Synthetic Hemostatic Agents for Surgical Use

Abstract

Disclosed herein is a hemostatic material and methods for making and using same. Disclosed herein is a kit for use in establishing localized hemostasis comprising a gelatin matrix and a synthetically derived hemostatic agent, further comprising at least one administration device, buffer, diluent, syringe, tubing, catheter, forceps, scissors, sterile pad, or lotion.

Description

[Technical field]

[0001] This specification relates to the preparation and use of hemostatic materials.

[0002]

[0002] In wound management, particularly for the management of wounds resulting from traumatic injury or surgery, for example, rapid control of localized bleeding is crucial. Typical methods of controlling bleeding employ the use of "passive" devices, including cotton gauze pads. However, passive devices do not initiate or accelerate blood clotting.

[0003] In contrast to passive devices, hemostatic agents are "active" substances that promote hemostasis through the use of hemostatic agents, such as fibrinogen or thrombin, and actively participate in the coagulation cascade to form fibrin clots. Thrombin is a serine protease that plays a key role in blood clotting (clotting). Thrombin, the main coagulation protease, converts soluble fibrinogen into a fibrin network cross-linked by transglutaminase (FXIII). In addition, thrombin is the most potent activator of platelets by stimulating protease-activated receptors (PARs). Upon activation by thrombin, platelets physically change the configuration of the GP IIb / IIa receptor, providing high affinity binding sites for fibrinogen and forming fibrinogen-crosslinked platelet aggregates.

[0004]

[0004] However, the use of biological clotting factors such as thrombin in hemostatic formulations can increase costs and introduce additional problems such as supply chain impacts, etc. Thus, improved systems, devices, and methods are needed.

[0005] [overview]

[0005] The present disclosure provides a novel class of hemostatic materials with excellent mechanical properties, high fluid uptake, and biocompatibility for use in methods of establishing localized hemostasis, as well as methods of making the same. The disclosed embodiments are also capable of providing an antimicrobial effect. For example, the disclosed methods may be used to prevent, limit, or reduce antimicrobial activity.

[0006] The disclosed hemostatic materials and devices utilize synthetic biopolymers that can be converted into biological agents, such as thrombin, in the hemostatic formulation.

[0007]

[0007] Disclosed embodiments include particles that contain a cross-linked protein matrix and a synthetic biopolymer, such as feracrilum.

[0008] In an embodiment, the hemostatic material is provided in a flowable state such that the hemostatic material is capable of "soaking up" liquid materials, such as blood.

[0009]

[0009] The disclosed embodiments include methods of use. For example, the disclosed methods and devices can be used to reduce or stop bleeding, such as bleeding associated with surgical procedures, injuries, wounds, etc. Embodiments can include treatment of various categories of bleeding, such as:

[0010]

[0010] Grade 1: Mild For example, detachment of the liver capsule. Grade 1 bleeding represents total leakage that overflows over 1-2 minutes after blotting with gauze.

[0011]

[0011] Grade 2: Moderate a. Grade 2 bleeding is visible overflowing after suction and is usually considered an interference with the surgical procedure.

[0012]

[0012] Grade 3: Severe For example, rupture of the venous plexus during a posterior lumbar laminectomy. Grade 3 bleeding occurs immediately after suction and requires intervention to continue the surgical procedure.

[0013]

[0013] Grade 4: Fatal For example, abdominal aortic rupture. Grade 4 bleeding is life-threatening and requires immediate surgical intervention. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows thromboelastography (TEG, a hemostatic test that measures the shear elasticity and kinetics of clot formation, as well as the strength and stability of the formed clot) profiles for a 10% solution of Feracrilam in saline (in triplicate). The polymer alone has poor hemostatic properties. Colors represent triplicate experiments. [Diagram 2] Figure 3 shows TEG profiles (in triplicate) demonstrating that cross-linked gelatin matrix FLOSEAL reconstituted with the disclosed feracrilum formulation is an effective hemostatic agent, resulting in rapid and strong clot formation as shown by the curve. Steeper angles indicate shorter clotting times. This curve compares favorably with the TEG profile obtained for FLOSEAL matrix reconstituted with thrombin solution by the current FLOSEAL IFU depicted in Figure 3. [Diagram 3] FIG. 2 shows FLOSEAL matrix reconstituted with thrombin solution using the current FLOSEAL IFU. In comparison with FIG. 2, FIG. 2 shows a shorter clotting time. [Figure 4] FIG. 1 shows that FLOSEAL matrix reconstituted without a clotting enhancer (i.e., reconstituted with 0.9% saline) has no clotting activity. Detailed Description

[0015]

[0018] In recent years, research efforts regarding hemostatic materials have focused on the use of bioactive agents, specifically hemostatic agents, however, many current formulations and devices still utilize materials derived from animal products.

[0016]

[0019] definition

[0020] "Administration" or "administering" refers to the step of giving (i.e., administering) a hemostatic device, substance, or agent to a subject. The substances disclosed herein can be administered via a number of suitable routes.

[0017]

[0021] "Hemostatic agents" refers to agents capable of initiating and stabilizing the growth of a blood clot during bleeding, and include biologics such as thrombin, small molecules such as tranexamic acid (TXA), polymers such as fecracrilam, peptides such as thrombin receptor activating peptide (TRAP), polysulfonic acid polymers, sulfated icodextrin, sulfated carbohydrates, and inorganic substances such as kaolin.

[0018]

[0022] By "hemostatic material" is meant a material that contains a hemostatic agent in a form suitable for application to a patient.

[0019]

[0023] "Patient" means a human or non-human subject receiving medical or veterinary care.

[0020]

[0024] "Pharmaceutical composition" refers to a formulation that includes an active ingredient. The term "formulation" means that in addition to the active ingredient, there is at least one additional ingredient in the pharmaceutical composition, such as, by way of example and not limitation, albumin (e.g., human serum albumin or recombinant human albumin) and / or sodium chloride. Thus, a pharmaceutical composition is a formulation suitable for diagnostic, therapeutic or cosmetic administration to a subject, e.g., a human patient. A pharmaceutical composition may be, for example, lyophilized or vacuum-dried, a solution formed after reconstitution of a lyophilized or vacuum-dried pharmaceutical composition with saline or water, or a solution that does not require reconstitution. As stated, a pharmaceutical composition may be liquid, semi-solid, or solid. A pharmaceutical composition may be free of animal protein.

[0021]

[0025] "Therapeutically effective amount" refers to the level, amount or concentration of a drug, substance or composition required to achieve a treatment goal.

[0022]

[0026] "Treat," "treating," or "treatment" means the alleviation or reduction (including partial reduction, significant reduction, near complete reduction, and complete reduction), resolution, or prevention (either temporarily or permanently) of symptoms, disease, disorder, or condition to achieve a desired therapeutic or cosmetic result, for example, by healing damaged or injured tissue, or by altering, altering, enhancing, ameliorating, mitigating, and / or beautifying an existing or suffered disease, disorder, or condition.

[0023]

[0027] The present disclosure provides a hemostatic material comprising at least one hemostatic agent and at least one substrate.

[0024]

[0028] Hemostatic agents

[0029] Disclosed hemostatic materials include hemostatic agents, for example, in embodiments, the hemostatic agents can include small molecules such as tranexamic acid (TXA), peptides such as felacrylam, thrombin receptor activating peptide (TRAP), polysulfonic acid polymers, sulfated icodextrin, sulfated carbohydrates, and inorganic materials such as kaolin.

[0025]

[0030] In embodiments, the hemostatic agent can include a synthetic agent, such as an acid biocompatible polymer, such as polyacrylic acid. In embodiments, the hemostatic agent can include a polyacrylic polymer, such as a ferric salt of a polyacrylic polymer, a salt thereof, or an incomplete salt thereof.

[0026]

[0031] In embodiments, the hemostatic agent may include feracrilam.

[0027] [ka]

[0028]

[0032] In disclosed embodiments, the hemostatic agent, e.g., felacrylam, is present in the hemostatic material at a weight or volume percentage, e.g., at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, or more.

[0029]

[0033] substrate

[0034] Disclosed embodiments include carrier matrices, such as granules, including granules containing crosslinked hydrogels that contain at least one biological or non-biological polymer, such as proteins, polysaccharides, and synthetic polymers.

[0030]

[0035] In an embodiment, the matrix polymer is biodegradable. Biodegradable polymers release the drug contained therein as the matrix is ​​consumed or biodegraded during treatment. The polymer is usually selected to degrade into subunits that are biocompatible with the surrounding tissue. The persistence of the biodegradable polymer in vivo depends on the molecular weight and degree of crosslinking of the biodegradable polymer, with higher molecular weights and degrees of crosslinking resulting in longer life spans. Common biodegradable polymers include polylactic acid (PLA, also called polylactide), polyglycolic acid (PGA), copolymers of PLA and PGA, polyamides, and copolymers of polyamides and polyesters.

[0031]

[0036] In various embodiments, the matrix material comprises a recombinant polymer. In particular, the recombinant polymer may be a recombinant human collagen, such as, for example, recombinant human collagen type I, recombinant human collagen type III, or a combination thereof. In one embodiment, the matrix material comprises recombinant human collagen type III. In another embodiment, the matrix material comprises recombinant human collagen type I. For example, recombinant human gelatin may be derived from recombinant human collagen type III. In yet another embodiment, the matrix material may comprise recombinant gelatin derived from recombinant human collagen type I. In a further embodiment, the matrix material comprises recombinant gelatin produced directly by expression of an encoding polynucleotide.

[0032]

[0037] Polysaccharides for use as biocompatible matrix materials in disclosed embodiments can include, for example, cellulose, alkyl cellulose, methyl cellulose, alkyl hydroxyalkyl cellulose, hydroxyalkyl cellulose, cellulose sulfate, carboxymethyl cellulose salts, carboxymethyl cellulose, carboxyethyl cellulose, chitin, carboxymethyl chitin, hyaluronic acid, hyaluronate salts, alginate, alginic acid, propylene glycol alginate, glycogen, dextran, dextran sulfate, curdlan, pectin, pullulan, xanthan, chondroitin, chondroitin sulfate, carboxymethyl dextran, carboxymethyl chitosan, chitosan, heparin, heparin sulfate, heparan, heparan sulfate, dermatan sulfate, keratan sulfate, carrageenan, chitosan, starch, amylose, amylopectin, poly-N-glucosamine, polymannuronic acid, polyglucuronic acid, polyguluronic acid, derivatives of the aforementioned polysaccharides, or combinations thereof.

[0033]

[0038] The biocompatible matrix materials of the present invention may also be based on synthetic polymers. The synthetic absorbable polymers may be aliphatic polyester polymers, aliphatic polyester copolymers, or combinations thereof.

[0034]

[0039] In embodiments, the polymers are crosslinked and capable of hydrating to form hydrogels. Exemplary polymers include proteins selected from gelatin, collagen (e.g., soluble collagen), albumin, hemoglobin, fibrinogen, fibrin, fibronectin, elastin, keratin, laminin, casein, and derivatives and combinations thereof. Alternatively, the polymers can include polysaccharides, such as glycosaminoglycans (e.g., hyaluronic acid or chondroitin sulfate), starch derivatives, cellulose derivatives, hemicellulose derivatives, xylan, agarose, alginates, chitosan, and combinations thereof. As a further alternative, the polymers can include non-biological hydrogel-forming polymers, such as polyacrylates, polymethacrylates, polyacrylamides, polyvinyl polymers, polylactides glycolides, polycaprolactones, polyoxyethylenes, and derivatives and combinations thereof.

[0035]

[0040] Crosslinking of the polymers can be accomplished in any conventional manner. For example, in the case of proteins, crosslinking can be achieved using suitable crosslinking agents, such as aldehydes, sodium periodate, epoxy compounds, and others. Alternatively, crosslinking can be introduced by exposure to radiation, such as gamma radiation or electron beam irradiation. Polysaccharides and non-biological polymers can also be crosslinked using suitable crosslinking agents and radiation. Additionally, non-biological polymers can be synthesized as crosslinked polymers and copolymers. For example, reaction between monounsaturated and polyunsaturated monomers can result in synthetic polymers with controlled crosslinking degrees. Typically, the polymer molecules each have a molecular weight in the range of 20 kD to 200 kD and have at least one linkage to another polymer molecule in the network, often 1 to 5 links, where the actual level of crosslinking is selected in part to provide the desired biodegradation rate in the range described below. An exemplary method for making molecular crosslinked gelatin is as follows.

[0036]

[0041] The gelatin is obtained and placed in an aqueous buffer to form an uncrosslinked hydrogel, typically having a solids content of 1% to 70% w / w, usually 3% to 10% by weight. The gelatin is then typically crosslinked by exposure to either glutaraldehyde (e.g., 0.01% to 0.05% w / w in aqueous buffer at 0° C. to 15° C. overnight), sodium periodate (e.g., 0.05M, held at 0° C. to 15° C. for 48 hours), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ("EDC") (e.g., 0.5% to 1.5% w / w, at room temperature overnight), or by exposure to about 0.3 to 3 megarads of gamma radiation or electron beam irradiation.

[0037]

[0042] Alternatively, the gelatin particles may be suspended in alcohol, preferably methyl or ethyl alcohol, at a solids content of 1 w / w% to 70 w / w%, usually 3 w / w% to 10 w / w%, and crosslinked by exposure to a crosslinking agent, typically glutaraldehyde (e.g., 0.01 w / w% to 0.1 w / w%, overnight at room temperature). In the case of aldehydes, the pH should be kept at about 6 to 11, preferably 7 to 10. In the case of crosslinking with glutaraldehyde, the crosslinks are formed via Schiff bases, which may be stabilized by subsequent reduction, for example by treatment with sodium borohydride. After crosslinking, the resulting granules may be washed in water to the desired degree of hydration in an aqueous medium with the desired buffer and pH, optionally rinsed in alcohol, dried and resuspended. The resulting hydrogel may then be loaded into an applicator of the invention, as described in more detail below. Alternatively, the hydrogel may be mechanically ground before or after crosslinking, also as described in more detail below. In embodiments, genipin may be employed as a cross-linking agent.

[0038]

[0043] The degree of crosslinking of the polymer has an impact on several functional properties of the hydrogel, including extrudability, adsorption of surrounding biological fluids, cohesiveness, space-filling ability, swellability, and ability to adhere to tissue sites. The degree of crosslinking of the polymeric hydrogel composition can be controlled by adjusting the concentration of the crosslinker, controlling exposure to crosslinking radiation, varying the relative amounts of monounsaturated and polyunsaturated monomers, altering reaction conditions, etc. Typically, the degree of crosslinking is controlled by adjusting the concentration of the crosslinker.

[0039]

[0044] The hydrogel compositions of the present invention typically have a solids content in the range of 1% to 70% w / w. Optionally, the composition may include at least one plasticizer, as described in more detail below. Suitable plasticizers include polyethylene glycol, sorbitol, glycerol, and others.

[0040]

[0045] The equilibrium expansion of the crosslinked polymers of the present disclosure can range from 400% to 5000%, 400% to 3000%, 400% to 2000%, typically 400% to 1300%, and preferably 500% to 1100%, depending on the intended use. Such equilibrium expansion can be controlled by varying the degree of crosslinking, which can be achieved by varying the crosslinking conditions, such as the type of crosslinking method, the duration of exposure to the crosslinking agent, the concentration of the crosslinking agent, the temperature of crosslinking, etc.

[0041]

[0046] Exposure to radiation, e.g., gamma radiation, may also be used to sterilize the composition before or after packaging. If the composition is comprised of a radiation sensitive material, it may be necessary to protect the composition from the undesirable effects of sterilizing radiation. For example, in some cases it may be desirable to add a stabilizer, e.g., ascorbic acid, to inhibit degradation of the material and / or further excessive cross-linking by free radical mechanisms.

[0042]

[0047] Method of production

[0048] In an embodiment, a Feracrilam hemostatic agent can be prepared by polymerizing acrylic acid in aqueous solution in the presence of this redox system: FeSO4(NH4)2SO4·6H2O / K2S2O8.

[0043]

[0049] In embodiments, the polymerization may be carried out at a temperature of, for example, 25°C.

[0044]

[0050] In an embodiment, FeSO4(NH4)2SO4·6H2O is in an amount of, for example, 0.8 to 2.2 percent (w / w). The concentration of acrylic acid in the solution may be, for example, 20 volume percent or less, such as 5%, 10%, 15%, 20%, etc. The resulting viscous red mass is dissolved in water at a concentration of, for example, 3 to 4%.

[0045]

[0051] To remove the initiator and unreacted acrylic acid, the ferric salt of incomplete polyacrylic acid (feracrilam) is reprecipitated from the aqueous solution with saturated aqueous sodium chloride, followed by dialysis of the polymer solution to remove trapped NaCl or by passage through a strong base anion exchange resin.

[0046]

[0052] The prepared and purified polymer solution can be diluted, for example to a concentration of 1-2 percent (in which form the solution is usable), or dried at atmospheric pressure and at a temperature of 50°C. The yield of feracrilum is 85-95 percent of the theoretical value, and the salt is a glassy, ​​brittle mass of orange-brown color. It dissolves readily in water, but not in alcohols, dioxane, aliphatic hydrocarbons, and their chlorinated derivatives.

[0047]

[0053] The molecular weight of the active ingredient of the preparation is 7 × 10 5 ~5×10 6 In an embodiment, the iron content in the salt is 0.1 to 0.3 w / w %.

[0048]

[0054] Products / Kits for Sale

[0055] The hemostatic material can be completed as a commercial product by steps commonly practiced in the art, such as appropriate sterilization and packaging steps. For example, the material can be treated with UV / vis irradiation (200-500 nm) using, for example, photoinitiators with different absorption wavelengths (e.g., Irgacure 184, 2959), preferably a water-soluble initiator (Irgacure 2959). Such irradiation is usually performed for irradiation times of 1-60 minutes, although longer irradiation times can also be applied depending on the particular method. The material according to the present disclosure can finally be packaged (e.g., by adding a specific product information leaflet) into a suitable container (box, etc.) in a sterile package to maintain sterility until use.

[0049]

[0056] According to further embodiments, the hemostatic material can also be provided in the form of a kit in combination with other components necessary for administration of the material to a patient. For example, if the substrate material is provided in a flowable dry form (e.g., as granules or as a powder) or as a flowable paste, such material is preferably provided with a liquid component containing a hemostatic agent that can be added shortly before administration to a patient. Buffer components, such as phosphates, carbonates, TRIS, etc., divalent metal ions, preferably Ca 2 ions, or other functional components (if not already present on or in the matrix), such as antibacterial agents, immunosuppressants, anti-inflammatory agents, antifibrinolytic agents such as aprotinin or ECEA, growth factors, vitamins, cells, etc. The kit may further include a means for administering or arranging for administration of the hemostatic agent, such as a syringe, tubing, catheter, forceps, scissors, sterile pads or lotion, etc.

[0050]

[0057] The disclosed kits, e.g., kits for use in surgery and / or in treating injuries and / or wounds, can include the disclosed hemostatic substances and at least one administration device, e.g., a buffer, a syringe, a tube, a catheter, forceps, scissors, gauze, a sterile pad, or a lotion.

[0051]

[0058] In embodiments, the buffer further comprises an antibacterial agent, an immunosuppressant, an anti-inflammatory agent, an antifibrinolytic agent, particularly aprotinin or ECEA, a growth factor, a vitamin, cells, or a mixture thereof. Alternatively, the kit may further comprise an antibacterial agent, an immunosuppressant, an anti-inflammatory agent, an antifibrinolytic agent, particularly aprotinin or ECEA, a growth factor, a vitamin, cells, or a mixture thereof.

[0052]

[0059] The kits are designed in a variety of configurations based on the particular defect that the kit is designed to treat.

[0053]

[0060] How to use

[0061] Methods of use of the disclosed embodiments can include reconstituting a substrate, such as cross-linked gelatin granules, with a solution containing a hemostatic agent, such as felacrylam, followed by application to a site where reduced bleeding is desired. For example, the disclosed methods include application of the disclosed embodiments to a site where reduced bleeding is desired, such as an injury or surgical procedure site. These methods are further described in the Examples below.

[0054]

[0062] The disclosed methods also include the application of a hemostatic agent to the site where it is desired to reduce bacterial growth. For example, felacrylam exhibits antibacterial efficacy comparable to that exhibited by povidone-iodine. EXAMPLES

[0055]

[0063] The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of representative embodiments, and should not be construed as limiting any of the embodiments described herein.

[0056] Example 1 Preparation of Feracrilum

[0064] Freshly distilled acrylic acid (28.8 g (0.4 mol)) is dissolved in 120 ml of distilled water. 1.7 g of K2S2O8 dissolved in 20 ml of water is added to the solution thus obtained. The reaction mixture is then stirred intensively while a solution of 0.24 g of FeSO4(NH4)2SO4·6H2O in 2 ml of water is added to the reaction mixture. The transparent viscous red mass thus produced is dissolved in 1 L of water. With the aim of removing the unreacted acrylic acid, the ferric salt of the incomplete polyacrylic acid (polymer) is reprecipitated from the aqueous solution two or three times using a saturated aqueous sodium chloride solution. The polymer is then dissolved again in water and dialyzed to remove the trapped NaCl. The purified solution is dried at 50 °C. Instead of salting out, the solution may be passed through an anion exchanger.

[0057]

[0065] The iron content of the polymer so produced is 0.11 weight percent.

[0058] Example 2 Preparation of Feracrilum

[0066] Freshly distilled acrylic acid (28.8 g (0.4 mol)) is dissolved in 120 ml of distilled water. 1.7 g of K2S2O8 dissolved in 20 mL of water is then added to the solution. The reaction mixture is stirred vigorously while a solution of 0.43 g of FeSO4(NH4)2SO4·6H2O is added to the reaction mixture. After this stage, the process is carried out as in Example 1.

[0059]

[0067] The iron content of the polymer so produced is 0.2 weight percent.

[0060] Example 3 Preparation of Feracrilum

[0068] Potassium persulfate (0.039 moles) is taken in a vessel containing 14.3 L of distilled water and stirred for 3 minutes. 26.08 moles of acrylic acid solution, previously dissolved in 1.2 L of distilled water, is added. This is further mixed with 0.0592 moles of ferrous ammonium sulfate dissolved in water. This is thoroughly mixed with continuous stirring for 3-4 hours. The mixture is diluted to 25 L and the whole is cooled to room temperature and kept for 2 hours. Resin is then added to remove impurities, the mixture is stirred for 30 minutes, filtered and evaporated under vacuum at 50°C-60°C using a rotary evaporator. The evaporated product is passed through a pulverizer to obtain fine, shiny pink crystals. These crystals are characterized by rapid solubility and meet common pharmaceutical specifications.

[0061]

[0069] Feracrilum has the following specifications: a. Water (Karl Fischer) 1%, max. b. Color concentration of 1% aqueous solution, maximum 0.1 per 1 cm cell at 420 nm; c. Bulk density (g / mL), min 0.6, max 0.85; d. Particle size, average particle size 500 microns.

[0062]

[0070] Feracrilam so prepared is readily soluble in water at 25°C, is readily filterable, and can be easily sterilized.

[0063] Example 4 Preparation of hemostatic material

[0071] Feracrilam prepared in Examples 1-3 is added to a matrix containing cross-linked gelatin granules to form a hemostatic material.

[0064] Example 5 Treatment of injuries

[0072] A traffic accident victim suffers a traumatic injury to the abdomen. To stop blood loss, the disclosed hemostatic material is applied to the injury site. Blood loss is reduced within minutes.

[0065] Example 6 Surgical incision management

[0073] The disclosed hemostatic material is applied to a surgical incision site to stop blood loss. Blood loss is reduced within minutes and the hemostatic material also provides an antibacterial effect.

[0066]

[0074] In conclusion, although aspects of the present specification are emphasized by referring to specific embodiments, it is understood that those skilled in the art will readily recognize that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to the specific methodology, protocols, and / or reagents, etc. described herein. Thus, various modifications or changes to the disclosed subject matter, or alternative configurations of the disclosed subject matter, can be made in accordance with the teachings of the present specification without departing from the spirit of the specification. Finally, the terms used in the present specification are for the purpose of describing specific embodiments only, and are not intended to limit the scope of the present disclosure, which is defined solely by the claims. Thus, the embodiments of the present disclosure are not limited to those precisely as shown and described.

[0067]

[0075] Certain embodiments are described herein, including the best mode known to the inventors for using the methods and devices described herein. Of course, variations of these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, unless otherwise indicated herein or otherwise clearly contradicted by context, this disclosure includes any combination of the above-described embodiments in all possible variations thereof.

[0068]

[0076] Grouping of alternative embodiments, elements or steps of the present disclosure is not to be construed as limiting. Each member of a group may be referred to and claimed individually or in any combination with other members of the group disclosed herein. It is anticipated that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is considered to include the group as modified and thereby conform to the written description of all Markush groups used in the appended claims.

[0069]

[0077] Unless otherwise indicated, all numbers expressing features, items, amounts, parameters, properties, conditions, etc. used in the specification and claims are understood to be modified in all instances by the word "about". As used herein, the term "about" means that the feature, item, amount, parameter, property, or condition so qualified encompasses a range of plus or minus 10 percent above and below the value of the stated feature, item, amount, parameter, property, or condition. Thus, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations and may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the present disclosure are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical range or value inherently encompasses certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of numerical ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated herein as if it were individually referred to herein.

[0070]

[0078] The words "a," "an," "the," and similar referents used in the context of describing this disclosure (particularly in the context of the claims that follow) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "for example") provided herein is intended merely to facilitate a better understanding of the disclosure and does not impose limitations on the scope of what is otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the embodiments disclosed herein.

[0071]

[0079] Particular embodiments disclosed herein may be further limited in the claims using language that the claims consist of, or consist essentially of. When used in a claim, whether as filed or added as an amendment, the transition term "consisting of" excludes any element, step, or material not specified in the claim. The transition term "consisting essentially of" limits the claim to the specified substances or steps and those that do not materially affect the basic and novel characteristic(s). The claimed embodiments of the disclosure are inherently or expressly described and enabled herein.

Claims

1. A hemostatic substance that is flowable in a dry form, comprising a gelatin matrix and a hemostatic agent, the hemostatic agent comprises a biodegradable polymer; the hemostatic agent comprises at least one of (i) feracrilam, (ii) a polyacrylic polymer, (iii) a polysulfonic acid polymer, (iv) a sulfated icodextrin, (v) a sulfated carbohydrate, and (vi) an inorganic material; A hemostatic material wherein the hemostatic agent does not include thrombin.

2. 10. The hemostat of claim 1, wherein the gelatin matrix comprises cross-linked gelatin.

3. 3. The hemostat of claim 2, wherein the cross-linked gelatin comprises gelatin granules.

4. The hemostatic material of any one of claims 1 to 3, wherein the biodegradable polymer comprises feracrilam.

5. A kit for use in establishing local hemostasis, comprising: the kit contains a flowable hemostatic substance in a dry form, the hemostatic substance comprising a gelatin matrix and a hemostatic agent, the hemostatic agent comprising a biodegradable polymer, the hemostatic agent comprising at least one of (i) feracrilam, (ii) a polyacrylic polymer, (iii) a polysulfonic acid polymer, (iv) a sulfated icodextrin, (v) a sulfated carbohydrate, and (vi) an inorganic substance, and the hemostatic agent does not comprise thrombin; The kit further comprises at least one administration device, buffer, diluent, syringe, tubing, catheter, forceps, scissors, sterile pad, or lotion.

6. The kit of claim 5 , wherein the gelatin matrix comprises cross-linked gelatin.

7. The kit of claim 6 , wherein the cross-linked gelatin comprises gelatin granules.

8. The kit of any one of claims 5 to 7, wherein the biodegradable polymer comprises feracrilam.

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