A hemostatic gel and method of making same

Abstract

The application relates to the technical field of medical materials, and discloses a hemostatic gel and a preparation method thereof. The hemostatic gel provided by the application comprises the following raw materials in parts by weight: modified chitosan 20-40 parts, hydrated gelatin particles 35-45 parts, fatty acid salt vesicles 5-20 parts, and a crosslinking agent 1-5 parts. The hemostatic gel takes modified chitosan as the main body, combines the hydrated gelatin particles and the fatty acid salt vesicles to form a ternary synergistic system, and is matched with the crosslinking agent, so that the uniformity and mechanical stability of the gel are ensured, the problem of insufficient hemostatic efficiency caused by single component of a traditional hemostatic agent is overcome, and the hemostatic gel has good biocompatibility and degradability, and is especially suitable for a hemostatic application scene of bleeding in a narrow anatomical space or a high-risk part.

Description

Technical Field

[0001] This invention relates to the field of medical materials technology, specifically to a hemostatic gel and its preparation method. Background Technology

[0002] Currently, commonly used hemostatic materials in clinical practice mainly include gelatin sponges, oxidized cellulose, chitosan, and other polysaccharide derivatives. The hemostatic mechanism of these materials largely relies on the water-absorbing swelling effect, that is, by rapidly absorbing water from the blood, local blood components are concentrated, promoting platelet aggregation and activation of coagulation factors, thereby accelerating thrombus formation. Existing hemostatic products commonly come in forms such as powders, fibers, sponges, and films, and can play a certain hemostatic role in general surgery and wound management. Their preparation methods typically involve chemically cross-linking, freeze-drying, or oxidizing natural polymers (such as gelatin, cellulose, or chitosan), and then processing them into different dosage forms to enhance water absorption and tissue adhesion.

[0003] However, the existing hemostatic materials mentioned above still have significant shortcomings in practical applications: 1) Risk of volume expansion: Gelatin and cellulose materials increase significantly in volume after absorbing blood. When used in confined anatomical spaces (such as the spinal canal, paradural space, cranial cavity, etc.), they may cause mechanical compression of surrounding nerves or blood vessels, leading to nerve dysfunction or local circulatory obstruction; 2) Limited hemostatic stability: Hemostasis relying on simple water absorption and concentration is easily washed away by blood flow in environments with continuous oozing or high-flow-rate bleeding, resulting in weak hemostasis and increasing the risk of rebleeding; 3) Residue and safety issues: Some materials degrade slowly in the body or are difficult to completely absorb, which may cause local inflammation and foreign body reactions, and are difficult to completely remove in complex surgical environments; 4) Limited applicability: Traditional water-absorbing and swelling hemostatic agents are mainly suitable for routine wounds. For irregular deep bleeding or scenarios with confined anatomical spaces, there are problems of inconvenient operation and high risk.

[0004] In summary, existing hemostatic materials, due to their water absorption and swelling properties and potential residual risks, are difficult to achieve safe, rapid, and stable hemostatic effects in the treatment of bleeding in confined anatomical spaces. There is an urgent need to develop new hemostatic materials that do not swell and have strong adaptability. Summary of the Invention

[0005] This invention provides a hemostatic gel and its preparation method to solve the problem that existing hemostatic materials are difficult to guarantee a stable hemostatic effect in the treatment of bleeding in confined anatomical spaces or irregular deep bleeding due to the safety hazards caused by material volume expansion and residue.

[0006] In a first aspect, the present invention provides a hemostatic gel comprising, by weight, the following raw materials: 20-40 parts modified chitosan, 35-45 parts hydrated gelatin particles, 5-20 parts fatty acid salt vesicles, and 1-5 parts crosslinking agent.

[0007] In one optional embodiment, the hemostatic gel, by weight, comprises the following raw materials: 25-35 parts modified chitosan, 35-45 parts hydrated gelatin particles, 8-15 parts fatty acid salt vesicles, 1-3 parts crosslinking agent, 30-60 parts water, 20-80 parts weak acid aqueous solution, and 5-60 parts alcohol aqueous solution. The alcohol aqueous solution is an ethanol aqueous solution, wherein the volume fraction of ethanol is 20-60%.

[0008] In one alternative embodiment, the modified chitosan has a structure represented by any one of the following formulas I to III:

[0009] Formula I, Formula II, Formula III, in, R1 is selected from C8-C18 straight-chain or branched alkyl groups; R2 is selected from C8-C18 straight-chain or branched alkyl groups; R3 is selected from C1-C20 straight-chain or branched alkyl groups.

[0010] In one optional embodiment, R1 is selected from C10-C18 straight-chain or branched alkyl groups; R2 is selected from unsubstituted C10-C18 straight-chain or branched alkyl groups; and R3 is selected from C10-C20 straight-chain or branched alkyl groups.

[0011] In one alternative embodiment, R1 is selected from C15 straight-chain alkyl groups; R2 is selected from C15 straight-chain alkyl groups; and R3 is selected from C16 straight-chain alkyl groups.

[0012] In one optional embodiment, the modified chitosan includes at least one of C5-C20 fatty acid or fatty acid anhydride modified chitosan and C5-C20 haloalkane modified chitosan.

[0013] In one optional embodiment, the modified chitosan includes at least one of palmitic acid or palmitic anhydride or lauric anhydride modified chitosan and 1-bromohexadecane modified chitosan.

[0014] In an optional embodiment, the preparation method of the modified chitosan represented by Formula I includes the following steps: mixing chitosan, fatty acyl chloride and / or fatty acid anhydride for an amidation reaction; specifically, stirring chitosan and glacial acetic acid aqueous solution at a speed of 300-500 rpm for 1-3 h to form a chitosan solution, stirring N,N-dimethylformamide, fatty acyl chloride and / or fatty acid anhydride at a speed of 300-500 rpm for 20-40 min to obtain a dispersion, then controlling the reaction temperature at 25-35℃ to carry out the amidation reaction for 16-20 h, and then dialysis and drying to obtain amidated modified chitosan.

[0015] In one alternative embodiment, the fatty acyl chloride includes at least one of octanoyl chloride, decanoyl chloride, lauroyl chloride, palmitoyl chloride, stearoyl chloride, and oleoyl chloride.

[0016] In one optional embodiment, the mass ratio of chitosan to fatty acyl chloride is 1:1-50, preferably 1:1-5.

[0017] In one alternative embodiment, the fatty acid anhydride includes at least one of caprylic anhydride, capric anhydride, lauric anhydride, palmitic anhydride, and stearic anhydride.

[0018] In one optional embodiment, the mass ratio of chitosan to fatty acid anhydride is 1:1-50, preferably 1:1-5.

[0019] In an optional embodiment, the preparation method of the modified chitosan represented by Formula II includes the following steps: mixing chitosan, halogenated hydrocarbons and / or epoxides, and carrying out an etherification reaction under alkaline conditions; specifically, stirring chitosan and isopropanol aqueous solution at 300-500 rpm for 20-40 min, adding sodium hydroxide solution to fully deprotonate the hydroxyl groups of chitosan, giving it good nucleophilicity; then adding halogenated hydrocarbons and / or epoxides, maintaining the reaction system at 50-70℃ and 300-500 rpm for 6-8 h to carry out the etherification reaction; after the reaction, dialysis and drying are performed to obtain etherified modified chitosan.

[0020] In one alternative embodiment, the haloalkane includes at least one selected from chlorooctane, bromooctane, chlorodecane, bromodecane, chlorododecane, bromododecane, and 1-bromohexadecane.

[0021] In one optional embodiment, the mass ratio of chitosan to haloalkanes is 1:0.5-40, preferably 1:0.5-5.

[0022] In one alternative embodiment, the epoxide comprises at least one of epoxide octane, epoxide decane, epoxide dodecane, and epoxide ethyl ether.

[0023] In one optional embodiment, the mass ratio of chitosan to epoxide is 1:0.5-40, preferably 1:0.5-5.

[0024] In an optional embodiment, the preparation method of the modified chitosan shown in Formula III includes the following steps: mixing chitosan, fatty acids and / or aromatic carboxylic acids, and carrying out an esterification reaction in the presence of an activator; specifically, stirring chitosan and an aqueous ethanol solution at 25-35°C and 300-500 rpm magnetically for 1-3 hours until a uniform chitosan dispersion is formed; pre-dissolving N-hydroxysuccinimide (NHS), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC•HCl), fatty acids and / or aromatic carboxylic acids in ethanol, and then slowly adding them to the chitosan dispersion; carrying out an esterification reaction by continuous stirring at 25-35°C and 300-500 rpm for 5-7 hours; and then dialysis and drying after the reaction to obtain esterified modified chitosan.

[0025] In one alternative embodiment, the fatty acid includes at least one of caprylic acid, capric acid, lauric acid, palmitic acid, stearic acid, and oleic acid.

[0026] In one optional embodiment, the mass ratio of chitosan to fatty acid is 1:1-60, preferably 1:1-5.

[0027] In one optional embodiment, the aromatic carboxylic acid includes at least one of benzoic acid, p-hydroxybenzoic acid, p-methoxybenzoic acid, phthalic acid, terephthalic acid, and naphtholic acid.

[0028] In one optional embodiment, the mass ratio of chitosan to aromatic carboxylic acid is 1:1-60, preferably 1:1-5.

[0029] In one alternative embodiment, the activator comprises N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide.

[0030] In one optional embodiment, the chitosan has a weight-average molecular weight of 150 kDa-300 kDa.

[0031] In one optional embodiment, the method for preparing the hydrated gelatin particles includes the following steps: mixing gelatin and water, cooling and drying to obtain hydrated gelatin particles.

[0032] In one optional embodiment, the particle size D50 of the hydrated gelatin particles is 50-200 μm.

[0033] In one optional embodiment, the mass ratio of gelatin to water is 1:0.8-3, preferably 1:1-3.

[0034] In one optional embodiment, the mixing temperature is 40-60°C and the time is 0.5-2 hours.

[0035] In one alternative implementation, the drying method includes freeze drying and / or spray drying.

[0036] In one optional embodiment, the freeze-drying temperature is -60 to -50°C, and the time is 6 to 48 hours.

[0037] In one optional embodiment, the spray drying temperature is 40-60°C and the time is 0.5-2 hours.

[0038] In one optional embodiment, the method for preparing the fatty acid salt vesicles includes the following steps: mixing fatty acids and an aqueous ethanol solution, adding an alkali metal hydroxide solution to react, dispersing, obtaining a fatty acid salt vesicle dispersion, and drying to obtain fatty acid salt vesicles.

[0039] In one alternative embodiment, the fatty acids include C12-C18 saturated fatty acids and / or unsaturated fatty acids.

[0040] In one alternative embodiment, the saturated fatty acid includes at least one of stearic acid, palmitic acid, lauric acid, and myristic acid.

[0041] In one alternative embodiment, the unsaturated fatty acid includes at least one of oleic acid, linoleic acid, and linolenic acid.

[0042] In one optional embodiment, the volume fraction of ethanol in the aqueous ethanol solution is 20-60%.

[0043] In one optional embodiment, the ratio of the fatty acid to the aqueous ethanol solution is 1:0.5-20, in g:mL.

[0044] In one alternative embodiment, the alkali metal hydroxide includes sodium hydroxide and / or potassium hydroxide.

[0045] In one optional embodiment, the ratio of the alkali metal hydroxide to the fatty acid is 0.5-5:1-20, in mL:g.

[0046] In one alternative embodiment, the mixing temperature is 30-50°C and the time is 20-40 minutes.

[0047] In one alternative implementation, the dispersion is performed using ultrasound.

[0048] In one optional embodiment, the temperature of the ultrasound is 30-50°C, the duration is 5-15 minutes, and the power is 100-300W.

[0049] In one optional embodiment, the drying process involves pre-freezing at -50 to -40°C for 4-12 hours, freeze-drying at -30 to -20°C for 8-16 hours, and then drying at 20 to 25°C for 2-4 hours.

[0050] In one optional embodiment, the crosslinking agent includes at least one of sodium borate, sodium citrate, sodium bicarbonate, sodium gluconate, sodium fumarate, and sodium tartrate.

[0051] Secondly, the present invention provides a method for preparing the above-mentioned hemostatic gel, comprising the following steps: Step S1: The modified chitosan is first mixed with a weak acid aqueous solution to obtain a modified chitosan solution; the fatty acid salt vesicles are second mixed with an ethanol aqueous solution to obtain a fatty acid salt vesicle solution. Step S2: Mix the modified chitosan solution with hydrated gelatin particles in the third stage, add fatty acid salt vesicle solution for the fourth stage, and disperse to obtain a composite mixture; or, mix the hydrated gelatin particles with fatty acid salt vesicle solution in the third stage, add the modified chitosan solution for the fourth stage, and disperse to obtain a composite mixture. Step S3: The composite mixture is subjected to a cross-linking reaction with a cross-linking agent to obtain a hemostatic gel.

[0052] In one alternative embodiment, in step S1, the weak acid includes at least one of acetic acid, lactic acid, and citric acid.

[0053] In one optional embodiment, the weak acid accounts for 0.5-2 wt% of the mass percentage of the weak acid aqueous solution.

[0054] In one optional embodiment, in step S1, the mass ratio of the modified chitosan to the weak acid aqueous solution is 1:1-2.

[0055] In one optional embodiment, in step S1, the ratio of the fatty acid salt vesicles to the aqueous ethanol solution is 1:1-3, in g:mL.

[0056] In one optional implementation, in step S1, the temperature of the first mixing is 25-40°C, and the time is 1-3 hours.

[0057] In one optional implementation, in step S2, the temperature of the third mixing is 30-40°C and the time is 20-60 min.

[0058] In one optional implementation, in step S2, the temperature of the fourth mixing is 30-50°C and the time is 20-40 minutes.

[0059] In an alternative implementation, in step S2, the dispersion is performed using ultrasound.

[0060] In one optional embodiment, the temperature of the ultrasound is 30-50°C, the duration is 5-10 minutes, and the power is 100-300W.

[0061] In one optional embodiment, in step S3, the crosslinking reaction is carried out at a temperature of 20-35°C for a time of 0.5-2 hours.

[0062] In one alternative embodiment, the crosslinking reaction is further preceded by a step of adjusting the pH to 6-7.

[0063] In one optional embodiment, the crosslinking reaction further includes a step of curing the resulting hemostatic gel by allowing it to stand at 2-8°C for 8-24 hours. After curing, the hemostatic gel is placed into a sterile container (such as a syringe) to obtain a ready-to-use hemostatic gel product.

[0064] The technical solution of this invention has the following advantages: 1. The hemostatic gel provided by the present invention comprises the following raw materials in parts by weight: 20-40 parts of modified chitosan, 35-45 parts of hydrated gelatin particles, 5-20 parts of fatty acid salt vesicles, and 1-5 parts of crosslinking agent. The hemostatic gel provided by this invention utilizes a three-dimensional network structure of modified chitosan and hydrated gelatin particles, combined with fatty acid salt vesicles to improve interfacial wettability and adhesion, forming a unique composite gel system when combined with a crosslinking agent. This system can rapidly induce blood cell aggregation and form a stable hemostatic barrier in a bleeding environment. Its hemostatic mechanism is achieved by inducing rapid erythrocyte aggregation through hydrophobic groups on modified chitosan, enhancing the capture and support capacity of blood cells through hydrated gelatin particles, and optimizing the interaction between the blood and gel interface through fatty acid salt vesicles. This allows for the formation of a stable hemostatic gel in a short time, maintaining efficient and rapid hemostasis even under continuous bleeding or high-flow-rate blood conditions. Furthermore, this hemostatic gel exhibits a very low expansion rate during hemostasis, maintaining volume stability and avoiding pressure on nerves or blood vessels caused by gel volume expansion. It also possesses high adhesion strength, strong mechanical properties, and good hemostatic stability. This hemostatic gel is based on modified chitosan, combined with hydrated gelatin particles and fatty acid salt vesicles to form a ternary synergistic system. With the addition of a cross-linking agent, it not only ensures the uniformity and mechanical stability of the gel, but also overcomes the problem of insufficient hemostatic efficiency caused by traditional hemostatic agents due to single components. It also has good biocompatibility and biodegradability, making it particularly suitable for hemostatic applications in confined anatomical spaces or high-risk sites.

[0065] 2. The preparation method of the hemostatic gel provided by the present invention includes the following steps: S1 step: first mixing modified chitosan with a weak acid aqueous solution to obtain a modified chitosan solution; second mixing fatty acid salt vesicles with an ethanol aqueous solution to obtain a fatty acid salt vesicle solution; S2 step: third mixing the modified chitosan solution with hydrated gelatin particles, adding the fatty acid salt vesicle solution for a fourth mixing, and dispersing to obtain a composite mixture; or, third mixing the hydrated gelatin particles with the fatty acid salt vesicle solution, adding the modified chitosan solution for a fourth mixing, and dispersing to obtain a composite mixture; S3 step: cross-linking the composite mixture with a cross-linking agent to obtain a hemostatic gel. This preparation method is simple, uses widely available raw materials, is low in cost, and the final hemostatic gel has good mechanical properties, stable hemostatic effect, can be degraded in vivo, and does not produce harmful residues. Detailed Implementation

[0066] The following embodiments are provided to better understand the present invention, but the following embodiments do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0067] Unless otherwise specified, all experimental steps or conditions in the examples were performed according to conventional experimental procedures and conditions in the art. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0068] The reagents used in the embodiments and comparative examples of this invention are as follows: Chitosan: Purchased from Zhejiang Jinke Pharmaceutical Co., Ltd., product number: LC03499, batch number: M-PK-2408001, weight average molecular weight is 200kDa; Gelatin: Purchased from Rousselot Gelatin Ltd., item number: PN05063, batch number: 4070552, specification: Rousselot 220PS8.

[0069] Test method for particle size D50: Disperse hydrated gelatin particles in water and place them in a laser particle size analyzer. The instrument calculates the particle size distribution by detecting the scattered light and obtains the particle size distribution curve.

[0070] Example 1 This embodiment provides a hemostatic gel comprising the following ingredients: 30g palmitic anhydride amidated chitosan, 40g hydrated gelatin particles, 10g sodium oleate vesicles, and 1.5g sodium borate. The preparation method of palmitic anhydride amidated chitosan is shown in the following formula:

[0071] 43g of chitosan was added to 4.3L of 1% (w / w) glacial acetic acid aqueous solution and stirred at 400rpm for 2h to form a homogeneous and transparent chitosan solution. 64.5g of palmitic anhydride was dispersed in 645mL of N,N-dimethylformamide (DMF) and stirred at 400rpm for 30min to homogenize it, obtaining a palmitic anhydride dispersion. The palmitic anhydride dispersion was slowly added dropwise to the chitosan solution at 400rpm, and the reaction temperature was controlled at 30℃ for an amidation reaction for 18h. After the reaction, the resulting reaction solution was transferred to a dialysis bag, which was then immersed in deionized water for dialysis to remove free palmitic anhydride and small molecule byproducts. The dialysis membrane was a Spectra / Por 6. A regenerated cellulose dialysis membrane with a molecular weight cutoff of 14000 Da and a deionized water to reaction solution volume ratio of 80:1 was used. Dialysis was performed at room temperature for 48 hours, with the deionized water replaced every 8 hours. After dialysis, the retained solution in the dialysis bag was pre-frozen at -40°C for 6 hours and then placed in a freeze dryer. The solution was freeze-dried at a cold trap temperature of -40°C and a vacuum degree of 10 Pa for 72 hours to obtain palmitic anhydride amidated chitosan.

[0072] Preparation method of hydrated gelatin particles: Dissolve 40g of gelatin in 45g of deionized water and stir at 50℃ for 1h to obtain gelatin solution; after cooling to room temperature, freeze dry at -50℃ for 12h to obtain hydrated gelatin particles with a particle size D50 of 100μm.

[0073] Preparation method of sodium oleate vesicles: Dissolve 10g of oleic acid in 10mL of 40% (v / v) ethanol aqueous solution and stir at 40℃ for 30min to ensure complete dissolution; slowly add 1.5mL of 10% NaOH aqueous solution for neutralization to form a milky white dispersion; then sonicate at 35℃ and 200W for 8min to obtain a stable sodium oleate vesicle dispersion; pre-freeze the sodium oleate vesicle dispersion at -50℃ for 8h, then freeze-dry at -20℃ for 10h, and then dry at 25℃ for 2h to obtain stable and dried sodium oleate vesicles.

[0074] This embodiment also provides a method for preparing a hemostatic gel, including the following steps: (1) Add 30g of the above palmitic anhydride amidated chitosan to 45g of 1wt% acetic acid aqueous solution and stir magnetically at 30℃ for 2h to obtain a transparent and uniform modified chitosan solution; dissolve 10g of the above sodium oleate vesicles in 10mL of 40% (v / v) ethanol aqueous solution to obtain sodium oleate vesicle solution. (2) Take 40g of the above hydrated gelatin particles and slowly add them to the modified chitosan solution. Stir at 35°C for 40min, then add sodium oleate vesicle solution and continue stirring at 35°C for 30min. Then, ultrasonically disperse at 35°C and 200W for 8min to obtain a uniform composite mixture. (3) Add 1.5g of sodium borate to the composite mixture and adjust the pH of the solution to 6.5 with 0.1M hydrochloric acid solution; react at 25℃ for 1h to obtain hemostatic gel.

[0075] (4) Place the obtained gel in a 4°C environment and let it stand for 12 hours to fully solidify. Finally, put it into a sterile syringe to obtain the hemostatic gel product.

[0076] Example 2 This embodiment provides a hemostatic gel comprising the following raw materials: 25g palmitate-esterified chitosan, 35g hydrated gelatin particles, 8g sodium oleate vesicles, and 2g sodium borate. The preparation method of palmitate-esterified chitosan is shown in the following formula:

[0077] 35g of chitosan was dispersed in 3.6L of 60% (v / v) ethanol aqueous solution and stirred magnetically at 30℃ and 400rpm for 2h until a homogeneous chitosan dispersion was formed. 43.8g of palmitic acid, 17.5g of N-hydroxysuccinimide (NHS), and 35g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC•HCl) were pre-dissolved in 200mL of ethanol and then slowly added to the chitosan dispersion. Esterification was carried out by continuous stirring at 30℃ and 400rpm for 6h. After the reaction, the resulting reaction solution was transferred to a dialysis bag, which was then immersed in deionized water for dialysis to remove free palmitic acid and small molecule byproducts. The dialysis membrane was a Spectra / Por 6. A regenerated cellulose dialysis membrane with a molecular weight cutoff of 14000 Da and a deionized water to reaction solution volume ratio of 80:1 was used. Dialysis was performed at room temperature for 48 hours, with the deionized water replaced every 8 hours. After dialysis, the retained solution in the dialysis bag was pre-frozen at -40℃ for 6 hours and then placed in a freeze dryer. The solution was freeze-dried at a cold trap temperature of -40℃ and a vacuum degree of 10 Pa for 72 hours to obtain palmitate-esterified chitosan.

[0078] Preparation method of hydrated gelatin particles: Dissolve 35g of gelatin in 45g of deionized water and stir at 40℃ for 2h to obtain gelatin solution; after cooling to room temperature, freeze dry at -50℃ for 12h to obtain hydrated gelatin particles with a particle size of 120μm.

[0079] Preparation method of sodium oleate vesicles: Dissolve 8g of oleic acid in 8mL of 60% (v / v) ethanol-water mixture and stir at 50℃ for 20min to ensure complete dissolution; slowly add 2mL of 10% NaOH aqueous solution for neutralization to form a milky white dispersion; then sonicate at 40℃ and 100W for 15min to obtain a stable sodium oleate vesicle dispersion; pre-freeze the sodium oleate vesicle dispersion at -45℃ for 4h, then freeze-dry at -25℃ for 8h, and then dry at 20℃ for 4h to obtain stable and dried sodium oleate vesicles.

[0080] This embodiment also provides a method for preparing a hemostatic gel, including the following steps: (1) Add 25g of the above palmitate esterified chitosan to 40g of 2wt% acetic acid aqueous solution and stir magnetically at 40℃ for 1h to obtain a transparent and uniform modified chitosan solution; dissolve 8g of the above sodium oleate vesicles in 16mL of 40% (v / v) ethanol aqueous solution to obtain sodium oleate vesicle solution. (2) Take 35g of the above hydrated gelatin particles and slowly add them to the modified chitosan solution. Stir at 40°C for 20min, then add sodium oleate vesicle solution and continue stirring at 40°C for 20min. Then, ultrasonically disperse at 40°C and 100W for 5min to obtain a uniform composite mixture. (3) Add 2g of sodium borate to the composite mixture and adjust the pH of the solution to 7 with 0.1M hydrochloric acid solution; react at 30℃ for 0.5h to obtain hemostatic gel; (4) Place the obtained gel in an 8°C environment and let it stand for 24 hours to fully solidify. Finally, put it into a sterile syringe to obtain the hemostatic gel product.

[0081] Example 3 This embodiment provides a hemostatic gel comprising the following raw materials: 35g hexadecyl etherified chitosan, 45g hydrated gelatin particles, 15g sodium oleate vesicles, and 3g sodium borate. The preparation method of hexadecyl etherified chitosan is shown in the following formula:

[0082] 50 g of chitosan was added to 3.75 L of 80% (v / v) isopropanol aqueous solution and stirred at 400 rpm for 30 min. Then, 200 mL of 40% (w / v) sodium hydroxide solution was added to fully deprotonate the hydroxyl groups of the chitosan, giving it good nucleophilicity. Next, 50 g of 1-bromohexadecane was added, and the reaction system was stirred at 60 °C and 400 rpm for 7 h to carry out the etherification reaction. After the reaction was completed, the resulting reaction solution was transferred to a dialysis bag, which was then immersed in deionized water for dialysis to remove unreacted raw materials and small molecule byproducts. The dialysis membrane was a Spectra / Por 6. A regenerated cellulose dialysis membrane with a molecular weight cutoff of 14000 Da and a deionized water to reaction solution volume ratio of 80:1 was used. Dialysis was performed at room temperature for 48 hours, with the deionized water replaced every 8 hours. After dialysis, the retained solution in the dialysis bag was pre-frozen at -40°C for 6 hours and then placed in a freeze dryer. The solution was freeze-dried at a cold trap temperature of -40°C and a vacuum degree of 10 Pa for 72 hours to obtain hexadecyl etherified chitosan.

[0083] Preparation method of hydrated gelatin particles: Dissolve 45g of gelatin in 50g of deionized water and stir at 60℃ for 0.5h to obtain gelatin solution; after cooling to room temperature, freeze dry at -55℃ for 6h to obtain hydrated gelatin particles with a particle size D50 of 80μm.

[0084] Preparation method of sodium oleate vesicles: 15g of oleic acid was dissolved in 20mL of 20% (v / v) ethanol-water mixture and stirred at 30℃ for 40min to ensure complete dissolution; 4mL of 10% NaOH aqueous solution was slowly added dropwise for neutralization to form a milky white dispersion; then, the dispersion was sonicated at 50℃ and 300W for 5min to obtain a stable sodium oleate vesicle dispersion; the sodium oleate vesicle dispersion was pre-frozen at -40℃ for 12h, then freeze-dried at -30℃ for 16h, and then dried at 23℃ for 3h to obtain stable dried sodium oleate vesicles.

[0085] This embodiment also provides a method for preparing a hemostatic gel, including the following steps: (1) Add 35g of the above hexadecyl etherified chitosan to 50g of 0.5wt% acetic acid aqueous solution and stir magnetically at 25℃ for 3h to obtain a transparent and uniform modified chitosan solution; dissolve 15g of the above sodium oleate vesicles in 45mL of 40% (v / v) ethanol aqueous solution to obtain sodium oleate vesicle solution. (2) Take 45g of the above hydrated gelatin particles and slowly add them to the modified chitosan solution. Stir at 30°C for 60min, then add sodium oleate vesicle solution and continue stirring at 30°C for 40min. Then, at 30°C, use ultrasonic dispersion at 300W for 10min to obtain a uniform composite mixture. (3) Add 3g of sodium borate to the composite mixture and adjust the pH of the solution to 6 with 0.1M hydrochloric acid solution; react at 20℃ for 2h to obtain hemostatic gel; (4) Place the obtained gel in a 2°C environment and let it stand for 8 hours to fully solidify. Finally, put it into a sterile syringe to obtain the hemostatic gel product.

[0086] Example 4 This embodiment provides a hemostatic gel comprising the following ingredients: 28g palmitic anhydride amidated chitosan, 33g hydrated gelatin particles, 7g sodium oleate vesicles, and 1.5g sodium borate. The preparation method of palmitic anhydride amidated chitosan is the same as in Example 1, except that the amount of raw materials is different. In this example, the amount of raw materials is 40g chitosan, 4L 1% (w / w) glacial acetic acid aqueous solution, 60g palmitic anhydride, and 600mL N,N-dimethylformamide (DMF).

[0087] Preparation method of hydrated gelatin particles: Dissolve 33g of gelatin in 38g of deionized water and stir at 50℃ for 1h to obtain gelatin solution; after cooling to room temperature, dry at -50℃ for 10h to obtain hydrated gelatin particles with a particle size D50 of 150μm.

[0088] Preparation method of sodium oleate vesicles: Dissolve 7g of oleic acid in 12mL of 40% (v / v) ethanol-water mixture and stir at 40℃ for 30min to ensure complete dissolution; slowly add 1mL of 10% NaOH aqueous solution for neutralization to form a milky white dispersion; then sonicate at 35℃ and 200W for 8min to obtain a stable sodium oleate vesicle dispersion; pre-freeze the sodium oleate vesicle dispersion at -50℃ for 8h, then freeze-dry at -20℃ for 10h, and then dry at 25℃ for 2h to obtain stable and dried sodium oleate vesicles.

[0089] This embodiment also provides a method for preparing a hemostatic gel, including the following steps: (1) Add 28g of the above palmitic anhydride amidated chitosan to 38g of 1wt% acetic acid aqueous solution and stir magnetically at 30℃ for 2h to obtain a transparent and uniform modified chitosan solution; dissolve 7g of the above sodium oleate vesicles in 10mL of 40% (v / v) ethanol aqueous solution to obtain sodium oleate vesicle solution. (2) Take 33g of the above hydrated gelatin particles and slowly add them to the modified chitosan solution. Stir at 35°C for 40min, then add sodium oleate vesicle solution and continue stirring at 35°C for 30min. Then, disperse the mixture at 50°C and 200W for 8min to obtain a uniform composite mixture. (3) Add 1.5g of sodium borate to the composite mixture and adjust the pH of the solution to 6.5 with 0.1M hydrochloric acid solution; react at 25℃ for 1h to obtain hemostatic gel; (4) Place the obtained gel in a 4°C environment and let it stand for 12 hours to fully solidify. Finally, put it into a sterile syringe to obtain the hemostatic gel product.

[0090] Example 5 This embodiment provides a hemostatic gel comprising the following ingredients: 38g of palmitic anhydride amidated chitosan, 48g of hydrated gelatin particles, 18g of potassium palmitate vesicles, and 4g of sodium citrate. The preparation method of palmitic anhydride amidated chitosan is the same as in Example 1, except that the amount of raw materials is different. In this example, the amount of raw materials is 54g chitosan, 5.4L 1% (w / w) glacial acetic acid aqueous solution, 81g palmitic anhydride, and 810 mL N,N-dimethylformamide (DMF).

[0091] Preparation method of hydrated gelatin particles: Dissolve 48g of gelatin in 55g of deionized water and stir at 50℃ for 1h to obtain gelatin solution; after cooling to room temperature, dry at -50℃ for 10h to obtain hydrated gelatin particles with a particle size D50 of 90μm.

[0092] Preparation method of potassium palmitate vesicles: 18g of palmitic acid was dissolved in 36mL of 40% (v / v) ethanol-water mixture and stirred at 40℃ for 30min to ensure complete dissolution; 5mL of 10% KOH aqueous solution was slowly added dropwise for neutralization to form a milky white dispersion; then, the dispersion was sonicated at 35℃ and 200W for 8min to obtain a stable potassium palmitate vesicle dispersion; the dispersion was then sonicated at 35℃ and 200W for 8min to obtain a stable potassium palmitate vesicle dispersion; the potassium palmitate vesicle dispersion was pre-frozen at -50℃ for 8h, then freeze-dried at -20℃ for 10h, and then dried at 25℃ for 2h to obtain stable dried potassium palmitate vesicles.

[0093] This embodiment also provides a method for preparing a hemostatic gel, including the following steps: (1) Add 38g of the above palmitic anhydride amidated chitosan to 55g of 1wt% acetic acid aqueous solution and stir magnetically at 30℃ for 2h to obtain a transparent and uniform modified chitosan solution; dissolve 18g of the above sodium oleate vesicles in 25mL of 40% (v / v) ethanol aqueous solution to obtain sodium oleate vesicle solution. (2) Take 48g of the above hydrated gelatin particles and slowly add them to the modified chitosan solution. Stir at 35°C for 40min, then add potassium palmitate vesicle solution and continue stirring at 35°C for 30min. Then, at 35°C, use ultrasonic dispersion at 200W for 8min to obtain a uniform composite mixture. (3) Add 4g of sodium citrate to the composite mixture and adjust the pH of the solution to 6.5 with 0.1M hydrochloric acid solution; react at 25℃ for 1h to obtain hemostatic gel; (4) Place the obtained gel in a 4°C environment and let it stand for 12 hours to fully solidify. Finally, put it into a sterile syringe to obtain the hemostatic gel product.

[0094] Example 6 This embodiment provides a hemostatic gel and its preparation method, which is basically the same as that in Example 1, except that the amount of raw materials used in the hemostatic gel is different. Specifically, the raw materials are: 40g of palmitic anhydride amidated chitosan, 50g of hydrated gelatin particles, 20g of sodium oleate vesicles, and 5g of sodium borate.

[0095] Example 7 This embodiment provides a hemostatic gel and its preparation method, which is basically the same as that in Example 1, except that the amount of raw materials used in the hemostatic gel is different. Specifically, the raw materials are: 20g of palmitic anhydride amidated chitosan, 30g of hydrated gelatin particles, 5g of sodium oleate vesicles, and 1g of sodium borate.

[0096] Example 8 This embodiment provides a hemostatic gel and its preparation method, which is basically the same as that in Example 1, except that the modified chitosan is different. Specifically, this embodiment uses lauric anhydride amidation-modified chitosan as shown in the following formula.

[0097] Its preparation method is as follows: 43g of chitosan was added to 4.3L of 1% (w / w) glacial acetic acid solution and stirred at 400rpm for 2h to form a homogeneous and transparent chitosan solution. 84.5g of lauric anhydride was dispersed in 810mL of DMF and stirred at 400rpm for 30min to homogenize it, obtaining a lauric anhydride dispersion. The lauric anhydride dispersion was slowly added dropwise to the chitosan solution at 400rpm, and the reaction temperature was controlled at 30℃ for an amidation reaction for 18h. After the reaction, the resulting reaction solution was transferred to a dialysis bag, which was then immersed in deionized water for dialysis to remove free lauric anhydride and small molecule byproducts. The dialysis membrane was a Spectra / Por 6. A regenerated cellulose dialysis membrane with a molecular weight cutoff of 14000 Da and a deionized water to reaction solution volume ratio of 80:1 was used. Dialysis was performed at room temperature for 48 hours, with the deionized water replaced every 8 hours. After dialysis, the retentate in the dialysis bag was pre-frozen at -40°C for 6 hours, and then placed in a freeze dryer and freeze-dried at a cold trap temperature of -40°C and a vacuum degree of 10 Pa for 72 hours to obtain lauric anhydride amidated chitosan.

[0098] Example 9 This embodiment provides a hemostatic gel and its preparation method, which is basically the same as that in Example 1, except that the hydrated gelatin particles are prepared as follows: 40g of gelatin is dissolved in 32g of deionized water and stirred at 50℃ for 1h to obtain a gelatin solution; after cooling to room temperature, it is dried at -50℃ for 12h to obtain hydrated gelatin particles with a particle size D50 of 100μm.

[0099] Example 10 This embodiment provides a hemostatic gel and its preparation method, which is basically the same as that in embodiment 1, except that step (2) is different. Specifically, 40g of hydrated gelatin particles are slowly added to sodium oleate vesicle solution and stirred at 35°C for 40min. Then, modified chitosan solution is added and stirred at 50°C for 30min. Finally, the mixture is ultrasonically dispersed at 35°C and 200W for 8min to obtain a composite mixture.

[0100] Comparative Example 1 This comparative example provides a hemostatic gel and its preparation method, which is basically the same as that in Example 1, except that palmitic anhydride amidated chitosan is replaced with an equal mass of chitosan, i.e., it is used directly without modification.

[0101] Comparative Example 2 This comparative example provides a hemostatic gel and its preparation method, which is basically the same as Example 1, except that the hydrated gelatin particles are omitted, and the step of adding the hydrated gelatin particles to the modified chitosan solution is omitted in step (2) of preparing the hemostatic gel.

[0102] Comparative Example 3 This comparative example provides a hemostatic gel and its preparation method, which is basically the same as Example 1, except that sodium oleate vesicles are omitted and the step of adding sodium oleate vesicle dispersion is omitted in step (2) of preparing the hemostatic gel.

[0103] Comparative Example 4 This comparative example provides a hemostatic gel and its preparation method, which is basically the same as Example 1, except that the cross-linking agent and the step (3) of preparing the hemostatic gel are omitted.

[0104] Experimental Example 1 This experimental example tested the performance of the hemostatic gels from each embodiment and comparative example.

[0105] 1. Testing Method (1) Whole blood clotting time (WBCT) Take 0.5 mL of fresh anticoagulated whole blood (rabbit blood) stored at room temperature for no more than 2 hours, add it to a culture dish containing 0.5 g of gel sample, mix gently, and gently blow it with a pipette every 15 seconds. Let it stand and observe, and record the time when the blood changes from a liquid state to no longer flowing. This is the whole blood clotting time (WBCT).

[0106] (2) Expansion rate Take a gel sample with an initial mass (M0) of 0.2 g, immerse it in PBS buffer (pH 7.4, 37℃) for 24 h, remove it, absorb the surface moisture, and weigh the sample after immersion (M0). t According to the formula [(M t The expansion rate (%) is calculated by multiplying [-M0) / M0] by 100%.

[0107] (3) Adhesion strength The Lap Shear Test method was used, in which 1.0 g of gel sample was sandwiched between two pieces of pigskin (1 cm² area). 2 After standing for 5 minutes to cure, the maximum shear force was tested on a universal testing machine (Instron, model: Instron 5567) at a tensile speed of 5 mm / min. The adhesive strength (kPa) was obtained by dividing the maximum shear force by the contact area.

[0108] (4) Compression modulus Each gel sample was poured into a porous flat mold, with each hole of the mold containing a cylindrical cavity (10 mm in diameter and 10 mm in height) to prepare a cylindrical gel. The gel was then subjected to compression testing at a rate of 1 mm / min on a universal testing machine. The stress-strain curve was recorded, and the slope within the 10-20% strain range was taken as the compressive modulus (kPa).

[0109] (5) Degradation rate After drying each gel sample to constant weight, a sample with an initial dry weight (M0) of 0.5 g was placed in 10 mL of PBS buffer containing lysozyme (1.5 μg / mL) and incubated at 37°C with shaking. The sample was removed and the solution replaced every 3 days. After 14 days, the sample was removed, dried to constant weight, and the dry weight after 14 days (M0) was obtained. 14 According to the formula [(M0-M)] 14 The degradation rate (%) is calculated by multiplying [M0] by 100%.

[0110] (6) Cell viability Gel sample extraction solution: Take 0.2g of gel sample from each example and comparative example, and extract at 37°C for 24h at a ratio of sample to PBS buffer of 0.1g:1mL to obtain the extraction solution.

[0111] Cell culture: L929 fibroblasts were cultured at a concentration of 1×10⁻⁶ cells / mL. 4 Cells were seeded per well in 96-well plates, and 100 μL of DMEM complete medium (Gibco, Thermo Fisher Scientific) containing 10% fetal bovine serum (FBS) was added to each well. Cells were randomly divided into experimental and control groups. The experimental group was given 10 μL of the corresponding extract solution per well the next day, while the control group was given 10 μL of complete medium per well. Cell viability was then determined using the CCK-8 assay according to the instructions of the CCK-8 kit (Dojindo, CK04). Cell viability (%) was calculated using the formula (experimental group - control group) / (control group) × 100%.

[0112] (7) Animal hemostasis time Experimental animals: SD rats, weighing 225±25g. Rats were randomly assigned to groups of 8 according to the examples and comparative examples.

[0113] Experimental procedure: Rats were anesthetized by intraperitoneal injection of sodium pentobarbital (dose 40 mg / kg rat body weight). After anesthesia, indicators such as loss of activity and absence of pain reflexes were observed to confirm adequate anesthesia. The femoral artery was incised with a wound length of 1 cm. Immediately after bleeding for 5 seconds, 100 mg of the corresponding group of gel sample was applied to the wound surface. After observing that there was no longer any spurting or continuous oozing blood flow from the wound surface, the observation continued for 30 seconds. If there was no re-bleeding during this period, it could be considered that the bleeding had completely stopped. The time required from the application of the gel to the complete cessation of bleeding (unit: seconds) was recorded as the animal hemostasis time.

[0114] 2. Test Results Table 1 Performance Test Results

[0115] As can be seen from Table 1, the whole blood clotting time of the examples is significantly shorter than that of the comparative examples. Among them, Example 1 has a clotting time of only 55s, which is the best hemostatic effect, indicating that it can quickly trigger the clotting reaction. The comparative examples are generally above 110s, especially Comparative Example 1 (using unmodified chitosan) with a whole blood clotting time of 150s, which is significantly less effective at stopping the bleeding.

[0116] Regarding the expansion rate, the expansion rate of Example 1 was only 0.9%, which was the lowest among all examples. It hardly produced any volume expansion, avoiding the risk of nerve or blood vessel compression caused by the expansion of traditional hemostatic agents in a confined space. In contrast, the expansion rates of the comparative examples were all higher than 5%, posing significant safety hazards.

[0117] Regarding adhesive strength and compressive modulus, Examples 1-10 exhibit high adhesive strength and relatively high compressive modulus. Among them, Example 1 has the highest adhesive strength (18.5 kPa) and a moderate compressive modulus (45 kPa), balancing flexibility and support. In contrast, the adhesive strength of the comparative examples is below 9 kPa and the compressive modulus is also low, making it difficult to maintain structural stability under high-flow-rate bleeding conditions.

[0118] Regarding degradation performance and cell compatibility, all examples showed a degradation rate of ≥50% after 14 days, ensuring that the material could be gradually degraded and cleared after completing the hemostatic effect. At the same time, the cell viability was ≥90%, indicating excellent biocompatibility. In contrast, the comparative examples were generally worse in terms of degradation rate and cell viability, with low degradation rate and low cell viability.

[0119] Regarding the hemostasis time in animals, all examples were ≤120s, which is significantly better than the comparative examples. In particular, the hemostasis time in animals in Example 1 was only 60s, indicating that the hemostatic gel provided by the present invention can be highly compatible with the needs of controlling bleeding and clinical emergency hemostasis.

[0120] In summary, this invention combines a ternary synergistic system of modified chitosan, hydrated gelatin particles, and fatty acid salt vesicles with a crosslinking agent to obtain a hemostatic gel, which can achieve rapid, stable, and safe hemostatic effects. Among them, Example 1 achieves the best balance in terms of hemostatic speed, swelling rate, adhesion, mechanical properties, and biosafety.

[0121] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A hemostatic gel, characterized in that, By weight, it includes the following raw materials: 20-40 parts modified chitosan, 35-45 parts hydrated gelatin particles, 5-20 parts fatty acid salt vesicles, and 1-5 parts crosslinking agent.

2. The hemostatic gel according to claim 1, characterized in that, By weight, it includes the following raw materials: 25-35 parts modified chitosan, 35-45 parts hydrated gelatin particles, 8-15 parts fatty acid salt vesicles, 1-3 parts crosslinking agent, 30-60 parts water, 20-80 parts weak acid aqueous solution, and 5-60 parts alcohol aqueous solution.

3. The hemostatic gel according to claim 1 or 2, characterized in that, The modified chitosan has a structure shown in any of the following formulas I to III: Formula I, Formula II, Formula III, in, R1 is selected from C8-C18 straight-chain or branched alkyl groups; R2 is selected from C8-C18 straight-chain or branched alkyl groups; R3 is selected from C1-C20 straight-chain or branched alkyl groups; Preferably, R1 is selected from C10-C18 straight-chain or branched alkyl groups; R2 is selected from unsubstituted C10-C18 straight-chain or branched alkyl groups; and R3 is selected from C10-C20 straight-chain or branched alkyl groups. More preferably, R1 is selected from C15 straight-chain alkyl; R2 is selected from C15 straight-chain alkyl; and R3 is selected from C16 straight-chain alkyl.

4. The hemostatic gel according to claim 1 or 2, characterized in that, The modified chitosan includes at least one of C5-C20 fatty acid or fatty acid anhydride modified chitosan and C5-C20 haloalkane modified chitosan. Preferably, the modified chitosan includes at least one of palmitic acid or palmitic anhydride or lauric anhydride modified chitosan and 1-bromohexadecane modified chitosan.

5. The hemostatic gel according to claim 1 or 3, characterized in that, The method for preparing the modified chitosan shown in Formula I includes the following steps: mixing chitosan, fatty acyl chloride and / or fatty acid anhydride for an amidation reaction; optionally, the fatty acyl chloride includes at least one of octanoyl chloride, decanoyl chloride, lauroyl chloride, palmitoyl chloride, stearoyl chloride, and oleoyl chloride; optionally, the mass ratio of chitosan to fatty acyl chloride is 1:1-50, preferably 1:1-5; optionally, the fatty acid anhydride includes at least one of octanoic anhydride, decanoic anhydride, lauroic anhydride, palmitic anhydride, and stearic anhydride; optionally, the mass ratio of chitosan to fatty acid anhydride is 1:1-50, preferably 1:1-5; And / or, the preparation method of the modified chitosan shown in Formula II includes the following steps: mixing chitosan, halogenated hydrocarbons and / or epoxides, and carrying out an etherification reaction under alkaline conditions; optionally, the halogenated hydrocarbons include at least one selected from chlorooctane, bromooctane, chlorodecane, bromodecane, chlorododecane, bromododecane, and 1-bromohexadecane; optionally, the mass ratio of chitosan to halogenated hydrocarbons is 1:0.5-40, preferably 1:0.5-5; optionally, the epoxides include at least one selected from epioxide octane, epioxide decane, epioxide dodecane, and epioxide ethyl ether; optionally, the mass ratio of chitosan to epoxides is 1:0.5-40, preferably 1:0.5-5; And / or, the preparation method of the modified chitosan shown in Formula III includes the following steps: mixing chitosan, fatty acids and / or aromatic carboxylic acids, and carrying out an esterification reaction in the presence of an activator; optionally, the fatty acids include at least one selected from octanoic acid, capric acid, lauric acid, palmitic acid, stearic acid, and oleic acid; optionally, the mass ratio of chitosan to fatty acids is 1:1-60, preferably 1:1-5; optionally, the aromatic carboxylic acid includes at least one selected from benzoic acid, p-hydroxybenzoic acid, p-methoxybenzoic acid, phthalic acid, terephthalic acid, and naphtholic acid; optionally, the mass ratio of chitosan to aromatic carboxylic acid is 1:1-60, preferably 1:1-5; optionally, the activator includes N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide; Optionally, the weight-average molecular weight of the chitosan is 150kDa-300kDa.

6. The hemostatic gel according to claim 1 or 2, characterized in that, The method for preparing the hydrated gelatin particles includes the following steps: mixing gelatin and water, cooling and drying to obtain hydrated gelatin particles; And / or, the particle size D50 of the hydrated gelatin particles is 50-200 μm; Optionally, the mass ratio of gelatin to water is 1:0.8-3, preferably 1:1-3; Optionally, the mixing temperature is 40-60℃ and the time is 0.5-2h; Optionally, the drying method includes freeze drying and / or spray drying; Optionally, the freeze-drying temperature is -60~-50℃, and the time is 6-48h; Optionally, the spray drying temperature is 40-60℃ and the time is 0.5-2h.

7. The hemostatic gel according to claim 1 or 2, characterized in that, The method for preparing fatty acid salt vesicles includes the following steps: mixing fatty acids and an aqueous ethanol solution, adding an alkali metal hydroxide solution to react, dispersing, obtaining a fatty acid salt vesicle dispersion, and drying to obtain fatty acid salt vesicles. Optionally, the fatty acids include C12-C18 saturated fatty acids and / or unsaturated fatty acids; Optionally, the saturated fatty acid includes at least one of stearic acid, palmitic acid, lauric acid, and myristic acid; Optionally, the unsaturated fatty acid includes at least one of oleic acid, linoleic acid, and linolenic acid; Optionally, the volume fraction of ethanol in the ethanol-water solution is 20-60%; Optionally, the ratio of the fatty acid to the aqueous ethanol solution is 1:0.5-20, in g:mL; Optionally, the alkali metal hydroxide includes sodium hydroxide and / or potassium hydroxide; Optionally, the ratio of the alkali metal hydroxide to the fatty acid is 0.5-5:1-20, in mL:g; Optionally, the mixing temperature is 30-50°C and the time is 20-40 minutes; Optionally, the dispersion method is ultrasound; Optionally, the temperature of the ultrasound is 30-50℃, the duration is 5-15 min, and the power is 100-300W; Optionally, the drying process involves pre-freezing at -50 to -40°C for 4-12 hours, freeze-drying at -30 to -20°C for 8-16 hours, and then drying at 20 to 25°C for 2-4 hours.

8. The hemostatic gel according to claim 1 or 2, characterized in that, The crosslinking agent includes at least one of sodium borate, sodium citrate, sodium bicarbonate, sodium gluconate, sodium fumarate, and sodium tartrate.

9. A method for preparing the hemostatic gel according to any one of claims 1-8, characterized in that, Includes the following steps: Step S1: The modified chitosan is first mixed with a weak acid aqueous solution to obtain a modified chitosan solution; A second mixing of fatty acid salt vesicles with an aqueous ethanol solution yields a fatty acid salt vesicle solution. Step S2: Mix the modified chitosan solution with hydrated gelatin particles in the third stage, add fatty acid salt vesicle solution for the fourth stage, and disperse to obtain a composite mixture; or, mix the hydrated gelatin particles with fatty acid salt vesicle solution in the third stage, add the modified chitosan solution for the fourth stage, and disperse to obtain a composite mixture. Step S3: The composite mixture is subjected to a cross-linking reaction with a cross-linking agent to obtain a hemostatic gel.

10. The method for preparing the hemostatic gel according to claim 9, characterized in that, In step S1, the weak acid includes at least one of acetic acid, lactic acid, and citric acid; And / or, the weak acid constitutes 0.5-2 wt% of the aqueous solution of the weak acid; And / or, in step S1, the mass ratio of the modified chitosan to the weak acid aqueous solution is 1:1-2; And / or, in step S1, the mass ratio of the fatty acid salt vesicles to the aqueous ethanol solution is 1:1-3; And / or, in step S1, the temperature of the first mixing is 25-40°C and the time is 1-3 hours; And / or, in step S2, the temperature of the third mixing is 30-40°C and the time is 20-60 min; And / or, in step S2, the temperature of the fourth mixing is 30-50°C and the time is 20-40 min; And / or, in step S2, the dispersion is performed by ultrasound; Optionally, the temperature of the ultrasound is 30-50℃, the duration is 5-10 min, and the power is 100-300W; And / or, in step S3, the crosslinking reaction is carried out at a temperature of 20-35°C for a time of 0.5-2 hours; And / or, the crosslinking reaction further includes a step of adjusting the pH to 6-7; And / or, the crosslinking reaction further includes a step of curing the resulting hemostatic gel by standing at 2-8°C for 8-24 hours.

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