A one-sided adhesive hydrogel based on sodium unsaturated fatty acid and its preparation method and application

Abstract

The present invention discloses a single-sided adhesive hydrogel based on sodium unsaturated fatty acid, and its preparation method and application. In the present invention, a water-soluble monomer, a cross-linking agent, and an initiator are added to a sodium unsaturated fatty acid micelle solution, and polymerization is initiated by heating to prepare a hydrogel with single-sided adhesive properties, wherein the sodium unsaturated fatty acid is prepared by saponifying natural renewable saturated fatty acids. The upper surface of the single-sided adhesive hydrogel has good adhesive properties, while the bottom surface has almost no adhesive ability. The preparation process of the single-sided adhesive hydrogel is simple and has good biocompatibility, and can be used as a hydrogel patch for loading drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical hydrogel adhesive materials, and particularly relates to a single-sided adhesive hydrogel based on sodium unsaturated fatty acid, and a preparation method and application thereof. Background Art

[0002] Because the three-dimensional network structure rich in water of the hydrogel is similar to that of biological tissues, it is widely used in many medical fields such as wound repair, hemostasis and drug release. However, the increasingly complex use environment poses new requirements for the design of the hydrogel. The realization of the above application scenarios requires good contact to be formed at the interface between the hydrogel and biological tissues. The hydrogel with adhesion performance can effectively solve the above problems, enabling close contact between the adherends and effectively promoting wound closure, drug transport and wound healing.

[0003] Currently, the common method to improve the adhesion performance of the hydrogel is to add a functional monomer that can promote the adhesion performance to the main component monomer of the hydrogel, and prepare a viscous hydrogel through free radical copolymerization (Chem. Soc. Rev. 2020, 49, 433-464). The above method can endow the hydrogel with adhesion performance, but the large amount of functional monomer used results in too high a preparation cost of the adhesive hydrogel. Moreover, the adhesive hydrogel prepared by the monomer copolymerization method is homogeneous, that is, the adhesion ability of each surface of the hydrogel is the same (CN 113853222 A), which is often harmful in some application scenarios. For example, the in vivo use of a homogeneous adhesive hydrogel can lead to organ adhesion and even necrosis; the drug patch for in vitro use only requires single-sided adhesion performance. The existing methods for preparing single-sided adhesive hydrogels mainly include the soaking charge neutralization method, the stepwise in-situ generation method, the soaking dissolution method, etc. These preparation methods have cumbersome steps or use a large amount of organic solvents, which severely limit the practical application of the hydrogel (Adv. Funct. Mater. 2020, 30, 2005689). And the drug delivery adhesive hydrogel often contains a large amount of dopamine groups or their derivatives (Adv. Funct. Mater. 2020, 30, 2004407). The hydrogel prepared by using a large amount of dopamine components is prone to react with oxygen in the air and lose its adhesion performance. Moreover, the hydrogel material containing dopamine chemical composition usually has poor transparency, and its color changes from light brown to dark brown over time, which will cause discomfort to patients when used for wound adhesion and drug application. And the preparation conditions are complex and free radical polymerization needs to be carried out in an inert gas environment, which limits the large-scale preparation of the hydrogel (CN11234268 B). Therefore, designing a single-sided adhesive hydrogel patch prepared under an atmospheric atmosphere, with oxidation resistance, transparency and soft texture has broad application prospects. Summary of the Invention

[0004] To overcome the disadvantages of the preparation of single-sided adhesive hydrogels in the above-mentioned existing technologies, such as cumbersome steps, extensive use of toxic functional monomers and toxic organic solvents, etc., and to achieve the single-sided adhesion performance of hydrogels, the primary object of the present invention is to provide a preparation method of a single-sided adhesive hydrogel based on sodium unsaturated fatty acid. In this method, natural and renewable sodium unsaturated fatty acid molecules self-assemble into micelles under their own hydrophobic forces, and a single-sided adhesive hydrogel patch is prepared by free radical polymerization with a large number of water-soluble monomers. By regulating the concentration ratio of sodium unsaturated fatty acid, the adhesion performance and tensile performance of the hydrogel can be enhanced simultaneously, and by regulating the mass ratio of the cross-linking agent in the system, the mechanical properties of the hydrogel can be enhanced.

[0005] Another object of the present invention is to provide a single-sided adhesive hydrogel based on sodium unsaturated fatty acid prepared by the above preparation method. This hydrogel has excellent single-sided adhesion performance and the advantage of repeated adhesion, can be in close contact with the skin to provide a moist and good recovery environment for the affected area, and is a hydrogel material with application potential that is conducive to the long-term release of drugs.

[0006] Another object of the present invention is to provide an application of the above single-sided adhesive hydrogel based on sodium unsaturated fatty acid.

[0007] The object of the present invention is achieved by the following technical solutions:

[0008] A preparation method of a single-sided adhesive hydrogel based on sodium unsaturated fatty acid, comprising the following steps:

[0009] Mix sodium unsaturated fatty acid, water-soluble monomer, cross-linking agent, initiator and water evenly, heat and react in a closed or semi-closed reactor with a cavity, and remove the unreacted monomers to obtain a single-sided adhesive hydrogel patch.

[0010] Preferably, by mass, 0.1 - 6 parts of sodium unsaturated fatty acid, 10 - 25 parts of water-soluble monomer, 0.01 - 1 part of cross-linking agent, 0.05 - 0.5 part of initiator and 50 - 80 parts of water; more preferably 0.13 - 0.53 parts of sodium unsaturated fatty acid, 10 - 23.3 parts of water-soluble monomer, 0.01 - 0.04 part of cross-linking agent, 0.05 - 0.17 part of initiator and 66 - 80 parts of water.

[0011] Preferably, the sodium unsaturated fatty acid is prepared by saponifying polyunsaturated fatty acid, wherein the unsaturated fatty acid is a mono- to tetra-unsaturated fatty acid, specifically at least one of linoleic acid, linolenic acid, arachidonic acid and its isomers.

[0012] Preferably, the water-soluble monomer is at least one of acrylamide, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, N-isopropylacrylamide, N-(2-hydroxyethyl)acrylamide, and 3-[(3-acrylamidopropyl)dimethylammonium] propionate.

[0013] Preferably, the crosslinking agent is at least one of N,N'-methylenebisacrylamide and polyethylene glycol diacrylate.

[0014] Preferably, the initiator is at least one of potassium persulfate / N,N,N',N'-tetramethylethylenediamine, ammonium persulfate / N,N,N',N'-tetramethylethylenediamine, 1-hydroxycyclohexyl phenyl ketone, and 2-hydroxy-2-methyl-1-phenylpropanone; in the potassium persulfate / N,N,N',N'-tetramethylethylenediamine and ammonium persulfate / N,N,N',N'-tetramethylethylenediamine systems, the mass ratio of potassium persulfate or ammonium persulfate to N,N,N',N'-tetramethylethylenediamine is 10:3 to 10:5.

[0015] Preferably, in a closed or semi-closed reactor with a cavity, the distance between the interface of the mixed reaction solution and the top of the reactor is ≥ 10 mm.

[0016] Preferably, the temperature of the heating reaction is not lower than 40 °C and the time is not less than 12 hours. More preferably, the temperature is 50 - 80 °C and the time is 12 - 24 hours.

[0017] Preferably, the method for removing unreacted monomers is water rinsing and soaking.

[0018] Preferably, in the preparation method, sodium unsaturated fatty acid is first dissolved in water to obtain a transparent and clear solution, then the water-soluble monomer, crosslinking agent, and initiator are added and mixed to obtain a transparent and clear solution, and finally, a heating reaction is carried out in a closed or semi-closed reactor with a cavity.

[0019] A one-sided adhesive hydrogel based on sodium unsaturated fatty acid prepared by the above preparation method.

[0020] The application of the above one-sided adhesive hydrogel based on sodium unsaturated fatty acid in medical devices.

[0021] The one-sided hydrogel of the present invention exhibits adhesive ability to a variety of adhesive materials, including polar materials such as metals, glasses, and woods, and particularly has strong adhesion to non-polar materials such as polytetrafluoroethylene. It can be used as a one-sided adhesive hydrogel film and is suitable for the surface modification processing of medical devices.

[0022] The mechanism of the present invention is:

[0023] The present invention utilizes the amphiphilic characteristics of sodium unsaturated fatty acid surfactant. When its concentration in the aqueous solution exceeds its micelle critical concentration, micelles are formed. In a heated semi-closed reactor, due to the transpiration of water, a surface tension difference is formed between the gas-liquid interface and the interior of the aqueous solution, and ultimately a large amount of sodium unsaturated fatty acid aggregates at the gas / liquid interface. Through the free radical reaction initiated by the initiator, sodium unsaturated fatty acid and hydrophilic monomers undergo free radical copolymerization to form a high molecular polymer. Among them, due to the aggregation of sodium unsaturated fatty acid at the gas-liquid interface, differences in the upper and lower surface morphologies and adhesion capabilities of the hydrogel are caused. The upper surface of the obtained single-sided adhesive hydrogel contains more sodium fatty acid functional groups and has stronger adhesion ability, while the bottom surface only contains a small amount of functional groups, so the bottom surface has only very weak adhesion performance.

[0024] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0025] 1. Compared with the existing drug adhesion patches, derivatives of natural substances such as sodium unsaturated fatty acid in the present invention are used as basic materials, having strong and long-lasting single-sided adhesion performance; the usage amount of adhesion functional monomers can be greatly reduced, with good biocompatibility and higher economic value.

[0026] 2. The raw materials of the present invention are simple and easy to obtain, with low cost. The preparation process is simple and can be carried out in the atmospheric environment for free radical polymerization preparation, enabling large-scale synthesis. The obtained hydrogel is a light milky white semi-transparent gel, having good single-sided adhesion ability, biocompatibility and antioxidant property, and having good application prospects. Description of the Drawings

[0027] Figure 1 Schematic diagram of the semi-closed reaction vessel mentioned in the examples.

[0028] Figure 2 Infrared spectra of the upper and lower surfaces of the hydrogel in Example 1.

[0029] Figure 3 Raman spectrum of the hydrogel in Example 1.

[0030] Figure 4 Adhesion performance comparison test of the hydrogels obtained in Examples 1-3 and Comparative Example 1.

[0031] Figure 5 90° peel adhesion performance test of the hydrogels obtained in Examples 1-3 and Comparative Example 1 with pig skin.

[0032] Figure 6 Cytotoxicity experiment of the hydrogel obtained in Example 2 with human fibroblasts.

[0033] Figure 7It is a comparison test chart of the adhesion performance between the upper surface and the bottom surface of the hydrogel obtained in Example 2 and the polytetrafluoroethylene material. Detailed implementation mode

[0034] The present invention will be further described in detail below in conjunction with examples and drawings, but the implementation modes of the present invention are not limited thereto.

[0035] For those conditions not specified in the examples of the present invention, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. The raw materials, reagents, etc. that are not specified for the manufacturer can all be obtained as conventional products through commercial purchase.

[0036] Example 1

[0037] Prepare a single-sided adhesive hydrogel. The ratio of the pre-reaction solution of the hydrogel is to add 20 mg of α-linolenic acid sodium to 10 mL of deionized water and stir until clear, then add 2.5 g of acrylamide, 6 mg of N,N'-methylenebisacrylamide, 20 mg of potassium persulfate, and 6 mg of N,N,N',N'-tetramethylethylenediamine. Transfer the obtained reaction solution to a semi-sealed reactor, where the distance between the liquid surface of the reaction solution and the upper cover of the mold is not less than 10 mm, heat to 50 °C, and maintain for 24 hours. Wash the obtained hydrogel with deionized water, and use nitrogen to remove the moisture on the surface of the hydrogel to obtain the corresponding single-sided adhesive hydrogel, and put it into a sealed bag and store it in a -4 °C refrigerator.

[0038] Example 2

[0039] Prepare a single-sided adhesive hydrogel. The ratio of the pre-reaction solution of the hydrogel is to add 50 mg of α-linolenic acid sodium to 10 mL of deionized water and stir until clear, then add 2.5 g of acrylamide, 6 mg of N,N'-methylenebisacrylamide, 20 mg of potassium persulfate, and 6 mg of N,N,N',N'-tetramethylethylenediamine. Transfer the obtained reaction solution to a semi-sealed reactor, where the distance between the liquid surface of the reaction solution and the upper cover of the mold is not less than 10 mm, heat to 50 °C, and maintain for 24 hours. Wash the obtained hydrogel with deionized water, and use nitrogen to remove the moisture on the surface of the hydrogel to obtain the corresponding single-sided adhesive hydrogel, and put it into a sealed bag and store it in a -4 °C refrigerator.

[0040] Example 3

[0041] Prepare a single-sided adhesive hydrogel. The formulation of the hydrogel reaction precursor solution is to add 80 mg of sodium α-linolenate to 10 mL of deionized water and stir until clear, then add 2.5 g of acrylamide, 6 mg of N,N'-methylenebisacrylamide, 20 mg of potassium persulfate, and 6 mg of N,N,N',N'-tetramethylethylenediamine. Transfer the resulting reaction solution to a semi-sealed reactor, where the distance between the liquid level of the reaction solution and the upper cover of the mold is not less than 10 mm. Heat it to 50 °C and maintain for 24 hours. Wash the obtained hydrogel with deionized water and use nitrogen to remove the moisture on the surface of the hydrogel to obtain the corresponding single-sided adhesive hydrogel, and place it in a sealed bag and store it in a -4 °C refrigerator.

[0042] Example 4

[0043] Prepare a single-sided adhesive hydrogel. The formulation of the hydrogel reaction precursor solution is to add 50 mg of sodium α-linolenate to 10 mL of deionized water and stir until clear, then add 1.5 g of acrylamide, 6 mg of N,N'-methylenebisacrylamide, 20 mg of potassium persulfate, and 6 mg of N,N,N',N'-tetramethylethylenediamine. Transfer the resulting reaction solution to a semi-sealed reactor, where the distance between the liquid level of the reaction solution and the upper cover of the mold is not less than 10 mm. Heat it to 60 °C and maintain for 24 hours. Wash the obtained hydrogel with deionized water and use nitrogen to remove the moisture on the surface of the hydrogel to obtain the corresponding single-sided adhesive hydrogel, and place it in a sealed bag and store it in a -4 °C refrigerator.

[0044] Example 5

[0045] Prepare a single-sided adhesive hydrogel. The formulation of the hydrogel reaction precursor solution is to add 50 mg of sodium α-linolenate to 10 mL of deionized water and stir until clear, then add 2.5 g of acrylamide, 6 mg of N,N'-methylenebisacrylamide, 20 mg of potassium persulfate, and 6 mg of N,N,N',N'-tetramethylethylenediamine. Transfer the resulting reaction solution to a semi-sealed reactor, where the distance between the liquid level of the reaction solution and the upper cover of the mold is not less than 10 mm. Heat it to 70 °C and maintain for 24 hours. Wash the obtained hydrogel with deionized water and use nitrogen to remove the moisture on the surface of the hydrogel to obtain the corresponding single-sided adhesive hydrogel, and place it in a sealed bag and store it in a -4 °C refrigerator.

[0046] Example 6

[0047] Preparation of a single-sided adhesive hydrogel. The formulation of the hydrogel reaction precursor solution is to add 50 mg of sodium α-linolenate to 10 mL of deionized water and stir until clear, then add 3.5 g of acrylamide, 6 mg of N,N'-methylenebisacrylamide, 20 mg of potassium persulfate, and 6 mg of N,N,N',N'-tetramethylethylenediamine. Transfer the resulting reaction solution to a semi-sealed reactor, where the distance between the liquid level of the reaction solution and the upper cover of the mold is not less than 10 mm. Heat to 80 °C and maintain for 24 hours. Wash the obtained hydrogel with deionized water and remove the moisture on the surface of the hydrogel using nitrogen to obtain the corresponding single-sided adhesive hydrogel, and place it in a sealed bag and store it in a -4 °C refrigerator.

[0048] Comparative Example 1

[0049] Preparation of a single-sided adhesive hydrogel. The formulation of the hydrogel reaction precursor solution is to add 2.5 g of acrylamide, 6 mg of N,N'-methylenebisacrylamide, 20 mg of potassium persulfate, and 6 mg of N,N,N',N'-tetramethylethylenediamine to 10 mL of deionized water. Transfer the resulting reaction solution to a semi-sealed reactor, where the distance between the liquid level of the reaction solution and the upper cover of the mold is not less than 10 mm. Heat to 50 °C and maintain for 24 hours. Wash the obtained hydrogel with deionized water and remove the moisture on the surface of the hydrogel using nitrogen to obtain the corresponding single-sided adhesive hydrogel, and place it in a sealed bag and store it in a -4 °C refrigerator.

[0050] Comparative Example 2

[0051] Preparation of a linoleic acid-containing hydrogel. The formulation of the hydrogel reaction precursor solution is to add 50 mg of α-linolenic acid to 10 mL of deionized water, then add 2.5 g of acrylamide, 6 mg of N,N'-methylenebisacrylamide, 20 mg of potassium persulfate, and 6 mg of N,N,N',N'-tetramethylethylenediamine. Transfer the resulting reaction solution to a semi-sealed reactor, where the distance between the liquid level of the reaction solution and the upper cover of the mold is not less than 10 mm. Heat to 50 °C and maintain for 24 hours. Wash the obtained hydrogel with deionized water and remove the moisture on the surface of the hydrogel using nitrogen to obtain the corresponding single-sided adhesive hydrogel, and place it in a sealed bag and store it in a -4 °C refrigerator. Testing the adhesion properties of the upper and lower surfaces of the hydrogel found that there was no significant difference in the adhesion properties of the upper and lower surfaces of the hydrogel prepared in this comparative example.

[0052] Characterization of the composition, adhesion properties, and biocompatibility of the single-sided hydrogel:

[0053] 1. Chemical composition characterization of the single-sided adhesive hydrogel

[0054] The chemical compositions of the upper and lower surfaces of the single-sided adhesive hydrogel prepared in Example 1 were characterized. In the present invention, infrared spectroscopy and Raman spectroscopy were used to determine the chemical compositions of the upper and lower surfaces of the hydrogel as shown in Figure 2 , and are represented by 3. The test results show that there are obvious differences in the chemical compositions of the upper and lower surfaces of the same hydrogel, and the upper surface of the hydrogel contains more sodium fatty acid.

[0055] 2. Characterization of the adhesion performance of the single-sided adhesive hydrogel

[0056] The adhesion performance of the hydrogel was characterized through a legend demonstration experiment, and various different test methods were adopted to characterize the adhesion performance of the upper and lower surfaces of the hydrogel, namely the flat pressing adhesion test method and the 90° peeling experiment. The results show that there are obvious differences in the adhesion performance between the upper and lower surfaces of the hydrogel, and the upper surface of the hydrogel has stronger adhesion performance.

[0057] Through the flat pressing method adhesion performance test, the adhesion performance of each surface of the hydrogel was evaluated. The instrument used was the Kejian Instrument KJ-1065A universal tensile machine, the force sensor model was 50N, and the tensile traction rate was 50mm / min. The adhesion performance of the hydrogels prepared in Examples 1-3 and Comparative Example 1 was tested respectively, and the difference was that their sodium fatty acid contents were different (in the figure, the sodium fatty acid content = the mass of sodium fatty acid ÷ the mass of the hydrogel × %). The experimental results show that the upper surface of the hydrogel exhibits strong adhesion performance, and the adhesion performance of the upper surface is always greater than that of its bottom surface. At the same time, the present invention also studied the differences in the adhesion performance of the hydrogels prepared in Examples 1-3 and Comparative Example 1. The results show that the content of unsaturated sodium fatty acid affects the adhesion performance of the hydrogel and shows a regular change.

[0058] Through the 90° peeling experiment test, the adhesion performance of the hydrogel to pig skin was evaluated. The specific test scheme is as shown in Figure 5 . The instrument used in this test was the KJ-1065A universal tensile machine, the force sensor model was 50N, and the tensile traction rate was 50mm / min. The results show that the hydrogel has strong adhesion performance to pig skin, and the adhesion energy of its upper surface is much greater than that of its bottom surface. Among them, the adhesion energy of the upper surface is 84 J·m -2 which is 20 times that of the bottom surface (the bottom surface is only 4 J·m -2 ), and the hydrogel shows single-sided adhesion ability.

[0059] 3. Evaluation of the biocompatibility of the single-sided hydrogel

[0060] The single-sided adhesive hydrogel obtained in Example 2 was cut into gel blocks with a size of (3×4×4 mm). The cut single-sided adhesive hydrogel sheets were immersed in a 24-well plate containing human fibroblasts and co-cultured for 24 hours. The cell proliferation was counted by the CCK-8 method, and the biosafety of the hydrogel was evaluated in combination with the blank sample. Among them, the cell proliferation rate is as Figure 6 shown, and the hydrogel exhibits good biocompatibility, with a cell proliferation rate of 101.88%.

[0061] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A preparation method of a single-sided adhesive hydrogel based on sodium unsaturated fatty acid, characterized in that, It includes the following steps: Mix sodium unsaturated fatty acid, water-soluble monomer, cross-linking agent, initiator and water evenly. After heating and reacting in a closed or semi-closed reactor with a cavity, remove the unreacted monomer to obtain a single-sided adhesive hydrogel patch; By mass, 0.1 to 6 parts of sodium unsaturated fatty acid, 10 to 25 parts of water-soluble monomer, 0.01 to 1 part of cross-linking agent, 0.05 to 0.5 part of initiator and 50 to 80 parts of water; The sodium unsaturated fatty acid is prepared by saponifying polyunsaturated fatty acid, wherein the unsaturated fatty acid is monounsaturated to tetraunsaturated fatty acid, specifically at least one of linoleic acid, linolenic acid, arachidonic acid, linoleic acid isomer, linolenic acid isomer and arachidonic acid isomer; The water-soluble monomer is at least one of acrylamide, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, N-isopropylacrylamide, N-(2-hydroxyethyl)acrylamide and 3-[(3-acrylamidopropyl)dimethylammonium]propionate.

2. The preparation method of a one-sided adhesive hydrogel based on sodium unsaturated fatty acid according to claim 1, wherein By mass, 0.13 to 0.53 parts of sodium unsaturated fatty acid, 10 to 23.3 parts of water-soluble monomer, 0.01 to 0.04 part of cross-linking agent, 0.05 to 0.17 part of initiator and 66 to 80 parts of water.

3. The preparation method of a single-sided adhesive hydrogel based on sodium unsaturated fatty acid according to claim 1, characterized in that, The cross-linking agent is at least one of N, N'-methylenebisacrylamide and polyethylene glycol diacrylate; The initiator is at least one of potassium persulfate / N,N,N',N'-tetramethylethylenediamine, ammonium persulfate / N,N,N',N'-tetramethylethylenediamine, 1-hydroxycyclohexyl phenyl ketone and 2-hydroxy-2-methyl-1-phenylpropanone; in the potassium persulfate / N,N,N',N'-tetramethylethylenediamine, ammonium persulfate / N,N,N',N'-tetramethylethylenediamine system, the mass ratio of potassium persulfate or ammonium persulfate to N,N,N',N'-tetramethylethylenediamine is 10:3 to 10:

5.

4. The preparation method of a one-sided adhesive hydrogel based on sodium unsaturated fatty acid according to claim 1, characterized in that, In a closed or semi-closed reactor with a cavity, the distance between the interface of the mixed reaction solution and the top of the reactor is ≥10 mm.

5. The preparation method of a single-sided adhesive hydrogel based on sodium unsaturated fatty acid according to claim 1, characterized in that, The temperature of the heating reaction is not lower than 40 °C and the time is not less than 12 hours.

6. The preparation method of a single-sided adhesive hydrogel based on sodium unsaturated fatty acid according to claim 1, wherein, In the preparation method, first dissolve sodium unsaturated fatty acid in water to obtain a transparent and clear solution, then add water-soluble monomer, cross-linking agent and initiator, mix to obtain a transparent and clear solution, and finally carry out a heating reaction in a closed or semi-closed reactor with a cavity.

7. A single-sided adhesive hydrogel based on sodium unsaturated fatty acid prepared by the preparation method according to any one of claims 1 to 6.

8. Use of the single-sided adhesive hydrogel based on sodium unsaturated fatty acid according to claim 7 in the preparation of medical devices.

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