An antibacterial hemostatic material and a method of making the same

Abstract

The application relates to the technical field of biomedical materials, and discloses an antibacterial hemostatic material and a preparation method thereof, which comprises the following components by weight: 2-3 parts of amino acid-terminated polyurethane, 1-3 parts of thiolated chitosan, 3-5 parts of sodium alginate and 2-4 parts of polyvinyl alcohol solution. Through the synergistic effect of the amino acid-terminated polyurethane-thiolated chitosan-sodium alginate, a double hemostatic mechanism of physical adsorption-chemical coagulation is constructed: the sodium alginate, as a natural polysaccharide, has strong hydrophilicity and cation adsorption capacity, can quickly absorb the moisture in the wound blood, concentrate the platelets and coagulation factors, accelerate the activation of thrombin, and shorten the coagulation time; the antibacterial hemostatic material has good antibacterial and hemostatic effects.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, specifically to an antibacterial hemostatic material and its preparation method. Background Technology

[0002] In the field of biomedical materials, wound hemostasis and infection control are core issues that urgently need to be addressed in clinical treatment, especially in scenarios such as surgery, battlefield trauma emergency care, and chronic wound repair, where there is an urgent need for hemostatic materials with both "rapid hemostasis" and "long-lasting antibacterial" properties. Currently, hemostatic materials on the market are mainly divided into two categories: traditional and functional. Traditional hemostatic materials, such as gelatin sponges and hemostatic gauze, while possessing certain physical hemostatic capabilities, exhibit slow hemostasis and lack antibacterial activity, easily leading to wound infection and delayed healing. Functional hemostatic materials, such as chitosan-based hemostatic agents and composite sponges, while improving single properties such as antibacterial or hemostasis, have significant drawbacks. Some materials containing silver ion antibacterial components, while inhibiting bacterial growth, may produce cytotoxicity to normal tissue cells, affecting wound repair. Therefore, developing an antibacterial hemostatic material with rapid hemostasis, strong antibacterial activity, and a simple preparation process has become a key requirement for solving this problem. Summary of the Invention

[0003] (a) Technical problems to be solved

[0004] To address the shortcomings of existing technologies, this invention provides an antibacterial hemostatic material and its preparation method, which exhibits good hemostatic and antibacterial effects.

[0005] (II) Technical Solution

[0006] To achieve the above objectives, the present invention provides the following technical solution: an antibacterial and hemostatic material comprising the following weight components: 2-3 parts by weight of amino acid-terminated polyurethane, 1-3 parts by weight of thiolated chitosan, 3-5 parts by weight of sodium alginate, and 2-4 parts by weight of polyvinyl alcohol solution.

[0007] Furthermore, the preparation method of the amino acid-terminated polyurethane is as follows:

[0008] S1. Add 30-40 mL of N,N-dimethylformamide solvent, 2-3 mmol of N-methyliminodiacetic acid, and 2.6-3.4 mmol of 3-chloro-1-propanol to the reactor, heat the reaction for 4-7 h, cool the reaction mixture after the reaction is completed, concentrate the mixture under reduced pressure, wash the mixture, and obtain the carboxyl quaternary ammonium salt intermediate.

[0009] S2. Add 1-2 mmol of carboxylated quaternary ammonium salt intermediate, 2-4 mmol of pentaerythritol and 0.01-0.02 g of p-toluenesulfonic acid to the reactor, mix well, and then add 3-4 mL of cyclohexane dehydrating agent. Reflux the reaction at 170-180 °C. After the reaction is completed, distill under reduced pressure and wash with anhydrous ethanol to obtain quaternary ammonium salt modified pentaerythritol ester.

[0010] S3. Add 2.4–3 mmol of polyethylene glycol to the reactor, heat in an oil bath at 85–90 °C, and stir for 0.5–1 h. Under a nitrogen atmosphere, add 0.1–0.2 mmol of dibutyltin dilaurate and 5–7 mmol of isophorone diisocyanate, and react at 75–80 °C for 2–3 h. Then, set the temperature to 70–75 °C, and add 0.3–0.5 mmol of quaternary ammonium salt-modified pentaerythritol ester and 30–40 mL of acetone, and react for 1–1.5 h. Then, add 0.2–0.3 g of L-arginine for end-capping, and react at 50–55 °C for 20–30 min. After the reaction is complete, centrifuge, rotary evaporate, and dialyze to obtain amino acid-terminated polyurethane.

[0011] Furthermore, the reaction temperature in S1 is 80–90°C.

[0012] Furthermore, the reflux reaction time in S2 is 2 to 3 hours.

[0013] Furthermore, the molecular weight of the polyethylene glycol in S3 is 400.

[0014] Furthermore, the method for preparing the thiolated chitosan is as follows:

[0015] Disperse 0.5–0.6 g of chitosan in a 2% acetic acid solution and stir until completely dissolved to obtain solution A. Add 1.82–1.94 g of N-acetylcysteine, 0.62–0.7 g of amide diimide hydrochloride, and 0.32–0.33 g of N-hydroxysuccinimide to deionized water and stir for 15–20 min to obtain solution B. Add solution B dropwise to solution A and react at room temperature for 40–48 h. Dialyze the reaction solution with deionized water for 6–7 days and recrystallize with acetone to obtain a white flocculent precipitate. Dry the precipitate in a vacuum oven at 55–60 °C to obtain thiolated chitosan.

[0016] Furthermore, the preparation method of the antibacterial hemostatic material is as follows: amino acid-terminated polyurethane, thiolated chitosan, sodium alginate, and polyvinyl alcohol solution are added to a reactor, stirred and mixed, and dried to obtain the antibacterial hemostatic material.

[0017] Furthermore, the mixing time is 20 to 30 minutes.

[0018] (iii) Beneficial technical effects

[0019] This invention constructs a dual hemostatic mechanism of "physical adsorption and chemical coagulation" through the synergistic effect of "amino acid-terminated polyurethane, thiolated chitosan, and sodium alginate": Sodium alginate, as a natural polysaccharide, has strong hydrophilicity and cationic adsorption capacity, which can quickly absorb water from the wound blood, concentrate platelets and coagulation factors, accelerate thrombin activation, and shorten coagulation time; The thiol group (-SH) of thiolated chitosan can form a coordination bond with the iron ions of hemoglobin in the blood, while its amino group (-NH2) can promote platelet adhesion and aggregation, forming a stable blood clot; L-arginine in amino acid-terminated polyurethane is a key medium in the wound healing process. It can be catalyzed by nitric oxide synthase and arginase at the wound site into nitric oxide and ornithine, respectively, which can regulate local vascular tension: In the early stage, it can slightly dilate capillaries, increase local blood perfusion, and provide conditions for the delivery of coagulation factors (such as thrombin and fibrinogen); In the later stage, it can promote vasoconstriction, reduce wound bleeding, and help stabilize the blood clot. Amino acid-capped polyurethane uses polyethylene glycol 400 (molecular weight 400) as the soft segment, which is both hydrophilic and biodegradable. It can be gradually degraded into small molecular fragments in the body, which are then metabolized and absorbed by the human body without residue. Thiolized chitosan and sodium alginate are both natural polysaccharide derivatives that can be degraded by biological enzymes such as lysozyme. They can participate in the metabolism and repair of wound tissue, promote the growth of granulation tissue, and achieve a better recovery effect. The amino acid-capped polyurethane, thiolated chitosan, and sodium alginate can form a cross-linked network with a large specific surface area, which can quickly adsorb water from the blood in the wound, concentrate platelets and coagulation factors in the pores, accelerate coagulation, and achieve a better coagulation effect. Detailed Implementation

[0020] 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.

[0021] To better understand the above technical solutions, specific embodiments will be provided below to illustrate the technical solutions in detail.

[0022] The molecular weight of polyvinyl alcohol is 20,000.

[0023] Polyvinyl alcohol granules were added to deionized water at a concentration of 5% w / v, stirred, heated to 90°C and maintained for 1 hour to form a homogeneous and transparent solution. The solution was then sterilized at 120°C for 20 minutes and cooled to room temperature to obtain a polyvinyl alcohol solution.

[0024] Example 1

[0025] S1. Add 30 mL of N,N-dimethylformamide solvent, 2 mmol of N-methyliminodiacetic acid, and 2.6 mmol of 3-chloro-1-propanol to the reactor, heat to 80 °C and react for 4 h. After the reaction is completed, cool, concentrate under reduced pressure, and wash to obtain the carboxyl quaternary ammonium salt intermediate.

[0026] S2. Add 1 mmol of carboxylic quaternary ammonium salt intermediate, 2 mmol of pentaerythritol and 0.01 g of p-toluenesulfonic acid to the reactor, mix well, and then add 3 mL of cyclohexane dehydrating agent. Reflux at 170 °C for 2 h. After the reaction is completed, distill under reduced pressure and wash with anhydrous ethanol to obtain quaternary ammonium salt modified pentaerythritol ester.

[0027] S3. Add 2.4 mmol of polyethylene glycol 400 to the reactor, heat in an oil bath at 85 °C, stir for 0.5 h, add 0.1 mmol of dibutyltin dilaurate and 5 mmol of isophorone diisocyanate under a nitrogen atmosphere, react at 75 °C for 2 h, then set the temperature to 70 °C, add 0.3 mmol of quaternary ammonium salt-modified pentaerythritol ester and 30 mL of acetone, react for 1 h, then add 0.2 g of L-arginine for end-capping, react at 50 °C for 20 min, centrifuge, rotary evaporate, dialyze to obtain amino acid-capped polyurethane;

[0028] S4. Disperse 0.5 g of chitosan in 50 mL of 2% acetic acid solution and stir until completely dissolved to obtain solution A; add 1.82 g of N-acetylcysteine, 0.62 g of amide hydrochloride and 0.32 g of N-hydroxysuccinimide to 20 mL of deionized water and stir for 15 min to obtain solution B; add solution B dropwise to solution A and react at room temperature for 40 h. Dialyze the reaction solution with deionized water for 6 days and recrystallize with acetone to obtain a white flocculent precipitate. Dry the precipitate in a vacuum oven at 55 °C to obtain thiolated chitosan.

[0029] S5. Add 2 parts by weight of amino acid-terminated polyurethane, 1 part by weight of thiolated chitosan, 3 parts by weight of sodium alginate, and 2 parts by weight of polyvinyl alcohol solution to the reactor, stir and mix for 20 minutes, and dry to obtain antibacterial hemostatic material.

[0030] Example 2

[0031] S1. Add 40 mL of N,N-dimethylformamide solvent, 3 mmol of N-methyliminodiacetic acid, and 3.4 mmol of 3-chloro-1-propanol to the reactor, heat to 90 °C and react for 7 h. After the reaction is completed, cool, concentrate under reduced pressure, and wash to obtain the carboxyl quaternary ammonium salt intermediate.

[0032] S2. Add 2 mmol of carboxylic quaternary ammonium salt intermediate, 4 mmol of pentaerythritol and 0.02 g of p-toluenesulfonic acid to the reactor, mix well, and then add 4 mL of cyclohexane dehydrating agent. Reflux at 180 °C for 3 h. After the reaction is completed, distill under reduced pressure and wash with anhydrous ethanol to obtain quaternary ammonium salt modified pentaerythritol ester.

[0033] S3. Add 3 mmol of polyethylene glycol 400 to the reactor, heat in an oil bath at 90 °C, stir for 1 h, add 0.2 mmol of dibutyltin dilaurate and 7 mmol of isophorone diisocyanate under a nitrogen atmosphere, react at 80 °C for 3 h, then set the temperature to 75 °C, add 0.5 mmol of quaternary ammonium salt modified pentaerythritol ester and 40 mL of acetone, react for 1.5 h, then add 0.3 g of L-arginine for end-capping, react at 55 °C for 30 min, centrifuge, rotary evaporate, dialyze to obtain amino acid-capped polyurethane;

[0034] S4. Disperse 0.6 g of chitosan in 55 mL of 2% acetic acid solution and stir until completely dissolved to obtain solution A; add 1.94 g of N-acetylcysteine, 0.7 g of amide hydrochloride and 0.33 g of N-hydroxysuccinimide to 25 mL of deionized water and stir for 20 min to obtain solution B; add solution B dropwise to solution A and react at room temperature for 48 h. Dialyze the reaction solution with deionized water for 7 days and recrystallize with acetone to obtain a white flocculent precipitate. Dry the precipitate in a vacuum oven at 55-60 °C to obtain thiolated chitosan.

[0035] S5. Add 3 parts by weight of amino acid-terminated polyurethane, 3 parts by weight of thiolated chitosan, 5 parts by weight of sodium alginate, and 4 parts by weight of polyvinyl alcohol solution to the reactor, stir and mix for 30 minutes, and dry to obtain antibacterial hemostatic material.

[0036] Example 3

[0037] S1. Add 35 mL of N,N-dimethylformamide solvent, 2.5 mmol of N-methyliminodiacetic acid, and 3.0 mmol of 3-chloro-1-propanol to the reactor, heat to 85 °C and react for 6 h. After the reaction is completed, cool, concentrate under reduced pressure, and wash to obtain the carboxyl quaternary ammonium salt intermediate.

[0038] S2. Add 1.5 mmol of carboxylic quaternary ammonium salt intermediate, 3 mmol of pentaerythritol and 0.015 g of p-toluenesulfonic acid to the reactor, mix well, and then add 3.5 mL of cyclohexane dehydrating agent. Reflux at 175 °C for 2 h. After the reaction is completed, distill under reduced pressure and wash with anhydrous ethanol to obtain quaternary ammonium salt modified pentaerythritol ester.

[0039] S3. Add 2.6 mmol of polyethylene glycol 400 to the reactor, heat in an oil bath at 87 °C, stir for 0.7 h, add 0.15 mmol of dibutyltin dilaurate and 5-7 mmol of isophorone diisocyanate under a nitrogen atmosphere, react at 78 °C for 3 h, then set the temperature to 73 °C, add 0.4 mmol of quaternary ammonium salt-modified pentaerythritol ester and 35 mL of acetone, react for 1.2 h, then add 0.25 g of L-arginine for end-capping, react at 53 °C for 26 min, centrifuge, rotary evaporate, dialyze to obtain amino acid-capped polyurethane;

[0040] S4. Disperse 0.55 g of chitosan in 52 mL of 2% acetic acid solution and stir until completely dissolved to obtain solution A; add 1.86 g of N-acetylcysteine, 0.66 g of amide hydrochloride and 0.32 g of N-hydroxysuccinimide to 22 mL of deionized water and stir for 17 min to obtain solution B; add solution B dropwise to solution A and react at room temperature for 45 h. Dialyze the reaction solution with deionized water for 6 days and recrystallize with acetone to obtain a white flocculent precipitate. Dry the precipitate in a vacuum oven at 56 °C to obtain thiolated chitosan.

[0041] S5. Add 2.5 parts by weight of amino acid-terminated polyurethane, 1.5 parts by weight of thiolated chitosan, 4 parts by weight of sodium alginate, and 3 parts by weight of polyvinyl alcohol solution to the reactor, stir and mix for 25 minutes, and dry to obtain antibacterial hemostatic material.

[0042] Example 4

[0043] S1. Add 30 mL of N,N-dimethylformamide solvent, 2 mmol of N-methyliminodiacetic acid, and 2.6 mmol of 3-chloro-1-propanol to the reactor, heat to 80 °C and react for 4 h. After the reaction is completed, cool, concentrate under reduced pressure, and wash to obtain the carboxyl quaternary ammonium salt intermediate.

[0044] S2. Add 1 mmol of carboxylic quaternary ammonium salt intermediate, 2 mmol of pentaerythritol and 0.01 g of p-toluenesulfonic acid to the reactor, mix well, and then add 3 mL of cyclohexane dehydrating agent. Reflux at 170 °C for 2 h. After the reaction is completed, distill under reduced pressure and wash with anhydrous ethanol to obtain quaternary ammonium salt modified pentaerythritol ester.

[0045] S3. Add 3 mmol of polyethylene glycol 400 to the reactor, heat in an oil bath at 90 °C, stir for 1 h, add 0.2 mmol of dibutyltin dilaurate and 7 mmol of isophorone diisocyanate under a nitrogen atmosphere, react at 80 °C for 3 h, then set the temperature to 75 °C, add 0.5 mmol of quaternary ammonium salt modified pentaerythritol ester and 40 mL of acetone, react for 1.5 h, then add 0.3 g of L-arginine for end-capping, react at 55 °C for 30 min, centrifuge, rotary evaporate, dialyze to obtain amino acid-capped polyurethane;

[0046] S4. Disperse 0.55 g of chitosan in 52 mL of 2% acetic acid solution and stir until completely dissolved to obtain solution A; add 1.86 g of N-acetylcysteine, 0.66 g of amide hydrochloride and 0.32 g of N-hydroxysuccinimide to 22 mL of deionized water and stir for 17 min to obtain solution B; add solution B dropwise to solution A and react at room temperature for 45 h. Dialyze the reaction solution with deionized water for 6 days and recrystallize with acetone to obtain a white flocculent precipitate. Dry the precipitate in a vacuum oven at 56 °C to obtain thiolated chitosan.

[0047] S5. Add 2.5 parts by weight of amino acid-terminated polyurethane, 1.5 parts by weight of thiolated chitosan, 4 parts by weight of sodium alginate, and 3 parts by weight of polyvinyl alcohol solution to the reactor, stir and mix for 25 minutes, and dry to obtain antibacterial hemostatic material.

[0048] Comparative Example 1

[0049] The difference between this comparative example and Example 4 is that a quaternary ammonium salt-modified pentaerythritol ester was used instead of amino acid-terminated polyurethane.

[0050] Comparative Example 2

[0051] The difference between this comparative example and Example 4 is that no thiolated chitosan was added.

[0052] 120 mice weighing 25g were randomly selected as experimental subjects and randomly divided into 6 groups: Example 1-4, Example 3, and Comparative Examples 1-2. After being fed in the same environment for one week, the back fur of the mice was shaved, and a 1cm×1cm wound was artificially created. Immediately, 5mg of antibacterial hemostatic material of the corresponding group was applied for treatment, and the time to complete hemostasis was recorded. The average hemostasis time of each group was calculated. Staphylococcus aureus was selected as the test species according to standard GB / T20944.3-2008, and the antibacterial rate was tested.

[0053] Table 1 shows the performance test results of the examples and comparative examples.

[0054]

[0055] As shown in Table 1, the antibacterial and hemostatic material prepared by the present invention has good antibacterial and hemostatic effects.

[0056] 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.

[0057] 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.

[0058] 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. An antibacterial and hemostatic material, characterized in that, It includes the following components by weight: 2-3 parts by weight of amino acid-terminated polyurethane, 1-3 parts by weight of thiolated chitosan, 3-5 parts by weight of sodium alginate, and 2-4 parts by weight of polyvinyl alcohol solution. The preparation method of the amino acid-terminated polyurethane is as follows: S1. Add 30-40 mL of N,N-dimethylformamide solvent, 2-3 mmol of N-methyliminodiacetic acid, and 2.6-3.4 mmol of 3-chloro-1-propanol to the reactor, heat the reaction for 4-7 h, cool the reaction mixture after the reaction is completed, concentrate the mixture under reduced pressure, wash the mixture, and obtain the carboxyl quaternary ammonium salt intermediate. S2. Add 1-2 mmol of carboxylated quaternary ammonium salt intermediate, 2-4 mmol of pentaerythritol and 0.01-0.02 g of p-toluenesulfonic acid to the reactor, mix well, and then add 3-4 mL of cyclohexane dehydrating agent. Reflux the reaction at 170-180 °C. After the reaction is completed, distill under reduced pressure and wash with anhydrous ethanol to obtain quaternary ammonium salt modified pentaerythritol ester. S3. Add 2.4–3 mmol of polyethylene glycol to the reactor, heat in an oil bath at 85–90 °C, and stir for 0.5–1 h. Under a nitrogen atmosphere, add 0.1–0.2 mmol of dibutyltin dilaurate and 5–7 mmol of isophorone diisocyanate, and react at 75–80 °C for 2–3 h. Then, set the temperature to 70–75 °C, and add 0.3–0.5 mmol of quaternary ammonium salt-modified pentaerythritol ester and 30–40 mL of acetone, and react for 1–1.5 h. Then, add 0.2–0.3 g of L-arginine for end-capping, and react at 50–55 °C for 20–30 min. After the reaction is complete, centrifuge, rotary evaporate, and dialyze to obtain amino acid-terminated polyurethane.

2. The antibacterial and hemostatic material according to claim 1, characterized in that, The reaction temperature in S1 is 80–90°C.

3. The antibacterial and hemostatic material according to claim 1, characterized in that, The reflux reaction time in S2 is 2 to 3 hours.

4. The antibacterial and hemostatic material according to claim 1, characterized in that, The molecular weight of the polyethylene glycol in S3 is 400.

5. The antibacterial and hemostatic material according to claim 1, characterized in that, The method for preparing the thiolized chitosan is as follows: Disperse 0.5–0.6 g of chitosan in a 2% acetic acid solution and stir until completely dissolved to obtain solution A. Add 1.82–1.94 g of N-acetylcysteine, 0.62–0.7 g of amide diimide hydrochloride, and 0.32–0.33 g of N-hydroxysuccinimide to deionized water and stir for 15–20 min to obtain solution B. Add solution B dropwise to solution A and react at room temperature for 40–48 h. Dialyze the reaction solution with deionized water for 6–7 days and recrystallize with acetone to obtain a white flocculent precipitate. Dry the precipitate in a vacuum oven at 55–60 °C to obtain thiolated chitosan.

6. A method for preparing the antibacterial hemostatic material as described in claim 1, characterized in that, The method for preparing the antibacterial hemostatic material is as follows: amino acid-terminated polyurethane, thiolated chitosan, sodium alginate, and polyvinyl alcohol solution are added to a reactor, stirred and mixed, and dried to obtain the antibacterial hemostatic material.

7. The method for preparing the antibacterial hemostatic material according to claim 6, characterized in that, The mixing time is 20 to 30 minutes.

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