Hemostatic material and method of making same

Abstract

The application provides a hemostatic material and a preparation method thereof. The preparation raw material of the hemostatic material comprises gelatin and a natural polymer material, and the preparation process of the hemostatic material comprises the step of crushing gelatin gel in the presence of the natural polymer material; wherein the gelatin gel is obtained by gelation after cross-linking of the gelatin. The hemostatic material of the application comprises gelatin and a natural polymer material, and the gelatin gel is crushed in the presence of the natural polymer material, so that the particle size of the gel can be reduced, and finally the hemostatic material with good hemostatic effect is obtained.

Description

Technical Field

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

[0002] Currently, commonly used absorbable hemostatic materials in clinical practice include hemostatic sponges, hemostatic powders, and hemostatic gauze. However, these hemostatic materials have shortcomings and defects in terms of hemostatic effect, degradation cycle, production cost, and applicable sites. Therefore, there is a need to provide a hemostatic material with good hemostatic effect, low production cost, good biocompatibility, and ease of use to meet clinical needs.

[0003] Gelatin is widely used in clinical hemostasis due to its good biocompatibility and biodegradability. Currently, gelatin sponges are the most common type. However, gelatin sponges have a slow hemostatic speed, and because of their sponge-like form, they are limited to use on exposed and easily accessible wounds. They cannot be used on wounds with narrow operating surfaces, deep bleeding, or narrow body cavities, especially on wounds with diffuse bleeding on uneven surfaces or in deep or narrow areas. In other words, they are not suitable for minimally invasive and laparoscopic surgeries.

[0004] Fluid gelatin, due to its fluidity, can be squeezed out and applied to bleeding wounds through instruments, enabling its use in areas where traditional gelatin sponges cannot be used and improving hemostatic performance. However, it still suffers from problems such as unsatisfactory hemostatic effect and biocompatibility, as well as cumbersome preparation methods leading to high production costs.

[0005] Reference 1 discloses a method for preparing a fluid hemostatic adhesive, comprising cross-linked chitosan or its derivatives, cross-linked water-soluble proteins or peptides, and a lubricant. This hemostatic adhesive is prepared by cross-linking chitosan or its derivatives and water-soluble proteins or peptides with chemical cross-linking agents such as 1,4-butanediol diglycidyl ether, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and glutaraldehyde, respectively. The cross-linked chitosan or its derivatives and cross-linked water-soluble proteins or peptides are then obtained through pulverization and drying, and subsequently compounded with a lubricant. The chemical cross-linking agents used in the preparation process may affect the biocompatibility of the hemostatic adhesive, and multiple freeze-drying operations are required, making the preparation process cumbersome.

[0006] Reference 2 discloses a method for preparing an absorbable hemostatic fluid gelatin material. The method involves cooling a gelatin hot solution under controlled cooling to obtain a gelatin gel, followed by freeze-drying to obtain a porous gelatin sponge. This sponge is then subjected to high-temperature vacuum cross-linking, pulverization, and sieving to obtain gelatin particles. These particles are mixed with a solution containing a radiation stabilizer, and then subjected to aging treatment and irradiation sterilization to obtain the final product. This preparation method is also complex. Because the gelatin particles swell into a gel after absorbing liquid, they undergo further cross-linking under Co-60 gamma ray radiation, becoming unable to flow. Therefore, a formulation solution containing a radiation stabilizer is needed to eliminate free radicals generated during the radiation process, thus protecting the gelatin particles. However, the added radiation stabilizer may cause some cytotoxicity.

[0007] References:

[0008] Reference 1: CN111375085A

[0009] Reference 2: CN116251227A Summary of the Invention

[0010] The problem the invention aims to solve

[0011] In view of the problems of common hemostatic products in the prior art, such as inconvenience in use in minimally invasive surgery, unsatisfactory hemostatic effect and biocompatibility, and cumbersome preparation methods, the present invention first provides a hemostatic material, which includes gelatin and natural polymer materials. The gelatin gel is pulverized in the presence of natural polymer materials, which can reduce the particle size of the gel and the resulting hemostatic material has a good hemostatic effect.

[0012] The hemostatic material of this invention is in paste or powder form and can be pre-filled in containers for storage. It achieves good hemostatic effect when applied to the hemostatic site. When pre-filled in paste form, the effects of irradiation sterilization are avoided, eliminating the need for radiation stabilizers that may cause cytotoxicity. Furthermore, it does not require reconstitution before use, reducing preoperative procedures and facilitating use by medical personnel. When pre-filled in powder form, it can be easily reconstituted using a solvent, forming an extrudable paste that is convenient for application to the hemostatic site.

[0013] Solution for solving the problem

[0014] This invention provides a hemostatic material, the raw materials for which the hemostatic material is prepared include gelatin and a natural polymer material, and the preparation process of the hemostatic material includes a step of pulverizing the gelatin gel in the presence of the natural polymer material; wherein...

[0015] The gelatin gel is obtained by cross-linking the gelatin and then gelling it.

[0016] Further, the mass ratio of the gelatin to the natural polymer material is 1:(1-5); preferably, the natural polymer material includes one or more of chitosan, sodium alginate, cellulose or its derivatives.

[0017] Furthermore, the natural polymeric material is mixed with the gelatin in powder form before or after the formation of the gelatin gel, and / or the natural polymeric material exists in particulate form inside or outside the gelatin gel.

[0018] Further, the crosslinking includes physical crosslinking and chemical crosslinking; preferably, the physical crosslinking includes high-temperature crosslinking and / or gamma-ray radiation crosslinking; preferably, the crosslinking agent used in the chemical crosslinking includes one or more of ferric chloride, tannic acid, and aldehyde-modified polysaccharides; preferably, in the chemical crosslinking, the mass ratio of gelatin to the crosslinking agent is 1:(0.001-0.1); preferably, the aldehyde-modified polysaccharide is a polysaccharide compound with an aldehyde group, wherein the polysaccharide compound includes one or more of sodium alginate, hyaluronic acid, cellulose or its derivatives.

[0019] Furthermore, the hemostatic material is in paste or powder form; preferably, the hemostatic material is pre-filled in a container.

[0020] The present invention also provides a method for preparing the hemostatic material according to the present invention, comprising the following steps:

[0021] Gelatin was cross-linked to obtain cross-linked gelatin products;

[0022] The cross-linked gelatin product is gelled to obtain a gelatin gel.

[0023] The gelatin gel is pulverized in the presence of natural polymer materials;

[0024] Preferably, the preparation method further includes a step of sterilizing after pulverization to obtain a paste-like hemostatic material, or a step of freeze-drying and sterilizing sequentially after pulverization to obtain a powdered hemostatic material.

[0025] Preferably, the sterilization method is irradiation sterilization; more preferably, the irradiation sterilization dose is 15-25 kGy.

[0026] Further, the crosslinking treatment includes the steps of physically crosslinking the gelatin followed by chemical crosslinking; preferably, the physical crosslinking includes high-temperature crosslinking and / or gamma-ray radiation crosslinking of the gelatin powder; preferably, the chemical crosslinking includes the steps of preparing the physically crosslinked gelatin into a solution and then adding a crosslinking agent for chemical crosslinking; preferably, in the solution, the mass-volume concentration of the gelatin is 40-150 mg / mL, and the mass-volume concentration of the crosslinking agent is 0.1-8 mg / mL.

[0027] Furthermore, the natural polymer material is added in powder form before the cross-linked gelatin product is gelled or after the gelatin gel is formed.

[0028] Furthermore, the natural polymer material is added before the cross-linked gelatin product is gelled, meaning the natural polymer material is added to the chemically cross-linked gelatin solution, wherein the amount of natural polymer material added is 100–400 mg of natural polymer material per mL of gelatin solution; and / or,

[0029] The natural polymer material is added after the gelatin gel is formed. This can be done by adding the natural polymer material while pulverizing the gelatin gel, or by pulverizing the gelatin gel once, then adding the natural polymer material, mixing it evenly, and then pulverizing it a second time.

[0030] Further, the gelation includes incubating the cross-linked gelatin product at 1–8°C for 0.5–4 h to obtain the gelatin gel.

[0031] The effects of the invention

[0032] The hemostatic material of the present invention comprises gelatin and natural polymer materials. The gelatin gel is pulverized in the presence of natural polymer materials, which can reduce the particle size of the gel. The resulting hemostatic material has a good hemostatic effect.

[0033] The hemostatic material of this invention is in paste or powder form and can be pre-filled in containers for storage. It achieves good hemostatic effect when applied to the hemostatic site. When pre-filled in paste form, the effects of irradiation sterilization are avoided, eliminating the need for radiation stabilizers that may cause cytotoxicity. Furthermore, it does not require reconstitution before use; it can be directly injected into the application site after a few pushes with two syringes, reducing preoperative procedures and facilitating use by medical personnel. When pre-filled in powder form, it can be easily reconstituted using a solvent, forming an extrudable paste that is convenient for application to the hemostatic site.

[0034] The hemostatic material of this invention can be applied to wounds with narrow operating surfaces, deep bleeding, or narrow body cavities, especially to wounds with diffuse bleeding on uneven surfaces or in deep or narrow areas. It is suitable for minimally invasive and laparoscopic surgeries. After being applied to the site of use, it can quickly absorb wound fluid, concentrate wound plasma, form a good coagulation environment, accelerate blood coagulation, and has a good hemostatic effect.

[0035] The preparation method of the hemostatic material of the present invention is simple and easy to implement, the raw materials are easy to obtain, and it is suitable for mass production. Attached Figure Description

[0036] Figure 1 A photograph of the hemostatic material of Example 1 is shown;

[0037] Figure 2 A photograph shows the hemostatic material of Example 3 being extruded through a long catheter;

[0038] Figure 3 The hemostatic effect diagram of the hemostatic material of Example 1 is shown;

[0039] Figure 4 The hemostatic effect diagram of the hemostatic material of Example 2 is shown;

[0040] Figure 5 The hemostatic effect diagram of the hemostatic material of Example 3 is shown;

[0041] Figure 6 The hemostatic effect diagram of the hemostatic material of Example 4 is shown;

[0042] Figure 7 The hemostatic effect diagram of the hemostatic material of Example 5 is shown;

[0043] Figure 8 The hemostatic effect of the hemostatic material in Comparative Example 3 is shown in the diagram.

[0044] Figure 9 The hemostatic effect of the hemostatic material in Comparative Example 4 is shown in the figure. Detailed Implementation

[0045] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The term "exemplary" as used herein means "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior to or better than other embodiments.

[0046] Furthermore, to better illustrate the present invention, numerous specific details are set forth in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In other instances, methods, means, apparatus, and steps well known to those skilled in the art have not been described in detail in order to highlight the spirit of the present invention.

[0047] Unless otherwise stated, all units used in this specification are international standard units, and all numerical values ​​and ranges appearing in this invention should be understood to include systematic errors that are unavoidable in industrial production.

[0048] In this specification, the word "may" has two meanings: to perform a certain process and not to perform a certain process.

[0049] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "implementation," etc., refer to specific elements (e.g., features, structures, properties, and / or characteristics) related to that embodiment, which are included in at least one of the embodiments described herein and may or may not be present in other embodiments. Furthermore, it should be understood that these elements may be combined in any suitable manner in various embodiments.

[0050] In this specification, the range of values ​​referred to as "value A to value B" refers to the range including the endpoint values ​​A and B.

[0051] <First Aspect>

[0052] A first aspect of this invention provides a hemostatic material, the raw materials for which the hemostatic material is prepared include gelatin and a natural polymer material. The preparation process of the hemostatic material includes a step of pulverizing the gelatin gel in the presence of the natural polymer material; wherein the gelatin gel is obtained by cross-linking the gelatin followed by gelation. The hemostatic material of this invention includes gelatin and a natural polymer material, and pulverizing the gelatin gel in the presence of the natural polymer material can reduce the particle size of the gel, thereby improving the hemostatic effect of the final material.

[0053] Furthermore, in this invention, the hemostatic material exists in a paste or powder form; preferably, the hemostatic material is pre-filled in a container. When pre-filled in a paste form, the effects of irradiation sterilization can be avoided, eliminating the need for radiation stabilizers that may cause cytotoxicity, and reconstitution is not required before use, reducing preoperative procedures and facilitating use by medical personnel. Although the hemostatic material in paste form does not contain radiation stabilizers, it will not experience cross-linking and thickening that leads to poor flowability and difficulty in extrusion, or water separation that makes it difficult to extrude, even after irradiation treatment. When pre-filled in a powder form, it can be better reconstituted using a solvent to form an extrudable paste, which is convenient for application to the hemostatic site.

[0054] The hemostatic material of the present invention can be applied to wounds with narrow operating surfaces, deep bleeding, or narrow body cavities, especially to wounds with diffuse bleeding on uneven surfaces or in deep or narrow areas. It is suitable for minimally invasive and laparoscopic surgeries. After being applied to the site of use, it can quickly absorb wound fluid, concentrate wound plasma, form a good coagulation environment, accelerate blood coagulation, and has a good hemostatic effect.

[0055] Gelatin gel

[0056] The gelatin gel of this invention is obtained by cross-linking gelatin followed by gelation. In this invention, the cross-linking includes physical cross-linking and chemical cross-linking, resulting in cross-linked gelatin. The inventors of this invention have discovered that combining physical and chemical cross-linking can increase the degree of cross-linking in gelatin, avoid the effects of irradiation, and increase the porosity of the hemostatic material, thereby improving its hemostatic effect.

[0057] In some specific implementations, the physical crosslinking includes high-temperature crosslinking and / or gamma-ray radiation crosslinking, preferably high-temperature crosslinking; the high-temperature crosslinking includes atmospheric pressure-high-temperature crosslinking or vacuum-high-temperature crosslinking.

[0058] Specifically, the chemical crosslinking includes crosslinking using a crosslinking agent. The crosslinking agent reacts with gelatin to increase the degree of crosslinking in the gelatin. The crosslinking agent includes one or more of ferric chloride, tannic acid, and aldehyde-modified polysaccharides. Ferric chloride itself has certain hemostatic properties, and forms metal-ionic coordination bonds with gelatin, resulting in rapid crosslinking. Tannic acid also has certain anti-inflammatory effects, and forms hydrogen bonds, π bonds, and other chemical bonds with gelatin. Considering the potential slight toxicity of ferric chloride and tannic acid, this invention preferably uses aldehyde-modified polysaccharides. Aldehyde-modified polysaccharides are naturally sourced biological crosslinking agents, and their aldehyde groups can undergo a Schiff base reaction with the amino groups of gelatin to achieve crosslinking.

[0059] In some specific embodiments, in the chemical crosslinking, the mass ratio of the gelatin to the crosslinking agent is 1:(0.001 to 0.1). When the mass ratio of the gelatin to the crosslinking agent is 1:(0.001 to 0.1), the degree of crosslinking of the gelatin can be further increased.

[0060] In some specific embodiments, the aldehyde-modified polysaccharide is a polysaccharide compound having an aldehyde group. The polysaccharide compound may be, for example, one or a combination of two or more of chitosan, sodium alginate, cellulose, or their derivatives. The aldehyde-modified polysaccharide of the present invention can be obtained commercially available or through conventional oxidative modification methods.

[0061] In some specific embodiments, the gelatin gel is obtained by gelling a solution of cross-linked gelatin, or by gelling a mixed solution of cross-linked gelatin and a natural polymer material in powder form.

[0062] Natural polymer materials

[0063] In this invention, since gelatin gel is not easy to crush, the inventors discovered that adding natural polymer materials can help crush gelatin gel, reduce the particle size of gelatin gel, increase porosity, and thus improve the hemostatic effect of the final hemostatic material.

[0064] In some specific embodiments, the natural polymeric material is mixed with the gelatin in powder form before or after the formation of the gelatin gel, and / or the natural polymeric material exists in particulate form inside or outside the gelatin gel.

[0065] In some specific embodiments, the mass ratio of the gelatin to the natural polymer material is 1:(1-5). When the mass ratio of the gelatin to the natural polymer material is 1:(1-5), the gelatin gel can be further pulverized to the required particle size, i.e., there are no visible particles.

[0066] <Second aspect>

[0067] A second aspect of the present invention provides a method for preparing a hemostatic material according to the first aspect of the present invention, characterized by comprising the following steps:

[0068] Gelatin was cross-linked to obtain cross-linked gelatin products;

[0069] The cross-linked gelatin product is gelled to obtain a gelatin gel.

[0070] The gelatin gel is pulverized in the presence of natural polymer materials.

[0071] Furthermore, in this invention, the preparation method further includes the step of sterilizing after pulverization to obtain a paste-like hemostatic material, or the step of freeze-drying and sterilizing sequentially after pulverization to obtain a powdered hemostatic material.

[0072] More preferably, the sterilization method is irradiation sterilization, and even more preferably, the irradiation sterilization dose is 15-25 kGy.

[0073] The preparation method of the hemostatic material of the present invention is simple and easy to implement, the raw materials are easy to obtain, and it is suitable for mass production.

[0074] In some specific embodiments, the crosslinking treatment includes a step of physically crosslinking the gelatin followed by chemical crosslinking; this is because the obtained crosslinked gelatin product or gelatin gel contains water, and high-temperature crosslinking will cause water to evaporate. Therefore, gelatin powder is generally physically crosslinked. This invention improves the degree of crosslinking of gelatin by combining physical and chemical crosslinking, which avoids the effects of irradiation and increases the porosity of the hemostatic material, thereby improving its hemostatic effect.

[0075] In some specific embodiments, the physical crosslinking includes high-temperature crosslinking and / or gamma-ray radiation crosslinking of the gelatin powder, preferably high-temperature crosslinking; the high-temperature crosslinking includes atmospheric pressure-high-temperature crosslinking or vacuum-high-temperature crosslinking. Specifically, in this invention, the temperature for high-temperature crosslinking can be 110–150°C, and the crosslinking time can be 20–60 h.

[0076] Furthermore, in this invention, the chemical crosslinking includes the step of preparing physically crosslinked gelatin into a solution and then adding a crosslinking agent to perform chemical crosslinking. Preferably, in this invention, the mass-volume concentration of the gelatin in the solution is 40–150 mg / mL, and the mass-volume concentration of the crosslinking agent is 0.1–8 mg / mL.

[0077] In some specific embodiments, the gelation includes incubating the cross-linked gelatin product at 1–8°C for 0.5–4 hours to obtain the gelatin gel. By incubating at 1–8°C for 0.5–4 hours, the cross-linked gelatin product can be completely gelled, thereby obtaining the gelatin gel.

[0078] Furthermore, this invention does not impose any particular limitation on the timing of adding the natural polymer material, and it can be selected as needed. Considering the effective conduct of the reaction, the natural polymer material is added in powder form before the cross-linked gelatin product gelates or after the gel is formed.

[0079] In some specific embodiments, the natural polymer material is added before the cross-linked gelatin product is gelled. This can be done by adding the natural polymer material to the chemically cross-linked gelatin solution, wherein the amount of natural polymer material added is 100-400 mg of natural polymer material per mL of gelatin solution.

[0080] In some specific embodiments, the natural polymer material is added after the gelatin gel is formed. This can be done by adding the natural polymer material while the gelatin gel is being pulverized, or by pulverizing the gelatin gel once, then adding the natural polymer material, mixing thoroughly, and then pulverizing a second time until no visible particles remain. Specifically, in this invention, the pulverization method is not particularly limited and can be any commonly used pulverization method in the art. Specifically, common mechanical crushing methods can be used for pulverization.

[0081] In this invention, the application methods of the hemostatic material include two methods:

[0082] Method 1: Store the paste-like hemostatic material in syringe A. Use another empty syringe B to connect with syringe A via the connector and push them back and forth 2-5 times. Then, directly or separately connect a catheter and apply it to the hemostatic site.

[0083] Method 2: A powdered hemostatic material is stored in syringe A, and a liquid solvent is stored in syringe B. Syringes A and B are connected and pushed together using a connector to reconstitute the powdered hemostatic material into a paste. This paste is then applied directly or via a catheter to the hemostatic site. The liquid solvent is a medical aqueous solvent, preferably one or a combination of two or more of physiological saline, PBS buffer solution, and water for injection.

[0084] Example

[0085] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0086] Example 1

[0087] 1. Weigh 6g of gelatin powder and place it in a vacuum oven. Perform vacuum-high temperature crosslinking treatment at 120℃ for 30h. Then add it to 60mL of deionized water, heat to 60℃, and keep it warm while stirring until completely dissolved. Adjust the pH value to 7.4, add 0.45g of aldehyde-modified sodium alginate, and stir for 2h until crosslinking is complete. Then add 12g of chitosan to obtain the crosslinked gelatin product.

[0088] 2. Place the cross-linked gelatin product in a 4°C refrigerator for 1 hour to allow it to fully gel, thus obtaining gelatin gel.

[0089] 3. Crush the gelatin gel at room temperature until no particles are visible to the naked eye, prefill it into a syringe, and sterilize it by irradiation with 20 kGy Co-60 γ rays to obtain a paste-like hemostatic material.

[0090] Example 2

[0091] 1. Weigh 3g of gelatin powder and place it in a vacuum oven. Perform vacuum-high temperature crosslinking treatment at 130℃ for 24h. Then add it to 60mL of deionized water, heat to 60℃, and keep it warm while stirring until completely dissolved. Add 0.3g of aldehyde-modified hyaluronic acid and stir for 2h until crosslinking is complete. Adjust the pH value to 7.4 to obtain the crosslinked gelatin product.

[0092] 2. Place the cross-linked gelatin product in a 4°C refrigerator for 1 hour to allow it to fully gel, thus obtaining gelatin gel.

[0093] 3. Crush the gelatin gel into small pieces at room temperature, add 15g of sodium alginate and mix well, then crush until no particles are visible to the naked eye. Prefill the mixture into syringes and sterilize it by irradiation with 15kGy Co-60 γ rays to obtain a paste-like hemostatic material.

[0094] Example 3

[0095] 1. Weigh 6g of gelatin powder and place it in a vacuum oven. Perform vacuum-high temperature crosslinking treatment at 130℃ for 24h. Then add it to 60mL of deionized water, heat to 60℃, and keep warm while stirring until completely dissolved and homogeneous. Adjust the pH value to 7, add 0.24g of aldehyde-modified hyaluronic acid, and stir for 4h until crosslinking is complete to obtain the crosslinked gelatin product.

[0096] 2. Place the cross-linked gelatin product in a 4°C refrigerator for 2 hours to allow it to fully gel, thus obtaining gelatin gel.

[0097] 3. Crush the gelatin gel into small pieces at room temperature, add 12g of chitosan and mix evenly, then crush until no particles are visible to the naked eye. Freeze-dry using a freeze dryer, then pre-fill into syringes and sterilize by irradiation with 25kGy Co-60 γ rays to obtain a powdered hemostatic material.

[0098] Example 4

[0099] 1. Weigh 6g of gelatin powder and place it in a vacuum oven. Perform vacuum-high temperature crosslinking treatment at 150℃ for 20h. Then add 40mL of deionized water, heat to 60℃, keep warm and stir continuously until completely dissolved and homogeneous. Adjust the pH of the solution to 10.

[0100] 2. Dissolve 50 mg of tannic acid in 10 mL of sodium hydroxide solution with pH 10, add the above solution, stir for 3 h to complete cross-linking, adjust the pH value to 7.4, and obtain the cross-linked gelatin product.

[0101] 3. Place the above cross-linked gelatin product in a 4°C refrigerator for 1 hour to allow it to fully gel, thus obtaining gelatin gel.

[0102] 4. Grind the gelatin gel to small pieces at room temperature, add 18g of chitosan and mix well, then grind until no visible particles are present. Prefill the mixture into syringes and sterilize it by irradiation with 20kGy Co-60 γ rays to obtain a paste-like hemostatic material.

[0103] Example 5

[0104] 1. Weigh 6g of gelatin powder and place it in a vacuum oven. Perform vacuum-high temperature crosslinking treatment at 150℃ for 20h. Then add it to 60mL of deionized water, heat to 60℃, and keep warm while stirring until completely dissolved.

[0105] 2. Dissolve 10 mg of ferric chloride in 10 mL of water, add the above solution, stir for about 10 min to complete cross-linking, and then adjust the pH to about 7.4 to obtain the cross-linked gelatin product.

[0106] 3. Place the cross-linked gelatin product in a 4°C refrigerator for 1 hour to allow it to fully gel, thus obtaining gelatin gel.

[0107] 4. Crush the gelatin gel into small pieces at room temperature, add 7g of ethyl cellulose, mix well, and then crush until no particles are visible to the naked eye. Freeze-dry the mixture using a freeze dryer, then pre-fill it into syringes and sterilize it by irradiation with 15kGy Co-60 γ rays to obtain a powdered hemostatic material.

[0108] Comparative Example 1

[0109] Compared with Example 1, no chitosan was added in Comparative Example 1, but the other components were exactly the same as those in Example 1, and a hemostatic material was prepared.

[0110] During the preparation process, it was found that the gelatin gel particles were large and difficult to pulverize until there were no visible particles. The hemostatic material obtained after irradiation had water precipitation and was not easy to squeeze out.

[0111] Comparative Example 2

[0112] Compared with Example 1, the amount of chitosan used in Comparative Example 2 was 4g, and the remaining components were exactly the same as those in Example 1, thus preparing a hemostatic material.

[0113] The hemostatic material obtained after irradiation releases water and is not easily squeezed out.

[0114] Comparative Example 3

[0115] Compared with Example 1, the gelatin powder was not placed in a vacuum oven for vacuum-high temperature crosslinking treatment, but the composition and other preparation methods were the same as in Example 1, and a hemostatic material was prepared.

[0116] Comparative Example 4

[0117] Compared with Example 2, no aldehyde-modified hyaluronic acid was added, but the other components and preparation methods were the same as in Example 2, and a hemostatic material was prepared.

[0118] Performance testing

[0119] 1. Hemostatic effect test

[0120] After anesthetizing the experimental pigs, a 1 cm diameter hole was made in the liver using a biopsy punch. Bleeding was immediately observed, and the wound immediately filled with blood after the injury. Hemostatic material was injected into the hole until it was filled. After pressing with moistened medical gauze for 30 seconds, the gauze was removed, and the hemostasis was observed (whether there was bleeding).

[0121] Because the hemostatic materials of Comparative Examples 1 and 2 released water after irradiation treatment and were not easily squeezed out, no hemostatic effect test was performed.

[0122] The hemostatic effects of the hemostatic materials from Examples 1-5 were tested on pig liver. When using the hemostatic materials from Examples 1, 2, and 4, an empty syringe was connected to a syringe containing the paste-like hemostatic material via a connector and the syringe was pushed back and forth four times before being applied to the bleeding site. When using the hemostatic materials from Examples 3 and 5, a syringe containing physiological saline was connected to a syringe containing the powdered hemostatic material via a connector and the syringe was pushed back and forth until the hemostatic material re-dissolved to form a paste, which was then applied to the bleeding site; wherein the mass ratio of the powdered hemostatic material to physiological saline was 1:5. The test results are as follows: Figure 3-7 As shown.

[0123] Depend on Figure 3-7 It can be seen that after applying pressure with medical gauze for 30 seconds, the hemostatic materials of Examples 1-5 of this invention can all achieve hemostasis. Figure 8 and 9As shown, after using the hemostatic materials of Comparative Examples 3 and 4, bleeding continued even after applying pressure with medical gauze for 60 seconds, indicating that hemostasis could not be achieved within 60 seconds. This is because the hemostatic materials of Comparative Examples 3 and 4 had insufficient cross-linking and low porosity, resulting in poor hemostatic effect.

[0124] It should be noted that although the technical solution of the present invention has been described with specific examples, those skilled in the art will understand that the present invention should not be limited thereto.

[0125] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or technical improvements to the embodiments in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A hemostatic material, characterized in that, The raw materials for preparing the hemostatic material include gelatin and natural polymer materials. The preparation process of the hemostatic material includes a step of pulverizing the gelatin gel in the presence of the natural polymer materials; wherein... The gelatin gel is obtained by cross-linking the gelatin and then gelling it.

2. The hemostatic material according to claim 1, characterized in that, The mass ratio of the gelatin to the natural polymer material is 1:(1-5); Preferably, the natural polymer material includes one or more of chitosan, sodium alginate, cellulose, or their derivatives.

3. The hemostatic material according to claim 1 or 2, characterized in that, The natural polymeric material is mixed with the gelatin in powder form before or after the formation of the gelatin gel, and / or the natural polymeric material exists in particulate form inside or outside the gelatin gel.

4. The hemostatic material according to any one of claims 1-3, characterized in that, The crosslinking includes physical crosslinking and chemical crosslinking; Preferably, the physical crosslinking includes high-temperature crosslinking and / or gamma-ray radiation crosslinking; Preferably, the crosslinking agent used in the chemical crosslinking includes one or more of ferric chloride, tannic acid, and aldehyde polysaccharides; Preferably, in the chemical crosslinking, the mass ratio of the gelatin to the crosslinking agent is 1:(0.001~0.1); Preferably, the aldehyde-modified polysaccharide is a polysaccharide compound having an aldehyde group, wherein the polysaccharide compound includes one or more of sodium alginate, hyaluronic acid, cellulose or its derivatives.

5. The hemostatic material according to any one of claims 1-4, characterized in that, The hemostatic material is in paste or powder form; preferably, the hemostatic material is pre-filled in a container.

6. A method for preparing a hemostatic material according to any one of claims 1-5, characterized in that, Includes the following steps: Gelatin was cross-linked to obtain cross-linked gelatin products; The cross-linked gelatin product is gelled to obtain a gelatin gel. The gelatin gel is pulverized in the presence of natural polymer materials; Preferably, the preparation method further includes the step of sterilizing after pulverization to obtain a paste-like hemostatic material, or the step of freeze-drying and sterilizing sequentially after pulverization to obtain a powder-like hemostatic material; Preferably, the sterilization method is irradiation sterilization; more preferably, the irradiation sterilization dose is 15-25 kGy.

7. The method for preparing the hemostatic material according to claim 6, characterized in that, The crosslinking process includes the steps of physically crosslinking the gelatin followed by chemical crosslinking. Preferably, the physical crosslinking includes high-temperature crosslinking and / or gamma-ray radiation crosslinking of the gelatin powder; Preferably, the chemical crosslinking includes the step of preparing the physically crosslinked gelatin into a solution and then adding a crosslinking agent to perform chemical crosslinking; Preferably, in the solution, the mass-volume concentration of the gelatin is 40-150 mg / mL, and the mass-volume concentration of the crosslinking agent is 0.1-8 mg / mL.

8. The method for preparing the hemostatic material according to claim 6 or 7, characterized in that, The natural polymer material is added in powder form before or after the cross-linked gelatin product is gelled.

9. The method for preparing the hemostatic material according to claim 8, characterized in that, The natural polymer material is added before the cross-linked gelatin product is gelled, meaning the natural polymer material is added to the chemically cross-linked gelatin solution, wherein the amount of natural polymer material added is 100–400 mg of natural polymer material per mL of gelatin solution; and / or The natural polymer material is added after the gelatin gel is formed. This can be done by adding the natural polymer material while pulverizing the gelatin gel, or by pulverizing the gelatin gel once, then adding the natural polymer material, mixing it evenly, and then pulverizing it a second time.

10. The method for preparing the hemostatic material according to any one of claims 6-9, characterized in that, The gelation process involves incubating the cross-linked gelatin product at 1–8°C for 0.5–4 hours to obtain the gelatin gel.

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