Polycarboxylic acid-containing polymer hydrogel and preparation method and application thereof

Abstract

The present application belongs to the field of medical polymer technology, and in particular, relates to a polyacid polymer hydrogel, and its preparation method and application. The polyacid polymer hydrogel involved in the present application mainly contains a polyacid polymer aqueous phase; the preparation method provided includes first dissolving a polycarboxylic acid polymer in an alkaline solution, then dripping a pH adjuster and stirring, and standing to obtain a polycarboxylic acid polymer hydrogel. Among them, after lowering the pH of the alkaline aqueous solution of the polycarboxylic acid polymer, the polycarboxylic acid chains are entangled during the standing process, and the interaction force between the polymer chains is enhanced to form a polycarboxylic acid polymer hydrogel. This type of hydrogel has a simple source of materials and an easy preparation method, which solves the technical problems that the preparation process of the existing polycarboxylic acid-containing polymer hydrogel is cumbersome, toxic reagents are required, and the product hydrogel lacks adhesion and self-healing.

Description

Technical Field

[0001] The present application belongs to the field of medical polymer technology, and in particular relates to a polycarboxylic acid-containing polymer hydrogel and a preparation method and application thereof. Background Art

[0002] At present, the medical polymer hydrogel network containing polycarboxylic acid is formed by chemical or physical cross-linking of chain polymers. Chemical cross-linking methods usually rely on the coupling reaction of carboxyl groups or hydroxyaldehyde groups on polymers with special molecules, or chemical reactions with other substances after modification, such as the reaction of carboxyl groups with polyamines to form amides; for example, the hyaluronic acid (HA) molecules are first modified with double bonds or thiol groups before reacting, but the current chemical cross-linking methods are cumbersome and require toxic reagents (such as the records in CN202011043357.X, CN202010385998.7 and CN202010584704.3); while physical cross-linking methods rely on the physical interaction between polyacid polymers and specific molecules, such as the complexation of sodium alginate (SA) with multivalent cations to form gel (CN 103087334 A), but current physical cross-linking usually relies on specific polymers and is not universal; at the same time, the polymer hydrogels containing polycarboxylic acids obtained by physical and chemical cross-linking in the prior art lack adhesion and self-healing. Summary of the invention

[0003] In view of this, the present application provides a polycarboxylic acid-containing polymer hydrogel and a preparation method and application thereof, which are used to solve the technical problems that the preparation process of the existing polycarboxylic acid-containing polymer hydrogel is cumbersome, toxic reagents are required, and the product hydrogel lacks adhesion and self-healing.

[0004] In a first aspect, the present application provides a polycarboxylic acid-containing polymer hydrogel, the hydrogel comprising a polycarboxylic acid polymer chain and an aqueous phase;

[0005] The polycarboxylic acid polymer chains form a three-dimensional network structure through mutual entanglement and interaction between polymer chains;

[0006] The water phase exists in the gel by osmotic pressure.

[0007] Preferably, the mass ratio of the water phase in the hydrogel is 50-90%;

[0008] The second aspect of the present application provides a method for preparing a polycarboxylic acid-containing polymer hydrogel, comprising the following steps:

[0009] Step 1, dissolving a polycarboxylic acid polymer and / or a salt corresponding to the polycarboxylic acid polymer in an alkaline aqueous solution to obtain an alkaline aqueous solution of the polycarboxylic acid polymer;

[0010] Step 2: Add a pH adjuster to the alkaline aqueous solution of the polycarboxylic acid polymer, mix evenly, and let stand to obtain a polycarboxylic acid polymer hydrogel.

[0011] It should be noted that the pH adjuster in the present application is an adjuster that can lower the pH value of the system.

[0012] Preferably, in step 1, the polycarboxylic acid polymer is hyaluronic acid, carboxymethyl cellulose, carboxyethyl cellulose, carboxymethyl chitosan, pectin, xanthan gum, gum arabic, alginic acid, polyacrylic acid or polymethacrylic acid.

[0013] Preferably, the pH adjuster is citric acid, malic acid, lactic acid, tartaric acid, glucono-δ-lactone or glucono-δ-lactone.

[0014] Preferably, the pH adjuster is citric acid or glucono-δ-lactone.

[0015] Preferably, in step 1, the concentration of the polycarboxylic acid polymer in the polycarboxylic acid polymer alkaline solution is not less than 3 wt %;

[0016] The pH value of the alkaline solution is not less than 11;

[0017] In step 2, the pH value of the polycarboxylic acid polymer solution is not higher than 7.5.

[0018] Preferably, the polycarboxylic acid polymer is hyaluronic acid; the concentration of the hyaluronic acid is 5wt%.

[0019] Preferably, the polycarboxylic acid polymer is hyaluronic acid; the concentration of the hyaluronic acid is 16 wt %.

[0020] Preferably, the pH value of the alkaline solution is 13.2.

[0021] Preferably, the pH value of the polycarboxylic acid polymer solution is 3.4.

[0022] The third aspect of the present application provides a polycarboxylic acid-containing polymer hydrogel for use as a drug carrier, tissue engineering repair material or personal care.

[0023] It should be noted that the preparation process of the polycarboxylic acid-containing polymer hydrogel provided in the present application is green and environmentally friendly, does not use toxic reagents, is harmless to the human body, and can be used as a drug carrier in the human body; and in addition to having good biocompatibility, the polycarboxylic acid-containing polymer hydrogel provided in the present application is also formed by physical winding, so it has excellent adhesion and self-healing properties, and can be used in tissue engineering repair materials or personal care fields.

[0024] In summary, the present application provides a polycarboxylic acid polymer hydrogel and a preparation method and application thereof, wherein the preparation method of the polycarboxylic acid polymer hydrogel comprises first dissolving a polycarboxylic acid polymer in an alkaline solution to obtain a polycarboxylic acid polymer alkaline solution, then dripping a pH adjuster into the polycarboxylic acid polymer alkaline solution and stirring, and after standing for a period of time, obtaining a polycarboxylic acid polymer hydrogel; wherein, since the solubility of the polycarboxylic acid polymer increases with the increase of pH and decreases with the decrease of pH, when the polycarboxylic acid polymer is dissolved in an alkaline solution, the polycarboxylic acid chains are less entangled and the interaction force between the polymer chains is weak, and after the pH adjuster is dripped into the polycarboxylic acid polymer alkaline solution, the pH of the polycarboxylic acid aqueous solution is reduced due to the reduction of pH. H value, the polycarboxylic acid chains are entangled, the interaction force between polymer chains is enhanced, and the viscosity of the polycarboxylic acid is increased, thereby forming a polycarboxylic acid-containing polymer hydrogel with excellent adhesion and self-healing properties; compared with the prior art that the cross-linking method requires the use of toxic chemical reagents, the polycarboxylic acid polymer must be modified first, resulting in a cumbersome preparation process, and relies on carboxyl cross-linking, resulting in low adhesion and self-healing properties of the product hydrogel, and the physical cross-linking method relies on specific physical interaction gelation, resulting in low adhesion and self-healing properties of the product hydrogel, the preparation method provided by the present application has a simple process, does not require the use of toxic reagents and has a high carboxyl content, thereby solving the technical problems of the existing polycarboxylic acid-containing polymer hydrogel having a cumbersome preparation process, the need to use toxic reagents, and the lack of adhesion and self-healing properties of the product hydrogel. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0026] Figure 1 A flow chart of a method for preparing a polycarboxylic acid-containing polymer hydrogel provided in an embodiment of the present application;

[0027] Figure 2 This is a demonstration diagram of the gelation behavior of the hyaluronic acid hydrogel provided in Example 2 of the present application, wherein 2a is 16wt% hyaluronic acid with pH=13.2, and 2b is 16wt% hyaluronic acid with pH=6.5;

[0028] Figure 3 Viscosity diagrams of hyaluronic acid solutions of different concentrations under different pH conditions provided in Examples 1-6 of the present application, wherein the viscosity test conditions are shear rate: 1 / s; temperature: 25°C;

[0029] Figure 4 This is a scanning electron micrograph of the hyaluronic acid hydrogel provided in Example 1 of the present application;

[0030] Figure 5 The rheological diagram of the hyaluronic acid hydrogel provided in Example 1 of the present application;

[0031] Figure 6 This is a physical picture of the self-healing hyaluronic acid hydrogel provided in Example 1 of the present application. DETAILED DESCRIPTION

[0032] The present application provides a polycarboxylic acid-containing polymer hydrogel, a preparation method and application thereof, and utilizes the relationship between the solubility of carboxylic acid polymers and the pH value to improve the preparation method of the polycarboxylic acid-containing polymer hydrogel, thereby solving the technical problems that the preparation process of the existing polycarboxylic acid-containing polymer hydrogel is complicated, toxic reagents are required, and the product hydrogel lacks adhesion and self-healing.

[0033] The technical solutions in the embodiments of the present application are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present application.

[0034] Wherein, the reagents or raw materials used in the following examples are all commercially available or homemade.

[0035] Example 1

[0036] This embodiment 1 provides a polycarboxylic acid-containing polymer hydrogel, which is prepared by the preparation method provided in this embodiment 2. Figure 4 Scanning electron microscope images can be used to determine that the components of the polycarboxylic acid polymer hydrogel include a three-dimensional cross-linked network formed by the mutual entanglement of polycarboxylic acid polymers and an aqueous phase; since the polycarboxylic acid polymer hydrogel provided by the present application contains a large number of hydrophilic carboxyl groups, the polycarboxylic acid polymer hydrogel provided by the present application has a high water content and excellent swelling performance of the hydrogel. Figure 5 The rheological diagram shows that the hydrogel has excellent viscoelasticity and Figure 6 As shown, the hydrogel has excellent self-healing properties and a stable structure, so it can be used in drug carriers, tissue engineering repair materials or personal care.

[0037] Example 2

[0038] This embodiment 2 provides a method for preparing a polycarboxylic acid-containing polymer hydrogel, wherein the polycarboxylic acid polymer hydrogel is a hyaluronic acid hydrogel, and the preparation method comprises the following steps:

[0039] Step 1, first weighing an appropriate amount of sodium hydroxide and deionized water, dissolving the sodium hydroxide in the deionized water to obtain an alkaline solution with a sodium hydroxide concentration of 1wt%, then weighing an appropriate amount of hyaluronic acid, dissolving the hyaluronic acid in the alkaline sodium hydroxide solution to obtain a hyaluronic acid solution with a pH value of 13.2 and a hyaluronic acid concentration of 16wt%;

[0040] Step 2, weighing an appropriate amount of glucono-δ-lactone and dissolving it in deionized water to obtain a glucono-δ-lactone solution, then dropping the glucono-δ-lactone solution into a hyaluronic acid solution having a hyaluronic acid concentration of 16 wt % and stirring, and controlling the pH value to 6.5;

[0041] Step 3: Let stand until a hyaluronic acid hydrogel is formed.

[0042] It should be noted that the pH value is controlled by controlling the molar amounts of glucono-δ-lactone and sodium hydroxide in the present application.

[0043] Example 3

[0044] This Example 3 provides a method for preparing a polycarboxylic acid-containing polymer hydrogel, wherein the polycarboxylic acid polymer hydrogel is a hyaluronic acid hydrogel. The difference between the preparation method and Example 1 is that the pH regulator in step 2 is citric acid, and the final pH value of the system is controlled to be 5.4 by dripping citric acid solution.

[0045] Example 4

[0046] This Example 4 provides a method for preparing a polycarboxylic acid-containing polymer hydrogel, wherein the polycarboxylic acid polymer hydrogel is a hyaluronic acid hydrogel. The difference between the preparation method and that of Example 1 is that the concentration of hyaluronic acid is 5 wt %.

[0047] Example 5

[0048] This Example 5 provides a method for preparing a polycarboxylic acid-containing polymer hydrogel, wherein the polycarboxylic acid polymer hydrogel is a hyaluronic acid hydrogel. The difference between the preparation method and that of Example 3 is that the pH value of the glucono-δ-lactone solution added dropwise in step 2 is controlled to be 5.4.

[0049] Example 6

[0050] This Example 6 provides a method for preparing a polycarboxylic acid-containing polymer hydrogel, wherein the polycarboxylic acid polymer hydrogel is a hyaluronic acid hydrogel. The difference between the preparation method and that of Example 1 is that the concentration of hyaluronic acid is 1 wt %.

[0051] Example 7

[0052] This Example 7 provides a method for preparing a polycarboxylic acid-containing polymer hydrogel, wherein the polycarboxylic acid polymer hydrogel is a hyaluronic acid hydrogel. The difference between the preparation method and that of Example 5 is that the pH value of the glucono-δ-lactone solution added dropwise in step 2 is controlled to be 3.4.

[0053] Example 8

[0054] This Example 8 provides a method for preparing a polycarboxylic acid-containing polymer hydrogel, wherein the polycarboxylic acid polymer hydrogel is a carboxymethyl cellulose hydrogel, and the preparation method comprises the following steps:

[0055] Step 1, first weighing an appropriate amount of sodium hydroxide and deionized water, dissolving the sodium hydroxide in the deionized water to obtain an alkaline solution with a sodium hydroxide concentration of 1wt%, then weighing an appropriate amount of carboxymethyl cellulose, dissolving the carboxymethyl cellulose in the alkaline sodium hydroxide solution to obtain a carboxymethyl cellulose solution with a carboxymethyl cellulose concentration of 10wt%;

[0056] Step 2, weighing an appropriate amount of malic acid and dissolving it in deionized water to obtain a glucono-δ-lactone solution, then dripping the malic acid solution into a carboxymethyl cellulose solution having a carboxymethyl cellulose concentration of 10 wt% and stirring, wherein the molar amount of glucono-δ-lactone is 1.1 times the molar amount of sodium hydroxide;

[0057] Step 3: Let the mixture stand until a carboxymethyl cellulose hydrogel is formed.

[0058] Example 9

[0059] This embodiment 9 provides a method for preparing a polycarboxylic acid-containing polymer hydrogel, wherein the polycarboxylic acid polymer hydrogel is a sodium alginate hydrogel, and the preparation method comprises the following steps:

[0060] Step 1, first weighing an appropriate amount of sodium hydroxide and deionized water, dissolving the sodium hydroxide in the deionized water to obtain an alkaline solution with a sodium hydroxide concentration of 1wt%, then weighing an appropriate amount of sodium alginate, dissolving the sodium alginate in the alkaline sodium hydroxide solution to obtain an alginate solution with a sodium alginate concentration of 8wt%;

[0061] Step 2: weigh an appropriate amount of tartaric acid and dissolve it in deionized water to obtain a glucono-δ-lactone solution, then dropwise add all of the tartaric acid solution into a sodium alginate solution having a sodium alginate concentration of 8 wt% and stir, wherein the molar amount of glucono-δ-lactone is 0.8 times the molar amount of sodium hydroxide.

[0062] Step 3: Let stand until a sodium alginate hydrogel is formed.

[0063] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a polycarboxylic acid-containing polymer hydrogel, characterized in that: The preparation method of the polycarboxylic acid-containing polymer hydrogel comprises the following steps: Step 1, dissolving a polycarboxylic acid polymer and / or a salt corresponding to the polycarboxylic acid polymer in an alkaline aqueous solution to obtain an alkaline aqueous solution of the polycarboxylic acid polymer, wherein the polycarboxylic acid polymer is hyaluronic acid, carboxymethyl cellulose or alginic acid, and the pH value of the alkaline aqueous solution is 13.2; Step 2: Add a pH regulator to the alkaline aqueous solution of the polycarboxylic acid polymer, mix evenly, and let stand to obtain a polycarboxylic acid polymer hydrogel, wherein the pH regulator is citric acid, malic acid, tartaric acid or glucono-δ-lactone, and the pH value of the polycarboxylic acid polymer solution is 3.4-6.

5.

2. The preparation method according to claim 1, characterized in that: In step 1, the concentration of the polycarboxylic acid polymer in the polycarboxylic acid polymer alkaline aqueous solution is not less than 3 wt %.

3. The preparation method according to claim 1, characterized in that: The polycarboxylic acid polymer is hyaluronic acid; the concentration of the hyaluronic acid is 5 wt %.

4. The preparation method according to claim 1, characterized in that: The polycarboxylic acid polymer is hyaluronic acid; the concentration of the hyaluronic acid is 16 wt %.

5. Use of the polycarboxylic acid-containing polymer hydrogel prepared by the preparation method according to any one of claims 1 to 4 in drug carriers, tissue engineering repair materials or personal care.

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