A hemostatic gel and its preparation method

Abstract

This invention relates to the field of medical gel technology and discloses a hemostatic gel and its preparation method, comprising the following components by weight: 6-10 parts sodium alginate, 4-7 parts quaternary ammonium salt-modified silane, 2-3 parts glutaraldehyde, and 3-4 parts water. Using sodium alginate as a base material, the carboxyl groups in its molecular structure can undergo a cross-linking reaction with calcium ions in blood, rapidly forming a gel-like network structure that effectively encapsulates red blood cells and platelets, accelerating the coagulation process. Simultaneously, the introduction of quaternary ammonium salt-modified silane enhances the adhesion between the gel and wound tissue, tightly adhering to the wound surface, reducing blood exudation, and significantly shortening hemostasis time, making it particularly suitable for trauma emergency scenarios.

Description

Technical Field

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

[0002] In the field of medical hemostasis, rapid and efficient hemostasis and prevention of wound infection are key requirements for ensuring patient safety and promoting wound healing. Currently, commonly used hemostatic materials in clinical practice (such as hemostatic sponges, hemostatic powders, and traditional gels) have certain limitations: some materials have a slow hemostatic speed, making it difficult to meet the emergency needs of severe bleeding scenarios such as injuries to large blood vessels. For example, early clinical applications of cotton gauze required prolonged pressure to assist in hemostasis and were non-degradable, limiting their application in deep trauma or active bleeding scenarios. Even commercially available products such as QuikClot® gauze and CELOX® powder have problems such as insufficient adhesion in moist environments and poor sealing effect on irregular wounds, failing to effectively address pressure bleeding. Some hemostatic materials can only achieve preliminary hemostasis and lack the ability to inhibit pathogens, easily exposing the wound to a bacterial invasion environment. In clinical practice, infections caused by common pathogens such as Staphylococcus aureus and Escherichia coli, as well as multidrug-resistant bacteria, can trigger inflammatory reactions in wounds, significantly prolonging the healing process. Furthermore, materials with poor component stability or biocompatibility may cause local tissue irritation, allergic reactions, and even hinder subsequent tissue repair. Therefore, avoiding these phenomena is crucial to solving the problem. Summary of the Invention

[0003] (a) Technical problems to be solved

[0004] To address the shortcomings of existing technologies, this invention provides a hemostatic gel and its preparation method, which has good antibacterial and hemostatic effects, as well as good mechanical properties.

[0005] (II) Technical Solution

[0006] To achieve the above objectives, the present invention provides the following technical solution: a hemostatic gel comprising the following weight components: 6-10 parts by weight of sodium alginate, 4-7 parts by weight of quaternary ammonium salt modified silane, 2-3 parts by weight of glutaraldehyde, and 3-4 parts by weight of water.

[0007] Furthermore, the method for preparing the quaternary ammonium salt-modified silane is as follows:

[0008] S1. Trimercaptopropyltrimethoxysilane was added to methanol, followed by slow dropwise addition of 12–14 ml of 36–37% HCl to the reaction system. After the addition was complete, the reaction mixture was heated to reflux and maintained for 20–24 h. After the reaction was completed, it was cooled to room temperature. Then, the methanol in the supernatant was poured off, and the oily product was washed with ice-cold methanol. The ice-cold methanol was then poured off, and the oily product was dissolved with dichloromethane. Ice-cold methanol was added to obtain the precipitate, which was frozen overnight. The supernatant was then poured off to obtain the mercapto-modified silane (POSS-HS).

[0009] S2. Add N-methyldiethanolamine and acrylic acid to toluene solvent, stir to dissolve, continue to add p-toluenesulfonic acid catalyst, react at 90-100℃, cool to room temperature after completion, wash, dry with anhydrous magnesium sulfate to obtain alkenyl intermediate;

[0010] S3. Add 3-bromo-propyltrimethylammonium bromide and the alkenyl intermediate to the reactor, then continue to add ethanol, and react at 85-90℃ for 4-6 h. After the reaction is completed, wash with ethyl acetate and dry to obtain the alkenyl quaternary ammonium salt intermediate.

[0011] S4. Add mercapto-modified silane, alkenyl quaternary ammonium salt intermediate, and 2,2-dimethoxy-2-phenylacetophenone to 40-50 ml of ultra-dry dichloromethane and react under 365 nm UV light for 10-12 h. After the reaction is complete, wash, dry with anhydrous magnesium sulfate, filter, and distill the filtrate under reduced pressure to obtain quaternary ammonium salt modified silane.

[0012] Furthermore, the ratio of trimercaptopropyltrimethoxysilane to methanol in S1 is 3-6 ml: 110-120 ml.

[0013] Furthermore, in S2, the ratio of toluene, N-methyldiethanolamine, acrylic acid, and p-toluenesulfonic acid catalyst is 40-45 ml: 2-3 mmol: 4-6 mmol: 0.01-0.02 mmol.

[0014] Furthermore, the reaction time in S2 is 5 to 6 hours.

[0015] Furthermore, the ratio of 3-bromo-propyltrimethylammonium bromide, alkenyl intermediate, and ethanol in S3 is 1.4–1.8 mmol: 1.5–2 mmol: 30–45 ml.

[0016] Further, in S4, the ratio of mercapto-modified silane, alkenyl quaternary ammonium salt intermediate, and 2,2-dimethoxy-2-phenylacetophenone is 0.5–0.6 mmol: 1.2–1.4 mmol: 0.02–0.03 mmol.

[0017] Furthermore, the preparation method of the hemostatic gel is as follows: sodium alginate, quaternary ammonium salt modified silane, glutaraldehyde, and water are added to a stirrer and stirred for 20-30 minutes to obtain the hemostatic gel.

[0018] (iii) Beneficial technical effects

[0019] This invention uses sodium alginate as a base material. The carboxyl groups in its molecular structure can undergo cross-linking reactions with calcium ions in the blood to quickly form a gel-like network structure, which effectively encapsulates red blood cells and platelets, accelerating the coagulation process. At the same time, the introduction of quaternary ammonium salt-modified silane can enhance the adhesion between the gel and wound tissue, closely adhere to the wound surface, reduce blood exudation, and significantly shorten the hemostasis time, making it particularly suitable for trauma emergency scenarios.

[0020] Quaternary ammonium cations in silane molecules modified with quaternary ammonium salts possess strong positive charge, which can disrupt the integrity of bacterial cell membranes, leading to leakage of bacterial contents and death. This exhibits highly effective inhibition against common pathogenic bacteria, resulting in good antibacterial effects. Esterification of the hydroxyl group in N-methyldiethanolamine and the carboxyl group in acrylic acid introduces a bis-tertiary amine, yielding an alkenyl intermediate. Quaternization of the bromine in 3-bromo-propyltrimethylammonium bromide and the tertiary amine in the alkenyl intermediate generates a quaternary ammonium salt, thus yielding an alkenyl quaternary ammonium salt intermediate. This increases the degree of substitution of the quaternary ammonium salt, resulting in better antibacterial effects. The introduction of POSS creates an organic-inorganic hybrid hydrogel in the gel system, improving the mechanical properties of the PEG hydrogel. The molecular cross-linking network formed by sodium alginate, quaternary ammonium salt-modified silane, and glutaraldehyde can form a porous structure through cross-linking reactions, rapidly covering the wound surface, blocking blood exudation, and achieving good hemostasis. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] To better understand the above technical solutions, specific embodiments will be provided below to illustrate the technical solutions in detail.

[0023] Example 1

[0024] S1. Add 3 ml of trimercaptopropyltrimethoxysilane to 110 ml of methanol, and then slowly add 12 ml of 36% HCl dropwise to the reaction system. After the addition is complete, heat the reaction mixture to reflux and maintain the reaction for 20 h. After the reaction is complete, cool to room temperature, then pour off the methanol in the supernatant, wash the oily product with ice-cold methanol, then pour off the ice-cold methanol, dissolve the oily product with dichloromethane, add ice-cold methanol to obtain the precipitate, freeze overnight, pour off the supernatant to obtain mercapto-modified silane;

[0025] S2. Add 2 mmol of N-methyldiethanolamine and 4 mmol of acrylic acid to 40 ml of toluene solvent, stir to dissolve, and continue to add 0.01 mmol of p-toluenesulfonic acid catalyst. React at 90 °C for 5 h. After the reaction is completed, cool to room temperature, wash, and dry with anhydrous magnesium sulfate to obtain alkenyl intermediate.

[0026] S3. Add 1.4 mmol of 3-bromo-propyltrimethylammonium bromide and 1.5 mmol of alkenyl intermediate to the reactor, then add 30 ml of ethanol, and react at 85 °C for 4 h. After the reaction is complete, wash with ethyl acetate and dry to obtain alkenyl quaternary ammonium salt intermediate.

[0027] S4. Add 0.5 mmol of mercapto-modified silane, 1.2 mmol of alkenyl quaternary ammonium salt intermediate, and 0.02 mmol of 2,2-dimethoxy-2-phenylacetophenone to 40 mL of ultra-dry dichloromethane and react under 365 nm UV light for 10 h. After the reaction is complete, wash, dry with anhydrous magnesium sulfate, filter, and distill under reduced pressure to obtain quaternary ammonium salt-modified silane.

[0028] S5. Add 6 parts by weight of sodium alginate, 4 parts by weight of quaternary ammonium salt modified silane, 2 parts by weight of glutaraldehyde, and 3 parts by weight of water to a stirrer and stir for 20 minutes to obtain a hemostatic gel.

[0029] Example 2

[0030] S1. Add 6 ml of trimercaptopropyltrimethoxysilane to 120 ml of methanol, and then slowly add 14 ml of 37% HCl dropwise to the reaction system. After the addition is complete, heat the reaction mixture to reflux and maintain the reaction for 24 h. After the reaction is complete, cool to room temperature, then pour off the methanol in the supernatant, wash the oily product with ice-cold methanol, then pour off the ice-cold methanol, dissolve the oily product with dichloromethane, add ice-cold methanol to obtain the precipitate, freeze overnight, pour off the supernatant to obtain mercapto-modified silane;

[0031] S2. Add 3 mmol of N-methyldiethanolamine and 6 mmol of acrylic acid to 45 ml of toluene solvent, stir to dissolve, and continue to add 0.02 mmol of p-toluenesulfonic acid catalyst. React at 100 °C for 6 h. After the reaction is completed, cool to room temperature, wash, and dry with anhydrous magnesium sulfate to obtain alkenyl intermediate.

[0032] S3. Add 1.8 mmol of 3-bromopropyltrimethylammonium bromide and 2 mmol of alkenyl intermediate to the reactor, then add 45 ml of ethanol, and react at 90 °C for 6 h. After the reaction is complete, wash with ethyl acetate and dry to obtain alkenyl quaternary ammonium salt intermediate.

[0033] S4. 0.6 mmol of mercapto-modified silane, 1.4 mmol of alkenyl quaternary ammonium salt intermediate, and 0.03 mmol of 2,2-dimethoxy-2-phenylacetophenone were added to 50 mL of ultra-dry dichloromethane and reacted under 365 nm UV light for 12 h. After the reaction was completed, the mixture was washed, dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the quaternary ammonium salt-modified silane.

[0034] S5. Add 10 parts by weight of sodium alginate, 7 parts by weight of quaternary ammonium salt modified silane, 3 parts by weight of glutaraldehyde, and 4 parts by weight of water to a stirrer and stir for 30 minutes to obtain a hemostatic gel.

[0035] Example 3

[0036] S1. Add 5 ml of trimercaptopropyltrimethoxysilane to 115 ml of methanol, and then slowly add 13 ml of 36% HCl dropwise to the reaction system. After the addition is complete, heat the reaction mixture to reflux and maintain the reaction for 22 h. After the reaction is complete, cool to room temperature, then pour off the methanol in the supernatant, wash the oily product with ice-cold methanol, then pour off the ice-cold methanol, dissolve the oily product with dichloromethane, add ice-cold methanol to obtain the precipitate, freeze overnight, pour off the supernatant to obtain mercapto-modified silane;

[0037] S2. Add 2.5 mmol of N-methyldiethanolamine and 5 mmol of acrylic acid to 43 ml of toluene solvent, stir to dissolve, and continue to add 0.015 mmol of p-toluenesulfonic acid catalyst. React at 95 °C for 5 h. After the reaction is completed, cool to room temperature, wash, and dry with anhydrous magnesium sulfate to obtain alkenyl intermediate.

[0038] S3. Add 1.6 mmol of 3-bromo-propyltrimethylammonium bromide and 1.7 mmol of alkenyl intermediate to the reactor, then add 40 ml of ethanol, and react at 87 °C for 5 h. After the reaction is complete, wash with ethyl acetate and dry to obtain alkenyl quaternary ammonium salt intermediate.

[0039] S4. 0.55 mmol of mercapto-modified silane, 1.3 mmol of alkenyl quaternary ammonium salt intermediate, and 0.02 mmol of 2,2-dimethoxy-2-phenylacetophenone were added to 45 mL of ultra-dry dichloromethane and reacted under 365 nm UV light for 11 h. After the reaction was completed, the mixture was washed, dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the quaternary ammonium salt-modified silane.

[0040] S5. Add 8 parts by weight of sodium alginate, 5 parts by weight of quaternary ammonium salt modified silane, 2.5 parts by weight of glutaraldehyde, and 3.5 parts by weight of water to a stirrer and stir for 25 minutes to obtain a hemostatic gel.

[0041] Example 4

[0042] S1. Add 3 ml of trimercaptopropyltrimethoxysilane to 110 ml of methanol, and then slowly add 12 ml of 36% HCl dropwise to the reaction system. After the addition is complete, heat the reaction mixture to reflux and maintain the reaction for 20 h. After the reaction is complete, cool to room temperature, then pour off the methanol in the supernatant, wash the oily product with ice-cold methanol, then pour off the ice-cold methanol, dissolve the oily product with dichloromethane, add ice-cold methanol to obtain the precipitate, freeze overnight, pour off the supernatant to obtain mercapto-modified silane;

[0043] S2. Add 3 mmol of N-methyldiethanolamine and 6 mmol of acrylic acid to 45 ml of toluene solvent, stir to dissolve, and continue to add 0.02 mmol of p-toluenesulfonic acid catalyst. React at 100 °C for 6 h. After the reaction is completed, cool to room temperature, wash, and dry with anhydrous magnesium sulfate to obtain alkenyl intermediate.

[0044] S3. Add 1.8 mmol of 3-bromopropyltrimethylammonium bromide and 2 mmol of alkenyl intermediate to the reactor, then add 45 ml of ethanol, and react at 90 °C for 6 h. After the reaction is complete, wash with ethyl acetate and dry to obtain alkenyl quaternary ammonium salt intermediate.

[0045] S4. 0.55 mmol of mercapto-modified silane, 1.3 mmol of alkenyl quaternary ammonium salt intermediate, and 0.02 mmol of 2,2-dimethoxy-2-phenylacetophenone were added to 45 mL of ultra-dry dichloromethane and reacted under 365 nm UV light for 11 h. After the reaction was completed, the mixture was washed, dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain the quaternary ammonium salt-modified silane.

[0046] S5. Add 8 parts by weight of sodium alginate, 5 parts by weight of quaternary ammonium salt modified silane, 2.5 parts by weight of glutaraldehyde, and 3.5 parts by weight of water to a stirrer and stir for 25 minutes to obtain a hemostatic gel.

[0047] Example 5

[0048] S1. Add 6 ml of trimercaptopropyltrimethoxysilane to 120 ml of methanol, and then slowly add 14 ml of 37% HCl dropwise to the reaction system. After the addition is complete, heat the reaction mixture to reflux and maintain the reaction for 24 h. After the reaction is complete, cool to room temperature, then pour off the methanol in the supernatant, wash the oily product with ice-cold methanol, then pour off the ice-cold methanol, dissolve the oily product with dichloromethane, add ice-cold methanol to obtain the precipitate, freeze overnight, pour off the supernatant to obtain mercapto-modified silane;

[0049] S2. Add 2.5 mmol of N-methyldiethanolamine and 5 mmol of acrylic acid to 43 ml of toluene solvent, stir to dissolve, and continue to add 0.015 mmol of p-toluenesulfonic acid catalyst. React at 95 °C for 5 h. After the reaction is completed, cool to room temperature, wash, and dry with anhydrous magnesium sulfate to obtain alkenyl intermediate.

[0050] S3. Add 1.6 mmol of 3-bromo-propyltrimethylammonium bromide and 1.7 mmol of alkenyl intermediate to the reactor, then add 40 ml of ethanol, and react at 87 °C for 5 h. After the reaction is complete, wash with ethyl acetate and dry to obtain alkenyl quaternary ammonium salt intermediate.

[0051] S4. Add 0.5 mmol of mercapto-modified silane, 1.2 mmol of alkenyl quaternary ammonium salt intermediate, and 0.02 mmol of 2,2-dimethoxy-2-phenylacetophenone to 40 mL of ultra-dry dichloromethane and react under 365 nm UV light for 10 h. After the reaction is complete, wash, dry with anhydrous magnesium sulfate, filter, and distill under reduced pressure to obtain quaternary ammonium salt-modified silane.

[0052] S5. Add 6 parts by weight of sodium alginate, 4 parts by weight of quaternary ammonium salt modified silane, 2 parts by weight of glutaraldehyde, and 3-4 parts by weight of water to a stirrer and stir for 20 minutes to obtain a hemostatic gel.

[0053] Comparative Example 1

[0054] The difference between this comparative example and Example 5 is that a mercapto-modified silane was used instead of a quaternary ammonium salt-modified silane.

[0055] Comparative Example 2

[0056] The difference between this comparative example and Example 5 is that an alkenyl quaternary ammonium salt intermediate was used instead of a quaternary ammonium salt to modify the silane.

[0057] Mechanical property testing: DHR Diseovery rheometer was used for testing. A parallel plate fixture with a diameter of 20 mm was used to test the mechanical properties of the hydrogel. The measurement parameters were a fixed frequency of 1 Hz and a stress range of 0.1~100 Pa. The test temperature was 25 ℃.

[0058] Staphylococcus aureus was used as the test strain. 0.5 ml of activated test strain suspension (10⁸ CFU / ml) was evenly coated onto the surface of agar medium. A gel dressing film sterilized by UV irradiation was then attached to the surface of the medium. The medium was placed in a constant temperature incubator, and the incubation temperature was set to 37 °C for 48 h. The diameter of the inhibition zone was measured after incubation.

[0059] Thirty-five mice were randomly divided into seven groups, corresponding to the hemostatic gels of Examples 1-5 and Comparative Examples 1-2, with five mice in each group. A 5mm incision was made at the tail end of each mouse using a sterile scalpel. Once blood oozed out, 0.4ml of the corresponding hemostatic gel was immediately applied to the wound, and timing was started simultaneously. Observation was continuous, and bleeding was considered to have stopped when the wound ceased bleeding. The time from the start of bleeding to its cessation was defined as the hemostasis time (s).

[0060] Table 1 shows the performance test results of the examples and comparative examples.

[0061]

[0062] As shown in Table 1, the hemostatic gel prepared by this invention has good mechanical properties and antibacterial hemostatic properties.

[0063] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Unless otherwise specified, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0064] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

[0065] Those skilled in the art should understand that the above descriptions are merely several specific embodiments of the present invention, and not all embodiments.

Claims

1. A hemostatic gel, characterized in that, It comprises the following weight components: 6-10 parts by weight of sodium alginate, 4-7 parts by weight of quaternary ammonium salt modified silane, 2-3 parts by weight of glutaraldehyde, 3-4 parts by weight of water; The preparation method of the quaternary ammonium salt modified silane is: S1. Tri-mercapto-propyl trimethoxysilane is added to methanol, then 12-14 ml of 36-37 % HCl is slowly added dropwise in the reaction system, after the dropwise addition is completed, the reaction mixture is heated to reflux and kept for 20-24 h, after the reaction is completed, it is cooled to room temperature, then the methanol in the upper clear liquid is poured out, the oily product is washed with ice methanol, then the ice methanol is poured out, the oily product is dissolved with dichloromethane, the precipitated product is obtained by adding ice methanol, and it is refrigerated overnight, then the upper clear liquid is poured out, and the mercapto-modified silane is obtained. S2. N-methyl diethanolamine and acrylic acid are added to a toluene solvent, stirred and dissolved, then p-toluenesulfonic acid catalyst is continuously added, reaction is carried out at 90-100 ℃, after the reaction is completed, it is cooled to room temperature, washed, and dried with anhydrous magnesium sulfate, and the alkenyl intermediate is obtained. S3. 3-bromo-propyl trimethyl ammonium bromide and the alkenyl intermediate are added to a reactor, then ethanol is continuously added, reaction is carried out at 85-90 ℃ for 4-6 h, after the reaction is completed, it is washed with ethyl acetate and dried, and the alkenyl quaternary ammonium salt intermediate is obtained. S4. The mercapto-modified silane, the alkenyl quaternary ammonium salt intermediate and 2,2-dimethoxy-2-phenyl acetophenone are added to 40-50 ml of super-dry dichloromethane, reaction is carried out under the irradiation of a 365 nm ultraviolet lamp for 10-12 h, after the reaction is completed, it is washed, dried with anhydrous magnesium sulfate, filtered, and the filtrate is distilled under reduced pressure, and the quaternary ammonium salt modified silane is obtained.

2. The hemostatic gel of claim 1, wherein, The amount ratio of tri-mercapto-propyl trimethoxysilane to methanol in S1 is 3-6 ml: 110-120 ml.

3. The hemostatic gel of claim 1, wherein, The amount ratio of toluene, N-methyl diethanolamine, acrylic acid and p-toluenesulfonic acid catalyst in S2 is 40-45 ml: 2-3 mmol: 4-6 mmol: 0.01-0.02 mmol.

4. The hemostatic gel of claim 1, wherein, The reaction time in S2 is 5-6 h.

5. The hemostatic gel of claim 1, wherein, The amount ratio of 3-bromo-propyl trimethyl ammonium bromide, the alkenyl intermediate and ethanol in S3 is 1.4-1.8 mmol: 1.5-2 mmol: 30-45 ml.

6. The hemostatic gel of claim 1, wherein, The amount ratio of the mercapto-modified silane, the alkenyl quaternary ammonium salt intermediate and 2,2-dimethoxy-2-phenyl acetophenone in S4 is 0.5-0.6 mmol: 1.2-1.4 mmol: 0.02-0.03 mmol.

7. A method of preparing a haemostatic gel according to any one of claims 1 to 6, characterised in that, The preparation method of the hemostatic gel is that sodium alginate, quaternary ammonium salt modified silane, glutaraldehyde and water are added to a stirrer, stirred for 20-30 min, and the hemostatic gel is obtained.

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