Temperature-sensitive gel and preparation method thereof

Abstract

The invention discloses a temperature-sensitive gel and a preparation method thereof, and belongs to the technical field of gels, and the temperature-sensitive gel provided by the invention is prepared by mixing a temperature-sensitive material N-isopropylacrylamide containing double bonds with a self-made modified cross-linking agent, then adding a photoinitiator 2-hydroxy-1-[4-(2-hydroxyethoxy) phenyl]-2-methyl-1-acetone, then adding a photoinitiator 2-hydroxy-1-[4-(2-hydroxyethoxy) phenyl]-2-methyl-1-acetone, and finally adding an initiator 2-hydroxy-1-[4-(2-hydroxyethoxy) phenyl]-2-methyl-1-acetone to prepare the temperature- and finally, carrying out cross-linking polymerization under the action of ultraviolet rays with the wavelength of 365 nm. Through detection, the prepared temperature-sensitive gel has excellent temperature-sensitive characteristics, meanwhile, a modified cross-linking agent is prepared by improving the cross-linking agent, then the modified cross-linking agent is applied to the preparation process of the temperature-sensitive gel, and the finally prepared temperature-sensitive gel has the advantages that the antibacterial performance is remarkably improved on the basis that the excellent temperature-sensitive characteristics are reserved; the temperature-sensitive gel prepared by the invention can be applied to the field of repairing of wounds of skin, oral cavity, esophageal mucosa and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of gel, and in particular relates to a temperature-sensitive gel and a preparation method thereof. Background Art

[0002] Smart hydrogels, also known as stimulus-sensitive hydrogels or environmentally responsive hydrogels, can undergo corresponding changes in physical and chemical properties when the external environment changes (temperature, pH, magnetic field, etc.). Depending on the stimulus, smart hydrogels can be divided into temperature-sensitive hydrogels, pH-sensitive hydrogels, pressure-sensitive hydrogels, and photosensitive hydrogels. Among the many stimulus response factors, temperature is the easiest response condition to control, so temperature-responsive hydrogels have been widely studied.

[0003] Temperature-sensitive hydrogels (thermosensitive hydrogels for short) will shrink and swell dramatically when stimulated by changes in ambient temperature. The temperature responsiveness of thermosensitive hydrogels can be used to control the release of drugs, so they are widely used in the medical field.

[0004] In the medical field, thermosensitive gels are often used in wound dressings, drug delivery carriers, and other scenarios. In these applications, the patient's skin or tissue may have been damaged, and the immune system is in a relatively fragile state, which is extremely susceptible to invasion by bacteria and other pathogens. If the thermosensitive gel does not have good antibacterial properties, bacteria may breed and multiply on the surface or inside the gel, further increasing the patient's risk of infection, which will not only delay the healing process of the wound, but may also lead to serious complications such as sepsis, posing a huge threat to the patient's life and health; secondly, there are a large number of pathogenic microorganisms in the hospital environment, and the thermosensitive gel will inevitably come into contact with these microorganisms during use. If the antibacterial properties are insufficient, it will easily become a "hotbed" for bacteria. Summary of the invention

[0005] The object of the present invention is to provide a thermosensitive gel and a preparation method thereof, so as to improve the antibacterial property of the thermosensitive gel.

[0006] The purpose of the present invention can be achieved through the following technical solutions: A method for preparing a thermosensitive gel comprises the following steps: S1. Add N-isopropylacrylamide, modified crosslinking agent and poloxamer 188 to purified water and stir magnetically for 20 to 30 minutes to obtain solution component A. S2. Add 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone to dimethyl sulfoxide and stir magnetically for 20 to 30 minutes to obtain solution component B; S3. Mix solution component A and solution component B, and then stir magnetically for 20 to 30 minutes to obtain a mixed solution. Use a dropper to drop the mixed solution onto the gel mold, and then irradiate with a 365nm ultraviolet curing lamp for 1 minute to obtain a thermosensitive gel.

[0007] Furthermore, the usage ratio of purified water, N-isopropylacrylamide, modified crosslinking agent and poloxamer 188 in S1 is 100g: 9-10g: 0.2g: 3.2-3.5g.

[0008] Furthermore, the usage ratio of dimethyl sulfoxide and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone in S2 is 70g:33-35g.

[0009] Furthermore, in S3, the solution component A and the solution component B are mixed in a volume ratio of 50:1.

[0010] Further, the modified cross-linking agent described in S1 is prepared by the following steps: Add N,N-methylenebisacrylamide to anhydrous ethanol, stir for 1-2 hours, then add 6 mol / L sodium nitrite aqueous solution, fill with nitrogen protection, stir for 1-2 hours, then add 6 mol / L hydrochloric acid aqueous solution dropwise, stir while dropping, after the addition is complete, stir for 5-6 hours, after the stirring is complete, collect the precipitate by centrifugation, wash the precipitate three times with deionized water and 50% ethanol aqueous solution by volume, and then place it in a dark condition and vacuum dry for 24 hours to obtain a modified crosslinking agent. The preparation process of the modified crosslinking agent is as follows:

[0011] Furthermore, the dosage ratio of the anhydrous ethanol, N,N-methylenebisacrylamide, sodium nitrite aqueous solution and hydrochloric acid aqueous solution is 200mL:15.5-16.0g:200mL:200mL.

[0012] Furthermore, the thermosensitive gel is prepared by the above preparation method.

[0013] Beneficial effects of the present invention: The present invention provides a thermosensitive gel and a preparation method thereof. Specifically, the thermosensitive gel provided by the present invention is prepared by mixing N-isopropylacrylamide, a temperature-sensitive material containing double bonds, with a modified crosslinking agent prepared by the present invention, and then adding a photoinitiator 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone, and finally crosslinking and polymerizing under the action of ultraviolet rays with a wavelength of 365nm. After testing, the thermosensitive gel prepared by the present invention has excellent thermosensitive properties. Specifically, the present invention measures the equilibrium swelling rate of the prepared gel at different temperatures. The difference in the equilibrium swelling rate of the gel at different temperatures can reflect the response of the gel to temperature, thereby verifying its thermosensitive properties.

[0014] At the same time, the present invention improves the cross-linking agent to prepare a modified cross-linking agent, and then applies the modified cross-linking agent to the preparation process of the above-mentioned thermosensitive gel. The thermosensitive gel finally prepared has significantly improved antibacterial properties while retaining excellent thermosensitive properties. Specifically, the modified cross-linking agent of the present invention is formed by nitrosation of the secondary amine group of N,N-methylenebisacrylamide under acidic conditions. Nitrosation forms nitroso (-NO), and the NN bond between the nitroso and the main chain is easily broken under the action of light and heat, thereby releasing NO gas. NO has a broad-spectrum antibacterial property, promotes wound healing and anti-inflammatory effects. The present invention combines NO gas with gel to prepare a thermosensitive gel with excellent antibacterial properties. When the prepared thermosensitive gel is then coated on the skin surface, the thermosensitive gel can slowly discharge moisture and release NO gas through the heating of human skin, while keeping the skin surface moist, NO gas with antibacterial effect is released, thereby inhibiting the growth of bacteria. At the same time, NO also has anti-inflammatory and wound healing effects. DETAILED DESCRIPTION

[0015] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0016] Example 1

[0017] Preparation of modified crosslinking agent: To 200 mL of anhydrous ethanol (AR; 99.7%; purchased from Sinopharm Chemical Reagent Co., Ltd.), add 15.5 g of N,N-methylenebisacrylamide (CP; 98.0%; purchased from Sinopharm Chemical Reagent Co., Ltd.), stir for 1 hour, then add 200 mL of 6 mol / L sodium nitrite aqueous solution (laboratory configuration), fill with nitrogen protection, stir for another 1 hour, then add 200 mL of 6 mol / L hydrochloric acid aqueous solution (laboratory configuration) dropwise, stirring while dropping, after the addition is completed, stir for 5 hours, after stirring is completed, collect the precipitate by centrifugation, wash the precipitate three times with deionized water and 50% ethanol aqueous solution (laboratory configuration) by volume, and then place it in a light-proof condition and vacuum dry for 24 hours to obtain a modified cross-linking agent.

[0018] Example 2

[0019] Preparation of modified crosslinking agent: To 200 mL of anhydrous ethanol (AR; 99.7%; purchased from Sinopharm Chemical Reagent Co., Ltd.), add 15.8 g of N,N-methylenebisacrylamide (CP; 98.0%; purchased from Sinopharm Chemical Reagent Co., Ltd.), stir for 2 h, then add 200 mL of 6 mol / L sodium nitrite aqueous solution (laboratory configuration), fill with nitrogen protection, stir for another 2 h, then add 200 mL of 6 mol / L hydrochloric acid aqueous solution (laboratory configuration) dropwise, stirring while dropping, after the addition is completed, stir for 6 h, after stirring is completed, collect the precipitate by centrifugation, wash the precipitate three times with deionized water and 50% ethanol aqueous solution (laboratory configuration) by volume, and then place it in a light-proof condition and vacuum dry it for 24 h to obtain a modified cross-linking agent.

[0020] Example 3

[0021] Preparation of modified crosslinking agent: To 200 mL of anhydrous ethanol (AR; 99.7%; purchased from Sinopharm Chemical Reagent Co., Ltd.), add 16.0 g of N,N-methylenebisacrylamide (CP; 98.0%; purchased from Sinopharm Chemical Reagent Co., Ltd.), stir for 2 h, then add 200 mL of 6 mol / L sodium nitrite aqueous solution (laboratory configuration), fill with nitrogen protection, stir for another 2 h, then add 200 mL of 6 mol / L hydrochloric acid aqueous solution (laboratory configuration) dropwise, stirring while dropping, after the addition is completed, stir for 6 h, after stirring is completed, collect the precipitate by centrifugation, wash the precipitate three times with deionized water and 50% ethanol aqueous solution (laboratory configuration) by volume, and then place it in a light-proof condition and vacuum dry it for 24 h to obtain a modified cross-linking agent.

[0022] Example 4

[0023] A method for preparing a thermosensitive gel comprises the following steps: S1. Add temperature-sensitive material N-isopropylacrylamide (98%; purchased from Shanghai MacLean Biochemical Technology Co., Ltd.), the modified cross-linking agent prepared in Example 1 and poloxamer 188 (Shanghai MacLean Biochemical Technology Co., Ltd.) into purified water (sterile purified water, purchased from Shanghai Yuanye Biotechnology Co., Ltd.), and stir magnetically for 20 minutes to obtain solution component A, wherein the amount ratio of purified water, N-isopropylacrylamide, the modified cross-linking agent prepared in Example 1 and poloxamer 188 is 100 g:9 g:0.2 g:3.2 g; S2, add photoinitiator 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone (98.0%; purchased from Sinopharm Chemical Reagent Co., Ltd.) to dimethyl sulfoxide (99.7%; purchased from Sinopharm Chemical Reagent Co., Ltd.), stir magnetically for 30 minutes, and obtain solution component B, wherein the amount ratio of dimethyl sulfoxide and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone is 70g:33g; S3. Solution component A and solution component B were mixed at a volume ratio of 50:1, and then magnetically stirred for 20 minutes to obtain a mixed solution. The mixed solution was dripped onto the gel mold using a dropper, and then irradiated with a 365nm ultraviolet curing lamp for 1 minute to obtain a thermosensitive gel.

[0024] Example 5

[0025] A method for preparing a thermosensitive gel comprises the following steps: S1. Add temperature-sensitive material N-isopropylacrylamide (98%; purchased from Shanghai MacLean Biochemical Technology Co., Ltd.), the modified cross-linking agent prepared in Example 2 and poloxamer 188 (Shanghai MacLean Biochemical Technology Co., Ltd.) into purified water (sterile purified water, purchased from Shanghai Yuanye Biotechnology Co., Ltd.), and stir magnetically for 30 minutes to obtain solution component A, wherein the amount ratio of purified water, N-isopropylacrylamide, the modified cross-linking agent prepared in Example 2 and poloxamer 188 is 500 g:50 g:1 g:17 g; S2, add photoinitiator 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone (98.0%; purchased from Sinopharm Chemical Reagent Co., Ltd.) to dimethyl sulfoxide (99.7%; purchased from Sinopharm Chemical Reagent Co., Ltd.), stir magnetically for 30 minutes, and obtain solution component B, wherein the amount ratio of dimethyl sulfoxide and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone is 35g:17g; S3. Solution component A and solution component B were mixed at a volume ratio of 50:1, and then magnetically stirred for 30 minutes to obtain a mixed solution. The mixed solution was dripped onto the gel mold using a dropper, and then irradiated with a 365nm ultraviolet curing lamp for 1 minute to obtain a thermosensitive gel.

[0026] Example 6

[0027] A method for preparing a thermosensitive gel comprises the following steps: S1. Add temperature-sensitive material N-isopropylacrylamide (98%; purchased from Shanghai MacLean Biochemical Technology Co., Ltd.), the modified cross-linking agent prepared in Example 3 and poloxamer 188 (Shanghai MacLean Biochemical Technology Co., Ltd.) into purified water (sterile purified water, purchased from Shanghai Yuanye Biotechnology Co., Ltd.), and stir magnetically for 30 minutes to obtain solution component A, wherein the amount ratio of purified water, N-isopropylacrylamide, the modified cross-linking agent prepared in Example 3 and poloxamer 188 is 100 g:9.5 g:0.2 g:3.5 g; S2, add photoinitiator 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone (98.0%; purchased from Sinopharm Chemical Reagent Co., Ltd.) to dimethyl sulfoxide (99.7%; purchased from Sinopharm Chemical Reagent Co., Ltd.), and stir magnetically for 30 minutes to obtain solution component B, wherein the amount ratio of dimethyl sulfoxide to 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone is 2g:1g; S3. Solution component A and solution component B were mixed at a volume ratio of 50:1, and then magnetically stirred for 30 minutes to obtain a mixed solution. The mixed solution was dripped onto the gel mold using a dropper, and then irradiated with a 365nm ultraviolet curing lamp for 1 minute to obtain a thermosensitive gel.

[0028] Comparative Example 1 Comparative Example 1 is the control group of Example 5, in which the modified cross-linking agent prepared in Example 2 in Example 5 is replaced with N,N-methylenebisacrylamide (CP; 98.0%; purchased from Sinopharm Chemical Reagent Co., Ltd.), and the remaining raw materials, raw material amounts and preparation steps remain unchanged, and finally a thermosensitive gel is obtained.

[0029] Test Example 1 The performance test was performed on the thermosensitive gels prepared in Examples 4 to 6 and Comparative Example 1. The performance test process is as follows. The test results are shown in Table 1: (1) Equilibrium swelling rate test: The equilibrium swelling rates of the thermosensitive gels prepared in Examples 4 to 6 and Comparative Example 1 at different temperatures were measured by gravimetric method. The specific steps of gravimetric method are as follows: The thermosensitive gels prepared in Examples 4 to 6 and Comparative Example 1 were taken, and each group of Examples / Comparative Examples was divided into several groups. The thermosensitive gels of the same group of Examples / Comparative Examples were placed in a vacuum drying oven at 30°C and dried to constant weight. The dried thermosensitive gels were taken out to obtain dry thermosensitive gels, which were weighed. The dried thermosensitive gels were then divided into six groups, which were placed in pure water at 10°C, 20°C, 25°C, 30°C, 40°C, and 50°C for 12 h, respectively. After completion, the groups were taken out, the surface moisture was wiped off with absorbent paper, the gels were weighed, and the equilibrium swelling rate was calculated. The calculation formula of the equilibrium swelling rate is as follows. The calculation results are recorded in Table 1 below: Equilibrium swelling ratio = [(W b -W a ) / W a ]×100%; Among them, W a is the initial mass of the dry thermosensitive gel; Among them, W b is the mass of the thermosensitive gel after reaching swelling equilibrium at different temperatures.

[0030] (2) Antibacterial performance test: 0.1 g of the thermosensitive gel prepared in Examples 4 to 6 and Comparative Example 1 was mixed with 10 mL of 1×10 7 The mixture of Escherichia coli liquid and Staphylococcus aureus liquid was placed in a test tube and placed on a constant temperature shaker at 37°C and 120 r / min for 4 h. This was used as the experimental group, and the liquid without thermosensitive gel was used as the blank group. The liquid of the experimental group and the blank group was taken out and diluted to 1×10 5 CFU / mL, 100 μL of bacterial solution was applied to the surface of the agar plate, and placed in a shaking incubator at 37°C for 24 hours. The antibacterial rate was calculated by the plate colony counting method. The antibacterial rate calculation formula is as follows, and the calculation results are recorded in the following Table 1: Antibacterial rate = [(N a -N b ) / N a ]×100%; Among them, N a is the colony count of the blank group; N b is the colony number of the experimental group.

[0031] Table 1 Test results

[0032] It can be seen from Table 1 that the thermosensitive gels prepared in Examples 4 to 6 have excellent thermosensitive properties. From the antibacterial performance data of Comparative Example 1 and Example 5, it can be seen that the present invention significantly improves the antibacterial (Escherichia coli and Staphylococcus aureus) performance of the thermosensitive gel by improving the cross-linking agent.

[0033] At the same time, further extending, the equilibrium swelling rate of the thermosensitive gel prepared in Examples 4 to 6 has a large change rate at 30°C to 40°C, and the prepared thermosensitive gel is applied to the human body, which is in line with the human body temperature, that is, it has excellent thermosensitive properties within the range of human body temperature. Furthermore, the thermosensitive gel prepared in Examples 4 to 6 can be used in the field of repairing wounds such as skin, oral and esophageal mucosa.

[0034] It should be noted that, in this article, terms such as "include", "comprises" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or equipment that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or equipment.

[0035] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a thermosensitive gel, characterized in that: The following steps are involved: S1. Add N-isopropylacrylamide, modified crosslinking agent and poloxamer 188 to purified water and stir magnetically for 20 to 30 minutes to obtain solution component A. S2. Add 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone to dimethyl sulfoxide and stir magnetically for 20 to 30 minutes to obtain solution component B; S3. Mix solution component A and solution component B, and then stir magnetically for 20 to 30 minutes to obtain a mixed solution. Use a dropper to drop the mixed solution onto the gel mold, and then irradiate with a 365nm ultraviolet curing lamp for 1 minute to obtain a thermosensitive gel.

2. The method for preparing a thermosensitive gel according to claim 1, characterized in that: The usage ratio of purified water, N-isopropylacrylamide, modified crosslinking agent and poloxamer 188 in S1 is 100g: 9-10g: 0.2g: 3.2-3.5g.

3. The method for preparing a thermosensitive gel according to claim 1, characterized in that: The usage ratio of dimethyl sulfoxide and 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone in S2 is 70g:33-35g.

4. The method for preparing a thermosensitive gel according to claim 1, characterized in that: S3: The solution component A and the solution component B are mixed in a volume ratio of 50:

1.

5. The method for preparing a thermosensitive gel according to claim 1, characterized in that: The modified cross-linking agent described in S1 is prepared by the following steps: Add N,N-methylenebisacrylamide to anhydrous ethanol, stir for 1 to 2 hours, then add 6 mol / L sodium nitrite aqueous solution, fill with nitrogen protection, stir for 1 to 2 hours, then add 6 mol / L hydrochloric acid aqueous solution dropwise, stirring while dropping, after the addition is completed, stir for 5 to 6 hours, after the stirring is completed, collect the precipitate by centrifugation, wash the precipitate with deionized water and 50% ethanol aqueous solution by volume three times in sequence, and then place it in a light-proof condition and vacuum dry it for 24 hours to obtain a modified cross-linking agent.

6. The method for preparing a thermosensitive gel according to claim 5, characterized in that: The usage ratio of the anhydrous ethanol, N,N-methylenebisacrylamide, sodium nitrite aqueous solution and hydrochloric acid aqueous solution is 200mL:15.5-16.0g:200mL:200mL.

7. A thermosensitive gel, characterized in that: The method is prepared according to any one of claims 1 to 6.

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