide copolymers; thrombin or a fraction containing thrombin; and one or more hemostatic agents selected from the group consisting of reconstituted lyophilized platelets, reconstituted lyophilized blood cells; fibrin, and fibrinogen; being that said hemostatic textile is able to activate the hemostatic systems in the body when applied to a wound. The reference also presents the hemostatic textile that also includes a preservative selected from the group consisting of glycerol, propanediol, polyoxy ethylene glycol (PEG), trehalose, and combinations thereof.
    [0012] PCT patent publication #No. WO 1997028832 A1 entitled COMPOSITION FOR SEALING WOUNDS presents a hemostatic bandage containing fibrinogen and thrombin powder adhered to a fibrous matrix with a viscous, non-aqueous adhesive such as a viscous polysaccharide, glycol, or petroleum gel. The non-aqueous adhesive does not allow a hydrolytic reaction to occur between the
    5/24 fibrinogen and thrombin until the bandage is moistened by a body fluid, such as blood and teaches that the bandage can be prepared and stored for prolonged periods while retaining hemostatic activity. The reference also has a composition for decreasing blood flow from an injury, which comprises: a vehicle; coagulation constituents adhered to the vehicle by an adhesive selected from the group consisting of water at a pH in which thrombin and fibrinogen do not interact to form fibrin, and a viscous non-aqueous biocompatible adhesive, with coagulation constituents being present in an amount therapeutically sufficient to clot and decrease blood flow from the wound when the composition contacts the body fluids that activate clotting. The reference also shows the composition in which the adhesive is a non-aqueous liquid at 20 ° C that adheres the coagulation constituents to the vehicle. The reference also shows the composition in which the non-aqueous adhesive is selected from the group consisting of propylene glycol, glycerol, petroleum gel and polyethylene glycol.
    [0013] The reference also teaches a hemostatic wound dressing, which comprises: a fibrous matrix suitable for positioning as a compress applied over or inserted into an open, bleeding wound; a mixture of particles mixed with powder coagulation factors present on the matrix surface, and the particles are in close enough contact with each other to form a clot when exposed to an aqueous medium at a physiological pH, particles are adhered to the matrix by a viscous non-aqueous adhesive, which has a viscosity of at least 100 centipoise at 20 ° C, which inhibits a coagulation reaction between the mixed particles until the particles are exposed to an aqueous medium at
    6/24 physiological pH.
    [0014] The reference also features a hemostatic wound dressing, which comprises: a fibrous matrix suitable for positioning as a compress applied over or inserted into an open, bleeding wound; a mixture of particles mixed with powder coagulation factors present throughout the matrix, in close enough contact to form a clot when exposed to an aqueous medium at a physiological pH, the particles being adhered to the matrix by a non-aqueous adhesive viscous which inhibits a coagulation reaction between the mixed particles until the particles are exposed to an aqueous medium at physiological pH, the adhesive being selected from the group consisting of a polysaccharide, polyethylene glycol, propylene glycol, glycerol, and petroleum gel, the adhesive being applied to the matrix in a liquid form comprising less than 3% by weight of water.
    SUMMARY OF THE INVENTION [0015] Briefly, in one embodiment, the present invention is directed to a hemostatic compress with improved friability and wettability and to a method of manufacturing such a hemostatic compress, said hemostatic compress comprising: a bioabsorbable framework material or bio-resorbable; a lyophilized thrombin powder, a lyophilized fibrinogen powder, and a polyethylene glycol (PEG) powder, all disposed in the bioabsorbable framework material; the PEG powder binds the lyophilized thrombin powder and the lyophilized fibrinogen powder to the bioabsorbable framework material but does not completely envelop the particles of lyophilized thrombin powder and / or the lyophilized fibrinogen powder. The terms bioabsorbable and bioresorbable are used interchangeably in the present invention to mean materials
    7/24 that can be decomposed by the body and that do not require mechanical removal.
    [0016] In one embodiment, the present invention is directed to a method of manufacturing a hemostatic compress, comprising the steps of (a) forming a suspension of a lyophilized thrombin powder, a lyophilized fibrinogen powder, and a polyethylene glycol in powder in a non-aqueous fluid; (b) apply the suspension to a framework produced from a bio-resorbable material; (c) allow the fluid to evaporate, with the framework carrying a portion of thrombin powder, fibrinogen powder, and powdered polyethylene glycol; (d) heating the framework to a temperature that exceeds the melting point of polyethylene glycol but does not exceed the temperature due to significant denaturation of thrombin and fibrinogen; (e) cool the framework to room temperature to form the hemostatic pad.
    [0017] In one embodiment, the present invention is directed to a method for providing a hemostatic treatment or tissue sealing at a wound site, comprising the steps of: (a) forming the hemostatic compress as described above and (b) apply the hemostatic pad to the wound site.
    BRIEF DESCRIPTION OF THE FIGURES [0018] Figure 1 shows the data of the tissue detachment test and effects of the PEG additive.
    [0019] Figure 2 shows the leak test data from several tested systems.
    [0020] Figure 3 shows the results of the friability tests at different concentrations of PEG3.
    DETAILED DESCRIPTION [0021] Briefly, in one embodiment, the present invention is directed to a hemostatic compress with friability and
    8/24 improved wettability and a method of manufacturing such a hemostatic compress, the said hemostatic compress comprising: a bioabsorbable framework material; a lyophilized powder of thrombin, a lyophilized powder of fibrinogen, and a polyethylene glycol powder, all arranged in the bioabsorbable framework material; and the PEG powder binds the lyophilized thrombin powder and the lyophilized fibrinogen powder to the bioabsorbable framework material but does not completely envelop the particles of lyophilized thrombin powder and lyophilized fibrinogen powder.
    [0022] In accordance with one embodiment of the present invention, PEG that can be smelted, optionally in the presence of CMC, is used to create a stronger adhesion of lyophilized proteins to the bioabsorbable framework material and better wetting / adhesion of the resulting hemostatic compress so that the fused and resolidified PEG binds the proximal particles or powders and the fibers of the framework, but does not completely coat or envelop the powders / particles in order to allow moisture to access and readily activate these biological agents in a surgical context. This results in a low-cost solution for reducing friability and improved adhesion and sealing of the fabric.
    [0023] In one embodiment, the present invention relates to a hemostatic or tissue sealing pad or material. In another embodiment, the present invention also relates to a method for providing hemostatic treatment or tissue sealing at a wound site, comprising the steps of: (a) forming the hemostatic material or pad or for sealing tissue , as described above, and (b) apply the hemostatic or tissue sealing material to the wound site.
    [0024] Hemostatic compress containing fibrinogen and thrombin
    9/24 lyophilized [0025] According to one embodiment, the present invention relates to a hemostatic compress that contains lyophilized hemostasis promoting agents, optionally lyophilized, in a bioabsorbable framework or matrix. Preferably, the hemostatic frameworks are natural or genetically modified bioabsorbable polymers or synthetic bioabsorbable polymers, or mixtures thereof.
    [0026] Examples of natural or genetically modified bioabsorbable polymers are proteins, polysaccharides and combinations thereof. Polysaccharides include, but are not limited to, cellulose, oxidized cellulose, oxidized regenerated cellulose (ORC), alkylcellulose, for example, methylcellulose, alkylhydroxyalkylcellulose, hydroxyalkylcellulose, cellulose sulfate, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose. hyaluronic acid, hyaluronic acid salts, alginate, alginic acid, propylene glycol alginate, glycogen, dextran, dextran sulfate, curdlan, pectin, pullulan, xanthan, chondroitin, chondroitin sulfates, carboxymethylxylan, carboxymethyl chitosan, amyloid, amyloid, chylamine poly-glucosamine, polymanuronic acid, polyglucuronic acid, polyguluronic acid, and derivatives of any of these.
    [0027] Examples of synthetic bioabsorbable polymers are aliphatic polyester polymers, copolymers, and / or combinations thereof. Polyesters are typically synthesized in a ring opening polymerization of monomers that include, but are not limited to, lactic acid, lactide (including L-, D-, meso and mixtures of D and L), glycolic acid, glycolide, ε -caprolactone, pdioxanone (1,4-dioxan-2-one) and trimethylene carbonate (1,3-dioxan-2one).
    10/24 [0028] Hemostasis promoting agents include proteins, prothrombin, thrombin, fibrinogen, fibrin, fibronectin, heparinase, factor X / Xa, factor VII / VIIa, factor IX / IXa, factor XI / XIa, factor XII / XIIa, tissue factor, batroxobina, ancrodo, ecarina, von Willebrand factor, collagen, elastin, albumin, gelatin, platelet surface glycoproteins, vasopressin, vasopressin analogs, epinephrine, selectin, procoagulant poison, plasminogen activator inhibitor, agents of platelet activation, synthetic peptides with hemostatic activity, and / or combinations thereof.
    [0029] A hemostatic compress containing thrombin and fibrinogen lyophilized in a bioabsorbable framework used in the experimental tests of the present invention is called an improved compress containing hemostatic biological product, and consists of a composite matrix of polyglactin 910 fibers (PG910) that has been perforated by needle in a support layer of oxidized regenerated cellulose (ORC). The PG910 side of the matrix is coated with human fibrinogen and thrombin powders in a dry, unreacted state. When the compress containing improved hemostatic biological product is applied to local bleeding, the proteins are readily hydrated (within seconds) resulting in the conversion of fibrinogen to fibrin, forming a fibrin clot. The formation of fibrin on the tissue surface promotes hemostasis and adhesion to the tissue. Importantly, proteins remain in an unreacted state prior to application to tissue. The premature conversion of fibrinogen to fibrin (pre-activation), due to water exposure during production or storage, can have a negative impact on performance and stability.
    [0030] U.S. patent #No. 7,666,803 to Shetty, et al. Reinforced bioabsorable multilayered fabric for use in medical
    11/24 devices are hereby incorporated, as a reference in their entirety for all purposes and teaches a multilayered fabric comprising a first bioabsorbable non-woven material and a second bioabsorbable woven material comprising oxidized polysaccharides.
    [0031] U.S. patent application publication #No. 2009/0246238 A1 by Gorman et al., Entitled REINFORCED BIOABSORBABLE MULTILAYERED HEMOSTATIC WOUND DRESSING is incorporated here, as a reference in its entirety for all purposes and teaches a method to produce a wound dressing in multiple layers that has a first material bioabsorbable nonwoven, one or more second woven material or bioabsorbable mesh fabric, thrombin and / or fibrinogen, comprising the steps of: (a) crimping the polymer fibers or bioabsorbable yarns in the range of about 3.94 to 11, 8 friezes per centimeter (10 to 30 friezes per inch); (b) cutting the crimped fibers or threads to a length of the clamp between about 0.26 and 6.35 centimeters (0.1 and 2.5 inches); (c) carding the clamp to form the first bioabsorbable non-woven material while controlling humidity at about 20 to 60%, at an ambient temperature of about 15 to 24 ° C; (d) fixing the first bioabsorbable nonwoven material to the second woven material or bioabsorbable mesh fabric; (e) apply thrombin and / or fibrinogen to the first bioabsorbable non-woven material. The reference also presents a method for producing a wound dressing that comprises bioabsorbable non-woven material, thrombin and / or fibrinogen, which comprises the steps of: (a) suspending thrombin and / or fibrinogen in a perfluorinated hydrocarbon to form a suspension ; and (b) applying the suspension to the bioabsorbable non-woven material.
    [0032] European patent publication EP 2,052,746 A2,
    12/24 entitled Method for making an bioabsorable hemostat, by Gorman et al., Is incorporated here, as a reference in its entirety for all purposes, and presents a method for manufacturing a wound dressing, characterized by the fact that said method comprises: suspending the thrombin and / or fibrinogen powder in a conductive fluid of perfluorinated hydrocarbon in which it is not soluble, and applying the resulting suspension to a first bioabsorbable non-woven material.
    [0033] U.S. published patent application #No. 2006/0088589 A1, entitled Method for making an absorbable hemostat, by Gorman et al., Is incorporated here, as a reference in its entirety for all purposes, and presents a method for manufacturing a wound dressing, characterized by the fact that said method comprises: suspending the thrombin and / or fibrinogen powder in a fluid perfluorinated hydrocarbon vehicle in which it is not soluble, and applying the resulting suspension to a first absorbable non-woven material.
    [0034] The compresses containing hemostatic biological product produced as described in the references above were used in the experiments performed in the practice of the present invention.
    [0035] The compress matrix component containing hemostatic biological product consists of a mesh ORC support layer under a layer of polyglactin 910 non-woven fibers (PG910). During the matrix manufacturing process, PG910 fibers are carded in a filler and needle punched to the ORC support to produce the matrix for the improved compress containing hemostatic biological product.
    [0036] The biological components of the compress containing hemostatic biological product are preferably the lyophilized forms of the drug substances of human fibrinogen and
    13/24 human thrombin. The fibrinogen and thrombin substances can alternatively be obtained from non-human animal sources or synthetically derived in a manner known in the art. The composition of the compress containing hemostatic biological product used in the experiments will be evident from the data presented below. In addition to the amounts of the active powders as described below, the compresses containing the hemostatic biological product of the invention were optionally also coated with different amounts of PEG3000 and CMC, as described later in the text. The biological components of the fibrinogen-containing compress are preferably lyophilized forms of human fibrinogen and human thrombin. They contain the biologically active ingredients, fibrinogen and thrombin, and other excipients respectively. The compositions of human fibrinogen and human thrombin, as applied to a compress containing fibrinogen, have 2 to 20 mg / cm2 of fibrinogen and 1 to 150 IU / cm2 of thrombin. The composition of the scaffold component or compress matrix containing hemostatic biological product had about 5 to 30 mg / cm 2 of ORC (as a backing layer); and 5 and 30 mg / cm 2 of PG910 (as a conductor layer), with the total matrix weighing about 10 to 60 mg / cm 2 .
    [0037] The compositions of human fibrinogen and human thrombin as applied to the compress containing hemostatic biological product had about 2 to 20 mg / cm2 of fibrinogen and 1 to 150 IU / cm2 of thrombin, with other excipients present, such as calcium chloride , optional arginine, glycine, albumin, mannitol, buffer salts and other optional protein components conventionally found in blood plasma products.
    Example 1. Manufacture of compress test samples containing hemostatic biological product
    14/24 [0038] Following procedures similar to those described in the publication of U.S. patent application #No. 2009/0246238 A1 mentioned above and the European patent publication EP 2,052,746 A2, the poly (lactide-co-glycolide) (PGLA, 90/10 mol / mol) has been melted into fiber. An 80 denier multifilament yarn was consolidated into an 800 denier consolidated yarn. The consolidated wire was crimped at approximately 110 ° C. The crimped wire was cut into a clamp having a length of about 3.18 cm (1.25 '') and 20 grams of the crimped clamp was accurately weighed and evenly arranged on the conducting conveyor of a multi-cylinder carding machine . The environmental conditions (temp: 21 ° C / 55% relative humidity) were controlled. The clamp was then carded to create a non-woven filling. The filling was removed from the pickup cylinder and cut into 4 equal parts. These were swirled in the carder, perpendicular to the direction of collection. After this second pass, the filling was weighed (19.8 g: 99% of fabric yield) and then compacted on felt. The compacted felt was precisely placed on an ORC fabric and firmly fixed through needle drilling. The multilayered fabric was trimmed and washed in 3 separate isopropyl alcohol baths to remove spin finish oil and any machine oils. The washed fabric in multiple layers was dried in an oven at 70 ° C for 30 minutes, cooled and weighed.
    [0039] The multilayered fabric was then cut into pieces of 10.2x10.2 centimeters (4x4 inches). 1.70 grams of CBA-2 (Omrix Biopharmaceuticals, Inc.) with a specific activity (by Clauss) 0.3 g / g and 0.30 g of powder containing thrombin (also from Omrix Biopharmaceuticals, Inc.) and optionally 0, 40 g of polyethylene glycol (PEG) and optionally 0.30 g of carboxymethylcellulose powder (CMC) were mixed thoroughly with
    15/24 about 14 milliliters of non-aqueous fluid, HFE-7000 hydrofluoroether. The watery paste was poured into a tray with a well slightly larger than 10.2x10.2 centimeters (4x4 inches), to accommodate the fabric. The fabric was then applied to the aqueous paste to substantially deposit the powders on the fabric. The resulting multilayered hemostatic compress was air-dried for at least 15 minutes.
    [0040] The test samples containing PEG, with some samples also optionally containing CMC, were then subjected to heat treatment at a temperature exceeding the melting point of the PEG. The samples were placed in a standard vacuum oven with a set temperature of 65 to 70 ° C and heated for approximately 15 minutes. The lyophilized thrombin and fibrinogen particles applied to the bioabsorbable framework, and optionally the CMC particles, are thus fused to the framework by heating to temperature exceeding the PEG melting point. The test samples were then allowed to cool to room temperature.
    [0041] The hydrofluoroether (HFE) fluid was the 3M Novec ™ Engineered Fluid HFE-7000, 1-methoxy-heptafluoropropane which is commercially available from 3M Corporation. HFE-7000 is an inert, non-flammable, fluid with a low boiling point. HFE-7000 is employed as a vehicle for inert application for thrombin and fibrinogen and optionally PEG and / or CMC powder during manufacture, and is substantially completely removed by evaporation during the manufacturing process. Any other inert, non-flammable, low-boiling, non-aqueous fluid could be used as a vehicle of inert application for thrombin and fibrinogen and optionally PEG and / or CMC powder during the manufacture of the inventive hemostatic compresses.
    16/24 [0042] Any powder capable of biologically compatible and bioabsorbable smelting can be used in the practice of the present invention, as long as it is solid at room temperature and has a melting temperature below the temperature of significant denaturation of lyophilized proteins. The preferred binder is PEG which has an average molecular weight of 1,000 to 20,000 Daltons, and more preferably the PEG of 3,000 to 8,000. In the current example, PEG 3000 was used, obtained from Fluka, with a melting point of about 56 to 59 ° C and a number of particles with an average size of 45 microns. In a preferred embodiment, the binder particles are at least 95% per number of particles with a particle size in the range of about 25 to 60 microns, more preferably in the range of 35 to 55 microns.
    [0043] CMC (30,000 clear and stable PA) was obtained from Dow Wolff Cellulosics and had an average particle size of 20 microns.
    [0044] BAC-2 (biologically active component 2) is a blood product that primarily contains fibrinogen, the rest including albumin, buffer salts and other protein components conventionally found in blood plasma products.
    [0045] Three types of swabs samples containing hemostatic biological product were manufactured according to the process described above and tested experimentally:
    [0046] Compresses containing hemostatic biological product containing fibrinogen and thrombin;
    [0047] Compresses containing hemostatic biological product containing fibrinogen, thrombin, and PEG;
    [0048] Compresses containing hemostatic biological product containing fibrinogen, thrombin, PEG, and CMC.
    17/24 [0049] Compresses containing hemostatic biological product containing small amounts of PEG unexpectedly demonstrated improved properties, including improved peel resistance, friability and wettability. These improvements result, functionally, in improved tissue adhesion sealing properties, along with reduced asset friability.
    Example 2. Tissue Detachment Test [0050] The following varying levels of concentrations of the active components were used:
    [0051] Powder containing BAC-2 fibrinogen: 5.0 and 6.7 mg / cm 2 of fibrinogen or 1.27 grams and 1.7 grams of powder containing BAC-2 fibrinogen per 10.2x10.2 cm sample ( 4x4) of the compress containing hemostatic biological product.
    [0052] Powder containing thrombin: 300 mg of powder containing thrombin per 10.2x10.2 cm (4x4) sample of the compress containing hemostatic biological product.
    [0053] PEG: 0; 100, 400 mg per 10.2x10.2 cm 4 X 4) sample of the compress containing hemostatic biological product.
    [0054] CMC: 0; 300 mg per 10.2x10.2 cm (4X4) sample of the compress containing hemostatic biological product.
    [0055] The tissue detachment test was performed as follows: A test sample of a compress containing hemostatic biological product with a width of 1.9 centimeters and about 10.2 centimeters (0.75 inches and about 4 inches) in length was placed on moistened bovine corium tissue. A compression weight applying 23.9 kPa (180 mm Hg) of pressure was immediately placed on top of the test sample of the compress containing hemostatic biological product, and was left for three minutes for incubation and adherence to the tissue. Following incubation, the
    18/24 weight was removed and the compress sample containing hemostatic biological product was attached to a crosshead and then detached from the chorion tissue at 90 degrees and the detachment force was measured using a tensiometer.
    [0056] With reference now to Table 1 and Figure 1, the results of the tissue detachment test are presented.
    Table 1 Results of the Tissue Detachment Test
    Compress sample#At the. BAC2(g) Thrombin(mg) PEG3000(mg) CMC 30k(mg) Average Detachment Resistance (N / m) 9.14 (n = 6) 1,700 300 0 0 94.80 10 1,700 300 100 0 106.87 11 1,700 300 100 300 122.72 12 1,700 300 400 0 120.76 13 1,700 300 400 300 126.00 15 1,270 300 100 0 85.93 17 1,270 300 400 0 95.04 20 1,270 300 100 300 73.00 24 1,270 300 400 300 118.68
    Ό057] The analysis of the data presented in Table 1 indicates that the presence of PEG3000 in the range of 100 to 400 mg significantly optimizes the resistance to the detachment of the compress tissue containing the hemostatic biological product, with more PEG resulting in higher resistance to detachment . The additional analysis of the data indicates that, similarly, with the exception of one test, the presence of 30k of CMC in the amount of 300 mg optimizes the resistance to the detachment of the compress tissue containing the hemostatic biological product.
    [0058] With reference now to Figure 1, individual data points are presented as well as average values for the
    19/24 tissue detachment showing specifically the effects of 400 mg of PEG on tissue detachment. The table presents the data for compress containing hemostatic biological product with nominal amount for fibrinogen and thrombin (1700 mg and 300 mg respectively) in relation to the compress containing hemostatic biological product with an additional 400 mg PEG 3000. The analysis of the data indicates that the presence of PEG3000 significantly improved the resistance to the detachment of the tissue of the compress containing hemostatic biological product.
    Example 3. Leak test [0059] The leak test was performed as follows: A test sample of the compress containing hemostatic biological product was subjected to incubation in porcine plasma while under a compression weight for three minutes. The sample was then placed in a flat metal utensil with a 4.5 mm opening, and a transparent plastic at the top with a corresponding opening was attached to the compress containing hemostatic biological product. The sample was then subjected to porcine plasma released as a hydraulic fluid through the opening at a constant flow rate. Leakage was therefore the only permitted failure mode, and peak pressures were recorded as emissions.
    [0060] With reference to Table 2 and Figure 2, the results of the leak test are presented for two different amounts of BAC2: 1.7 g and 1.27 g of powder containing BAC-2 fibrinogen per 10.2x10 sample, 2 cm (4x4) of the compress containing hemostatic biological product; 0 and 400 mg of PEG3000; and 0 and 300 mg of CMC 30k; all quantities are per 10.2x10.2 cm (4 X 4) sample of the compress containing hemostatic biological product.
    20/24
    Table 2 Leak Test Results
    Compress sample #No. BAC2(g) Trombin a (mg) PEG3000(mg) CMC 30k(mg) Peak LeakMean P (mmHg) 14 (Nominal) 1,700 300 0 0 88 + 27 12 1,700 300 400 0 1226 + 523 13 1,700 300 400 300 1029 + 286 24 1,270 300 400 300 524 + 119
    Ό061] Data analysis indicates that the presence of PEG3000 significantly improves the resistance of the compress containing hemostatic biological product in the leak test (samples 12, 13 and 24) in relation to the compress containing hemostatic biological product without the addition of PEG (sample 14 ). The improvement in mean pressure in the leak test is in the range of about 6 times better to about 14 times better.
    Example 4. Friability Test [0062] Referring to Table 3 and Figure 3, the results of the friability test are presented for four different concentrations of PEG3000 (0, 100, 200, and 400 mg; all concentrations per sample of 10.2x10.2 cm (4 X 4) of the compress containing hemostatic biological product) after handling the compress containing hemostatic biological product.
    [0063] The friability test for weight loss of the powder after handling was performed as follows: A test sample of the compress containing hemostatic biological product was subjected to extreme handling practices employed. The weight of the compress containing a hemostatic biological product of 10.2x10.2 centimeters (4x4 inches) was recorded first. Then, the hemostatic pad was held in one hand about 7.6 centimeters (three inches) above the top of the bench, with the coated side facing down. The compress was cut using surgical scissors in
    21/24 approximately two pieces of 5.1x10.2 centimeters (2x4 inches). The unserved part was dropped into a surgical dressing on the top of the bench. Then each of the two 5.1x10.2 cm (2x4 inch) pieces was held 30.5 cm (12 inch) above the surgical dressing at the top of the bench, and both were dropped three times respectively. The two pieces were weighed on the scale, and a mass scale was conducted to calculate the percentage of powder loss from the original sample of 10.2x10.2 centimeters (4x4 inches). The samples used contained different amounts of PEG and did not contain CMC. The results are shown in Table 3
    Table 3 Friability Test: Weight loss of powder after handling
    Compress sample BAC2 (g) Thrombin(mg) PEG3000(mg) Percentage of Dust Loss 5 1,700 300 0 16.0 6 1,700 300 100 2.6 7 1,700 300 200 2.2 8 1,700 300 400 14 Ό064] Analysis of data from Table 3 indicates that the presence of
    PEG3000 resulted in significantly reduced friability of the compress containing hemostatic biological product in the friability test (samples 6, 7 and 8) in relation to the compress containing hemostatic biological product without the addition of PEG (sample 5), with the loss of powder decreasing by one factor of about 11 in the highest PEG content of 400 mg to about factor 6 in the lowest amount of PEG present which corresponds to 100 mg of PEG.
    [0065] The samples that were subjected to extreme handling practices, as described above, were then tested for tissue detachment as described in example 2. This test demonstrated the synergistic effects of reduced friability and intensified wetting and resistance to detachment of tissue for samples containing PEG amounts of 100, 200 and 400
    22/24 mg per 10.2x10.2 cm (4x4) device in relation to samples containing 0 mg of PEG. The detachment force of the tissue was measured for test samples of the compresses containing hemostatic biological product subjected to extreme standardized handling as described above, and the results are reflecting a synergistic combination of reduced friability and improved adhesion. The analysis of the experimental results presented in Figure 3 indicates that the presence of PEG3000 significantly improved the detachment force after the samples that were subjected to extreme handling. A positive response to PEG measurement was evidenced in the results of tissue detachment, with increasing PEG contents resulting in increased resistance to tissue detachment with an improvement factor of 2 to 2.5 for samples containing 400 mg of PEG in relation to to PEG-free samples. Example 5. Fibrin Gelation Test [0066] A fibrin gelation test that measures the time for a cogular sample of a fibrinogen solution (manual method) was performed as follows: Fibrinogen (ERL FIB3) was dissolved in 200 mM of buffered tris saline solution at a concentration of 10 mg / mL. A sample of a compress containing hemostatic biological product of the invention or a compress containing control hemostatic biological product, measuring about 1 cm 2 , was placed in the bottom of a 12x75 mm borosilicate glass tube. The sample was positioned with the coated side facing upwards in the tube. Then, 2 mL of the 10 mg / mL of the fibrinogen solution was added to the tube, which was covered and then immediately placed in the tube holder in a 37 ° C water bath. After ten seconds, the tube was manually inverted and then placed back on the shelf inside the water bath. Observations were made in each inversion, and the final point was the time in which the complete formation
    23/24 gel was observed, that is, no obvious movement in the fluid volume in the tube.
    [0067] The test results are as follows. For the control of the compress sample containing PEG-free hemostatic biological product and no CMC, the time per sample to co-regulate a fibrinogen solution in two tests was 230 and 270 seconds. For the compress containing hemostatic biological product of the invention containing 400 mg PEG3000 and 300 mg of CMC, in all concentrations per 10.2x10.2 cm (4 X 4) sample of the compress containing hemostatic biological product, the time for the cogular sample a fibrinogen solution in two tests was 90 and 120 seconds.
    [0068] The results indicate faster coagulation of the fibrinogen solution and thus faster wetting / less hydrophobic capacity / better availability of thrombin in compresses containing hemostatic biological product containing PEG and CMC.
    Example 6. Water Intake Study [0069] A water inlet study was performed as follows: A sample of the compress containing hemostatic biological product measuring about 1 cm 2 was subjected to a droplet of water released on its actively coated side with a syringe. The time for the water droplet to travel into the sample was then measured.
    [0070] The test results are as follows. For a compress containing nominal PEG-free hemostatic biological product, the time for the water droplet to travel inside the sample was observed to be in the order of minutes, that is, more than about 1 to 2 minutes. For the compress containing the hemostatic biological product of the invention containing 400 mg of PEG3000 and 300 mg of CMC, the
    24/24 time for the water droplet to travel inside the sample was in the order of milliseconds.
    [0071] The results indicate faster wetting and less hydrophobic capacity of compresses containing hemostatic biological product containing PEG and CMC.
    [0072] Although the above examples demonstrate certain embodiments of the invention, they should not be interpreted as limiting the scope of the invention, but preferably as contributing to a complete description of the invention.
    权利要求:
    Claims (15)
    [1]
    1. Hemostatic compress, characterized by the fact that it comprises:
    a) bioabsorbable framework material;
    b) lyophilized thrombin powder,
    c) lyophilized fibrinogen powder, and
    d) smelting agglutinating powder, said thrombin and fibrinogen powders being disposed in the bioabsorbable framework material and the smelting agglutinating powder links the thrombin powder and the fibrinogen powder to the bioabsorbable framework material, and in which the castable binder is polyethylene glycol polymer with an average molecular weight of 1,000 to 20,000 Daltons.
    [2]
    2. Hemostatic compress, according to claim
    1, characterized by the fact that the castable binder does not completely envelop the lyophilized thrombin powder and / or the lyophilized fibrinogen.
    [3]
    3. Hemostatic compress, according to claim
    2, characterized by the fact that the castable binder is a polyethylene glycol polymer with an average molecular weight of 3,000 to 8,000 Daltons.
    [4]
    4. Hemostatic compress according to claim 1, characterized by the fact that the binder particles have an average particle size number of about 45 microns.
    [5]
    5. Hemostatic compress, according to claim 1, characterized by the fact that the fraction by weight of lyophilized thrombin powder is 10 to 15%, the lyophilized fibrinogen powder is 55 to 85%, and polyethylene glycol is from 2 to 20%, each in relation to the total weight of thrombin, fibrinogen and polyethylene glycol powders in the hemostatic compress.
    Petition 870190040739, of 04/30/2019, p. 4/11
    2/4
    [6]
    6. Hemostatic compress, according to claim
    1, characterized by the fact that the material of the bioabsorbable framework is a natural or synthetic bioabsorbable material, woven or non-woven, or combinations thereof.
    [7]
    7. Hemostatic compress, according to claim
    1, characterized by the fact that the material of the bioabsorbable framework is a bilayer material that comprises a layer of polyglactin 910 non-woven fibers that has been perforated by needle in a layer of oxidized regenerated cellulose mesh, and said powders are arranged only in said layer of polyglactin 910 non-woven fibers.
    [8]
    8. Hemostatic compress, according to claim
    1, characterized by the fact that said lyophilized thrombin powder and said lyophilized fibrinogen powder are bonded to the bioabsorbable framework material by raising the temperature of the hemostatic compress to a point above the melting point of the polyethylene glycol polymer.
    [9]
    9. Hemostatic compress, according to claim
    1, characterized by the fact that said hemostatic compress contains 31 to 93 per cm 2 (200 to 600 IU thrombin per square inch) of said hemostatic compress, as measured when applied, contains fibrinogen in the amount of 3 to 12 mg per cm 2 (20 to 80 mg per square inch) of said hemostatic compress, as measured when applied, and polyethylene glycol is present in the amount of 0.93 to 3.88 per cm 2 (6 to 25 mg per square inch) of said compress hemostatic.
    [10]
    10. Hemostatic compress, according to claim 1, characterized by the fact that it also comprises CMC powder, optionally in which said CMC powder has a mean particle size number of about 20 microns and in which the said CMC powder
    Petition 870190040739, of 04/30/2019, p. 5/11
    3/4 is present in an amount of 2.3 to 3.1 mg per cm 2 (15 to 20 mg per square inch) of said hemostatic compress.
    [11]
    11. Method for the manufacture of a hemostatic compress, characterized by the fact that it comprises the steps of:
    (a) Form a non-aqueous suspension of lyophilized thrombin powder, lyophilized fibrinogen powder and polyethylene glycol powder;
    (b) Apply the suspension to a framework produced with a bio-resorbable material;
    (c) Allow the fluid to evaporate, with the framework carrying a portion of thrombin powder, fibrinogen powder and polyethylene glycol powder;
    (d) Heat the framework to a temperature that exceeds the melting point of the polyethylene glycol powder;
    (e) Cool the framework to a temperature below the melting point of the polyethylene glycol to form the hemostatic compress, and in which the polyethylene glycol powder has an average molecular weight of 1,000 to 20,000 Daltons, and in which said steps (d) and (e) result in the melting of said polyethylene glycol and the solidification of said polyethylene glycol for the melting of said lyophilized thrombin powder and said lyophilized fibrinogen powder on said framework.
    [12]
    12. Method according to claim 11, characterized in that the polyethylene glycol powder has an average molecular weight of 3,000 to 8,000 Daltons and the bioabsorbable framework material is a natural or synthetic bioabsorbable material, woven or non-woven or combinations of these and said polyethylene glycol powders have an average particle size number of about 45 microns.
    [13]
    13. Method according to claim 11, characterized by the fact that the material of the bioabsorbable framework is a bilayer material comprising a layer of nonwoven fibers of
    Petition 870190040739, of 04/30/2019, p. 6/11
    4/4 polyglactin 910 which was perforated by needle in a layer of oxidized regenerated cellulose mesh, said powders being disposed only in said polyglactin 910 non-woven fiber layer.
    [14]
    14. Method, according to claim 11, characterized by the fact that said non-aqueous suspension comprises HFE-7000 and said step of applying the suspension on said framework is carried out by immersing the framework in the suspension or spraying the suspension on the framework.
    [15]
    15. Fibrinogen, characterized by the fact that it is for use in a method to provide hemostatic treatment or tissue sealing at a wound site, where the fibrinogen is in the form of a hemostatic compress, as defined in claim 1, and which comprises the application of the hemostatic compress on the wound site.
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    同族专利:
    公开号 | 公开日
    AU2012346104A1|2014-05-29|
    US20150238366A1|2015-08-27|
    EP2785386A1|2014-10-08|
    US20130149343A1|2013-06-13|
    ES2659457T3|2018-03-15|
    CN103957947A|2014-07-30|
    RU2627426C2|2017-08-08|
    CN103957947B|2018-09-07|
    CA2857138A1|2013-06-06|
    BR112014013337A2|2017-06-13|
    JP6147760B2|2017-06-14|
    RU2014126807A|2016-02-10|
    US9056092B2|2015-06-16|
    AU2012346104B2|2015-11-12|
    EP2785386B1|2018-01-17|
    US9351883B2|2016-05-31|
    AU2015249039B2|2016-06-23|
    RU2646728C1|2018-03-06|
    AU2015249039A1|2015-11-12|
    WO2013082073A1|2013-06-06|
    JP2015500059A|2015-01-05|
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    法律状态:
    2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-01-15| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2019-04-02| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2019-08-20| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2019-10-15| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 28/11/2012, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 28/11/2012, OBSERVADAS AS CONDICOES LEGAIS |
    2021-09-21| B21F| Lapse acc. art. 78, item iv - on non-payment of the annual fees in time|Free format text: REFERENTE A 9A ANUIDADE. |
    2022-01-11| B24J| Lapse because of non-payment of annual fees (definitively: art 78 iv lpi, resolution 113/2013 art. 12)|Free format text: EM VIRTUDE DA EXTINCAO PUBLICADA NA RPI 2646 DE 21-09-2021 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDA A EXTINCAO DA PATENTE E SEUS CERTIFICADOS, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201161566051P| true| 2011-12-02|2011-12-02|
    US61/566,051|2011-12-02|
    US13/324,115|2011-12-13|
    US13/324,115|US9056092B2|2011-12-02|2011-12-13|Hemostatic bioabsorbable device with polyethylene glycol binder|
    PCT/US2012/066737|WO2013082073A1|2011-12-02|2012-11-28|Hemostatic bioabsorbable device with polyethylene glycol binder|
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