hemostatic agents

Abstract

This invention relates to the fields of materials science and medicine, and specifically to a novel hemostatic agent based on hyaluronic acid, which can be particularly used in hemostasis and wound healing medications. The proposed hemostatic agent achieves very rapid hemostasis and exhibits good adhesion to body tissues. This technological achievement is realized by the hemostatic agent being a composition comprising thrombin and hyaluronic acid provided in solid form, characterized in that the thrombin content is not less than 0.01 IU / cm³. 2 And not exceeding 109 IU / cm 2 The hemostatic agent may further contain antibacterial and / or analgesic and / or wound-healing promoting components.

Description

Technical Field

[0001] This invention relates to human necessities, and more specifically, to medical devices and compositions that can be used for hemostasis and wound healing. The hemostatic agents are biocompatible and bioabsorbable due to the combined use of hyaluronic acid (hyaluronic acid, its salts, and solvates) with thrombin (preferably human thrombin). Background Technology

[0002] Hyaluronic acid is a polysaccharide composed of repeating units of D-glucuronic acid and (N)-acetyl-D-glucosamine. Based on the number of repeating units, hyaluronic acid is classified into two categories: low molecular weight hyaluronic acid (upper limit 100,000-300,000 Da) and high molecular weight hyaluronic acid (not less than 500,000 Da, and in some cases exceeding 1,000,000 Da). Hyaluronic acid forms salts and solvates, including solvates of the salts. The term "hyaluronic acid" is generally used to refer to this broader class of compounds, while "hyaluronic acid salts" refers to a subset of various salts containing hyaluronic acid.

[0003] Hyaluronic acid shares some of the same properties as its ammonium, magnesium, and alkali metal salts, especially its water solubility (Petr Snetkov, Kseniia Zakharova, Svetlana Morozkina, Roman Olekhnovich, Mayya Uspenskaya, "Hyaluronic Acid: The Influence of Molecular Weight on the Structure, Physical, Physicochemical and Degradation Properties of Biopolymers", p. 3, document number doi: 10.3390 / polym12081800).

[0004] It is also well known in the art that when a solution of a substance is dried, a trace amount of solvent (i.e., "residual moisture") usually remains in the resulting solid phase. Such substances are generally called solvates. In addition, some substances, including hyaluronic acid, are highly hygroscopic and can even absorb moisture from the air.

[0005] According to scientific literature, hyaluronic acid exists primarily in the form of its high molecular weight sodium salt in mammals, including humans. Hyaluronic acid is continuously reabsorbed and synthesized in the body; up to one-third of the total hyaluronic acid in the human body is reabsorbed and resynthesized daily.

[0006] Scientific literature also records that hyaluronic acid chains can form various secondary and tertiary structures in solution, including water-retaining network structures.

[0007] Industrially, hyaluronic acid is mainly prepared through two routes: extraction from biological sources (primarily rooster combs) and synthesis via biotechnology. Industrially manufactured hyaluronic acid is an amorphous, fine white powder with a particle size ranging from 0.05 mm to 0.25 mm.

[0008] Thrombin is a known protein component in human blood (Earl W. Davie and John D. Kulman, "An Overview of the Structure and Function of Thrombin", document number doi: 10.1055 / s-2006-939550). During blood clotting, thrombin converts fibrinogen into fibrin and triggers other clotting factors. Fibrin forms a net that captures red blood cells, which, together with platelets, form a clot, thus achieving hemostasis.

[0009] Many polysaccharide-based hemostatic agents are known, including chitosan, cellulose, hyaluronic acid, and their derivatives. However, it should be noted that while hyaluronic acid exhibits the highest biocompatibility with humans due to its role in the formation of the extracellular matrix in vertebrates, cellulose and chitosan perform similar functions in plants and crustaceans, fungi, and insects, respectively. Cellulose and chitosan are not naturally occurring in the human body.

[0010] Specifically, a hemostatic sponge is known, which is composed of a biomaterial (porous matrix) and a material that enhances the adhesion of the matrix to organs (US 8,771,258). The porous matrix biomaterial is composed of various substances, including polysaccharides, primarily chitosan. The sponge also contains an adhesive material, which comprises two cross-linking components, primarily polyethylene glycol. In addition to containing exogenous substances, as shown in Example 10, the above-mentioned sponge also has the drawback of relatively slow hemostasis, taking approximately 2 minutes to achieve hemostasis.

[0011] In addition, a hemostatic sponge (US Patent 2021 / 0228764) is known, comprising a composition of oxidized cellulose and a gelatin-free bioadhesive material. The presence of exogenous cellulose constitutes a drawback of this formulation.

[0012] A quick-drying sealant and its preparation and application method are known in the art (WO 2008 / 016983). The composition comprises two crosslinkable components and a hydrogel-forming component, wherein the two crosslinkable components crosslink under suitable conditions to form a porous material. Polyethylene glycol is used as the crosslinkable component. This reagent was used in combination with different concentrations of thrombin (Example 23); however, no additional benefit of thrombin was observed. Disadvantages of this method include: a relatively long time required for hemostasis (1 minute in Example 22 to 2 minutes in Example 26); and the incorporation of polyethylene glycol (a foreign substance to the human body).

[0013] A hemostatic, antibacterial, and wound-healing sponge is known (Patent RU 2 226 406). This sponge is made of denatured collagen (gelatin) and can absorb 45 to 50 times its own weight in blood. The drawbacks of this agent include: swelling, which limits its use near nerves and blood vessels due to the risk of compression and related adverse consequences; and a relatively long hemostatic time (2 to 8 minutes).

[0014] A porous plastic material based on ionic polysaccharides is known (patent RU 2 762 729) for use as a wound and burn dressing. The porous plastic material is made from alginate, pectin, carrageenan, chondroitin sulfate, or chitosan and its derivatives. Hyaluronic acid is not used as a matrix material, and its hemostatic effect is unclear. Notably, according to claim 2, this material is made insoluble in water.

[0015] A bioplastic material with micron and nanostructures is known (Patent RU 2 481 127). This material is based on a nanostructure matrix composed of hyaluronic acid, which contains proteoglycans, glycoproteins, fibrils, and antibacterial agents. This material is used to treat burns; its hemostatic effect is unknown.

[0016] A method for preparing modified hyaluronic acid is known (Patent RU 2 191 782). The resulting chemically modified film promotes the regeneration of active tissues and prevents inflammation and adhesions, but its biodegradability is reduced, and its hemostatic effect is unclear.

[0017] A biomaterial for preventing postoperative adhesions is known, comprising a hyaluronic acid derivative (patent RU 2 177332), particularly its benzyl ester. The hemostatic effect of this material is unclear.

[0018] A wound dressing with hemostatic properties is known (Patent RU 2 624 242). This dressing is composed of bacterial cellulose-based biopolymers and bioactive components, containing no more than 10% hemostatic agent and no more than 3% antibacterial agent. This hemostatic agent has a relatively rapid onset of action. The drawbacks of this method include: the use of cellulose (a material derived from outside the human body); and a relatively high consumption of thrombin, a precious substance extracted from the patient's body, at a dosage of 0.5–150 IU / cm³. 2 .

[0019] A hemostatic composition comprising hyaluronic acid is known (Patent RU 2 486 921). This composition comprises gelatin and at least 10% natural (untreated with chemical crosslinking agents) hyaluronic acid or a derivative thereof. The compound is stable under dry heat conditions of 110 to 200°C. While this composition has the advantage of low swelling, its disadvantage is a relatively slow hemostatic speed, requiring 2 minutes or more to achieve hemostasis.

[0020] A known carrier containing fibrinogen and thrombin (patent US 7,399,483) has similar features to this invention, specifically: 1) it is used for hemostasis; 2) hyaluronic acid can be used as a carrier matrix, among other substances (but its application is not disclosed in specific embodiments: only lyophilized and foamed collagen, gelatin, oxidized cellulose, and polyglycolic acid / dioxanone sponge are used); 3) the carrier is coated with thrombin (1.5–2.5 IU / cm³). 2 ) and fibrinogen (4.3–6.7 mg / cm) 2 The drawbacks of this method include: relatively high thrombin consumption and the use of fibrinogen, both of which are valuable resources derived from the human body. Furthermore, medical literature (VA Gorsky, AM Zryanin, MA Agapov., "Application and Effect of Tahocomb in Hepatobiliary Surgery" / / *Modern Medical Technology*, 2011, Vol. 2, pp. 61-68) points out that another drawback is the relatively long hemostasis time, approximately 3 minutes.

[0021] A molded sheet article is known, comprising various compositions of proteins, aliphatic polyesters and water-soluble polymers, some variants of which have hemostatic effects (EP 2851095). Summary of the Invention

[0022] The disclosure of this invention indicates that not all such materials possess hemostatic effects (specifically, the combination of the water-soluble polymer (hyaluronic acid) and thrombin protected by the claims of this invention also does not exhibit hemostatic effects). Instead, the hemostatic effect originates from specific combinations, such as laminates formed from water-soluble polymers and fibrinogen, aliphatic polyesters and thrombin respectively (Example 21), or pre-laminated articles of the aforementioned layers (Examples 24, 27, 29, 31). Example 30 also claims the hemostatic effect of a composition (the effect appears after 3 minutes) containing thrombin (concentration of 24.2 IU / cm³). 2 ) and aliphatic polyesters.

[0023] However, this document does not provide any examples to demonstrate that a composition consisting solely of a water-soluble polymer and thrombin has hemostatic effects. The document also claims (page 12, paragraph 1) that products molded using the method described in this invention have superior structural properties compared to products prepared by freeze-drying. The hemostatic material claimed in this invention also possesses excellent structural properties and is prepared by freeze-drying, a feature that highlights a significant difference between the material proposed by the applicant and the materials described in the prior art.

[0024] Therefore, the hemostatic material claimed in this invention differs significantly in composition from the molded sheet composition described in patent EP 2851095.

[0025] The claims of patent EP 2851095 do not explicitly define hemostatic effect or the presence of thrombin. This disclosure also lacks information regarding the inclusion of thrombin (concentration range of 0.01 Iu / cm³). 2 Up to 100 IU / cm 2 Information on the hemostatic effect of compositions of hyaluronic acid and other water-soluble polymers. Specifically, page 7 (paragraph 1) of this disclosure states that the thrombin content is less than 0.01 IU / cm. 2 It cannot produce a hemostatic effect at times, but when the level exceeds 100 IU / cm 2 This will cause molded sheet products to become brittle. Furthermore, EP2851095 does not disclose a thrombin content of 0.01 IU / cm³. 2 Up to 100 IU / cm 2 Water-soluble polymers within this range have hemostatic effects. Only (in Example 30) was it confirmed that thrombin (concentration 24.2 IU / cm³) had hemostatic effects. 2 The combination of this polymer with an aliphatic polyester has a hemostatic effect. In other embodiments, which simultaneously comprise a water-soluble polymer that binds fibrinogen and an aliphatic polyester that binds thrombin, Aliphatic polyester The thrombin content in the blood was 14.7 IU / cm³. 2 (Example 20) up to 31.39 IU / cm 2 (Example 15).

[0026] therefore, Composed of water-soluble polymers and Concentration ranges from 0.01 to 100 IU / cm³ 2 of Hemostasis of compositions composed of thrombin Effect This is not described in the prior art (patent EP 2851095). Furthermore, the prior art (Dittrich, M., Snejdrova, E., 2014, "Cyclic Swelling: An Inherent Phenomenon in Biodegradable Polyesters," *Journal of Pharmaceutical Science*, Vol. 103, No. 11, pp. 3560-3566, doi: 10.1002 / jps.24146) discloses that biodegradable aliphatic polyesters are prone to swelling, and this inherent defect is precisely the technical problem that the present invention aims to solve.

[0027] The invention disclosed in patent EP 2851095 also claims protection for a "molded sheet article" (made by laminating, weaving, knitting, or other processing of one or more fibers). The necessity of producing molded products complicates the manufacturing process, a drawback that limits their potential applications, for example, in applications requiring free-flowing materials. Conversely, powdered hemostatic materials are highly valuable for hemostasis in confined areas where sheet articles are difficult to apply. The material claimed in this invention does not require molding and can be prepared into a wider range of ready-to-use forms, thereby broadening the technical application scope of existing hemostatic agents.

[0028] A pharmaceutical composition is known to comprise a polymeric carrier (e.g., hyaluronic acid) and thrombin or fibrinogen, wherein these active components are present within a vitreous carrier that is distributed within or on the surface of a second (polymeric) carrier (WO 2013004838A1). Detailed Implementation

[0029] According to the description of this composition, the time range for achieving hemostasis for moderate bleeding is 2 to 10 minutes (page 24, paragraph 4).

[0030] Thrombin is present in a vitreous carrier and is an essential technical feature of this composition. A disadvantage of this prior art composition is that it takes a relatively long time to achieve hemostasis, i.e., 120 seconds or more.

[0031] The technical problem of this invention is to expand the technical range of available hemostatic agents and shorten the hemostasis time.

[0032] The technical achievement of this invention is the creation of a novel hemostatic agent based on hyaluronic acid and thrombin, which has biocompatibility, bioabsorbability, non-swelling properties, adhesion to body tissues, and shortens the hemostasis time.

[0033] Preliminary experiments were conducted using different forms of hyaluronic acid and different concentrations of thrombin. The results unexpectedly showed that the aforementioned effect could be achieved when the hemostatic agent contained a composition of natural hyaluronic acid and thrombin, both in solid form, with a thrombin content of not less than 0.01 IU / cm² and not more than 10⁹ IU / cm². In some embodiments, hyaluronic acid may be in at least a partially crystalline polymer form. This effect is achieved because hyaluronic acid can bind water in plasma, thereby increasing the concentration of plasma components and promoting more efficient and rapid platelet aggregation; simultaneously, the thrombin in the formulation converts natural fibrinogen into fibrin, forming a fibrin network structure that complements the hyaluronic acid network structure and fixes red blood cells. This process leads to clot (thrombus) formation, thus effectively stopping bleeding. The reactivity of hyaluronic acid and the concentration of thrombin in the reagent are directly related to the rate of thrombus formation and hemostasis. Hemostatic agents may contain other coagulation factors, cell growth factors, antibacterial agents, anesthetics, and / or wound-healing substances (e.g., methyluracil or dextropanthenol) to impart additional properties or enhance their efficacy. The formulation may also contain excipients that do not affect its primary efficacy, such as riboflavin and silicone; these excipients serve to differentiate the active and inverted sides and facilitate application of the formulation to the wound. The agent may be sterilized using methods known to those skilled in the art, such as ethylene oxide or radiofrequency radiation.

[0034] This technical solution is novel and has not been disclosed in patent documents or scientific publications.

[0035] The proposed hemostatic agent can be used, for example, for hemostasis and wound healing.

[0036] The following examples illustrate the invention, features, and advantages of the hemostatic agent.

[0037] Example 1 10 g of biotechnology-derived sodium hyaluronate (molecular weight 11.6 × 10⁻⁶) produced by Swedlight AB, Sweden. 5 The solution was dissolved in 2 L of distilled water and then poured into a tray with an area of ​​1478 cm². Subsequently, PG-9A thrombin reagent solution (potency 9 IU), produced by the Renam Research and Production Department of a cross-regional charity for disabled hemophilia patients, was added to the hyaluronic acid solution and evenly spread on its surface. The resulting solution was frozen to -60°C in the tray and then placed in a freeze dryer for drying; the pressure was gradually increased and the temperature gradually raised from the freezing point to +25°C over 96 hours. In the final stage of drying, the freeze dryer was again evacuated to the maximum achievable vacuum. A uniform white nonwoven mesh was obtained and then cut into 3 cm × 4 cm samples. The thrombin concentration in the composition was 0.006 IU / cm².

[0038] Example 2 10 g of biotechnology-derived sodium hyaluronate (molecular weight 11.6 × 10⁻⁶) produced by Swedlight AB, Sweden. 5 The solution was dissolved in 2 L of distilled water and then poured into a tray with an area of ​​1478 cm². Subsequently, PG-9A thrombin reagent solution (potency 18 IU), produced by the Renam Research and Production Department of a cross-regional charity for disabled hemophilia patients, was added to the hyaluronic acid solution and evenly spread on its surface. The resulting solution was frozen to -60°C in the tray and then placed in a freeze dryer for drying; the pressure was gradually increased and the temperature gradually raised from the freezing point to +25°C over 96 hours. In the final stage of drying, the freeze dryer was again evacuated to the maximum achievable vacuum. A uniform white nonwoven mesh was obtained and then cut into 3 cm × 4 cm samples. The thrombin concentration in the composition was 0.01 IU / cm².

[0039] Example 3 10 g of biotechnology-derived sodium hyaluronate (molecular weight 11.6 × 10⁻⁶) produced by Swedlight AB, Sweden. 5 The solution was dissolved in 2 L of distilled water and then poured into a tray with an area of ​​1478 cm². Subsequently, PG-9A thrombin reagent solution (potency 90 IU), produced by the Renam Research and Production Department of a cross-regional charity for disabled hemophilia patients, was added to the hyaluronic acid solution and evenly spread on its surface. The resulting solution was frozen to -60°C in the tray and then placed in a freeze dryer for drying; the pressure was gradually increased and the temperature gradually raised from the freezing point to +25°C over 96 hours. In the final stage of drying, the freeze dryer was again evacuated to the maximum achievable vacuum. A uniform white nonwoven mesh was obtained and then cut into 3 cm × 4 cm samples. The thrombin concentration in the composition was 0.06 IU / cm².

[0040] Example 4 The experiment was conducted on adult female rabbits. In the experiment, a midline laparotomy was performed first to expose the edge of the liver, thereby simulating liver trauma. Then, the liver parenchyma and liver capsule were cut open, and the compositions of Examples 1-3 were applied to the wound.

[0041] The composition described in Example 1 dissolved, and no obvious changes were observed on the wound surface. No hemostatic effect was observed within 3 minutes.

[0042] The composition described in Example 2 initially adhered to the wound but almost completely dissolved within 15 seconds. The onset of thrombus formation was observed, and hemostasis was achieved after 1.5 minutes.

[0043] The composition described in Example 3 adhered to the wound but did not completely dissolve, achieving hemostasis after 15 minutes.

[0044] Example 5 10 g of biotechnology-derived sodium hyaluronate (molecular weight 11.6 × 10⁻⁶) produced by Swedlight AB, Sweden. 5 ) and 0.2 g benzyl dimethyl monohydrate [3 [(Myristylamino)propyl]ammonium chloride was dissolved in 2 L of distilled water and then poured into a tray with an area of ​​1478 cm². Subsequently, PG-9A thrombin reagent solution (potency 18 IU), produced by the R&D and Production Department of Renam, a cross-regional charity for disabled hemophilia patients, was added to the hyaluronic acid solution and evenly spread on its surface. The resulting solution was frozen to -60°C in the tray and then placed in a freeze dryer for drying; the pressure was gradually increased and the temperature gradually raised from the freezing point to +25°C over 96 hours. In the final stage of drying, the freeze dryer was again evacuated to the maximum achievable vacuum. A uniform white nonwoven mesh was obtained.

[0045] The prepared samples were used for microbial purity testing in accordance with Article 1.2.4.0002.18 of the General Pharmacopoeia (Source: Pharmacopoeia of the Russian Federation (Fourth Edition), Volume 1, Methods for Analytical Drugs). Statistical analysis methods Microbial purity, page 1128.

[0046] Microbial test strains and yeast-like test strains representing various bacterial taxa were used, specifically: Pseudomonas aeruginosa and Escherichia coli representing Gram-negative bacteria; Bacillus cereus representing Gram-positive spore-forming bacteria; Staphylococcus aureus representing Gram-positive bacteria; and Candida albicans representing yeast-like bacteria.

[0047] The test did not detect the growth of any of the aforementioned microorganisms.

[0048] Example 6 10 g of biotechnology-derived sodium hyaluronate (molecular weight 11.6 × 10⁻⁶) produced by Swedlight AB, Sweden. 5 ), 0.2 g benzyl dimethyl monohydrate [3 [(myristoylamino)propyl]ammonium chloride and 20 g of dioxomethyltetrahydropyrimidine were dissolved in 2 L of distilled water and then poured into 3 separate trays, each with an area of ​​1478 cm².

[0049] Subsequently, PG-9A solutions of thrombin reagent for hemostasis testing (potencies of 9, 18, and 90 IU, respectively), produced by the R&D and Production Department of Renam, a cross-regional charity for disabled hemophilia patients, were added to each tray and evenly spread on their surface. The resulting solutions were frozen to -60°C in the trays and then placed in a freeze dryer for drying; the pressure was gradually increased and the temperature was gradually raised from the freezing point to +25°C over 96 hours. In the final stage of drying, the freeze dryer was brought back to its maximum achievable vacuum level. A uniform white nonwoven mesh was obtained, which was then cut into 3 cm × 4 cm samples.

[0050] The obtained samples were tested on a thigh trauma model. Adult female rabbits were used in this experiment. To construct a thigh muscle injury model and simulate significant bleeding, a longitudinal incision was made penetrating the skin, subcutaneous adipose tissue, fascia, and muscle tissue itself. After applying a dressing, the wound was left exposed for 3 days.

[0051] The experimental results are as follows: The thrombin titer was 0.006 IU / cm³. 2 The dressing composition was as follows: it dissolved completely, and no hemostasis was observed within 3 minutes. After 3 days, a small amount of exudate and limited signs of inflammation were observed in the wound.

[0052] The thrombin titer was 0.01 IU / cm. 2 The composition: the dressing completely dissolved, achieving hemostasis within 2 minutes. Undissolved dressing residue was found in the wound 3 days later.

[0053] The thrombin titer was 0.06 IU / cm³. 2 The composition achieves hemostasis within 20 seconds. After 3 days, the wound is completely dry, with no exudate or inflammatory lesions, and undissolved dressing residue is visible inside the wound.

[0054] Example 7 10 g of biotechnology-derived sodium hyaluronate (molecular weight 11.6 × 10⁻⁶) produced by Swedlight AB, Sweden. 5 ), 0.2 g benzyl dimethyl monohydrate [3 [Myristoylamino]propyl]ammonium chloride and 20 g lidocaine were dissolved together in 2 L of distilled water and then poured into a tray with an area of ​​1478 cm². Subsequently, PG-9A thrombin reagent solution (potency 90 IU), produced by the R&D and Production Department of Renam, a cross-regional charity for disabled hemophilia patients, was added to the hyaluronic acid solution and evenly spread on its surface. The resulting solution was frozen to -60°C in the tray and then placed in a freeze dryer for drying; the pressure was gradually increased and the temperature gradually raised from the freezing point to +25°C over 96 hours. In the final stage of drying, the freeze dryer was again evacuated to the maximum achievable vacuum level. A uniform white nonwoven mesh was obtained. A 1 cm × 1 cm sample was cut from this nonwoven mesh.

[0055] The above-mentioned sample was applied to the extraction sockets of teeth 38 and 48 in two adult male patients to achieve hemostasis. Bleeding in both patients stopped within 10–15 seconds. At the follow-up visit 3 days later, the wounds had closed and showed no signs of inflammation, requiring no further anesthesia.

[0056] Example 8 1 g of biotechnology-derived sodium hyaluronate (molecular weight 11.6 × 10⁻⁶) produced by Swedlight AB, Sweden. 5 The PG-9A solution (potency 16,200 IU) for hemostasis testing, produced by the R&D and Production Department of Renam, a cross-regional charity for disabled people with hemophilia, was dissolved in 0.2 L of distilled water and poured into a container with an area of ​​148 cm². 2 The resulting solution was placed on a tray. The tray was frozen to -60°C, and then placed in a freeze dryer for drying; the pressure was gradually increased over 96 hours, and the temperature was gradually raised from the freezing point to +25°C. In the final stage of drying, the freeze dryer was brought back to its maximum achievable vacuum. A dense, uniform white nonwoven web was obtained. The thrombin concentration in the composition was 10⁹ IU / cm³. 2 The nonwoven mesh broke and partially fractured after being bent.

[0057] A piece of the material, approximately 1 cm × 1 cm in size, was torn into pieces and placed in a culture dish containing 6 mL of plasma prepared from control plasma KM-2 produced by Renam's R&D and manufacturing department. A blood clot formed almost instantly, but the material did not completely dissolve. Therefore, when the thrombin concentration reached as high as 10⁹ IU / cm³, [the clot formed]. 2 The material retains its hemostatic properties. It remains solid and can be used as a powder, for example, in laparoscopic surgery.

[0058] Example 9 The samples obtained in Example 2 were subjected to X-ray diffraction analysis using the ARL X'TRA X-ray diffraction system (see figure).

[0059] X-ray diffraction analysis showed that the sample had a partial amorphous structure (represented as a halo in the XPRD diffraction pattern) and a partial crystalline structure, with characteristic diffraction peaks appearing at approximately 24.8° and 43.8° at the 2θ angle, respectively.

[0060] Brief description of the attached figure: The attached figure, entitled "XPRD diffraction pattern of the sample described in this invention", shows the XPRD diffraction pattern of the sample prepared in Example 2.

[0061] Therefore, the above embodiments demonstrate that the hemostatic agent of the present invention has rapid onset of action and excellent hemostatic efficiency. It can be used in various forms and under various conditions, and can be used for hemostasis of infected wounds as well as for prevention of wound infection; moreover, due to its adhesive properties, it is very convenient to use.

Claims

1. A hemostatic agent comprising a composition of solid thrombin and hyaluronic acid, characterized in that, the content of the thrombin is not less than 0.01 IU / cm 2 and not more than 109 IU / cm 2 .

2. The hemostatic agent of claim 1, wherein, The hyaluronic acid portion exists in crystalline form.

3. The hemostatic agent of claim 1, wherein, The hemostatic agent also contains antibacterial and / or analgesic and / or wound-healing components.

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