阅读说明：本技术 水凝胶和水凝胶的制造方法 (Hydrogel and method for producing hydrogel ) 是由 岩田昌也 笠原真二郎 宫剑萍 黑川孝幸 野野山贵行 于 2019-04-23 设计创作，主要内容包括：水凝胶具备第1网络结构和第2网络结构。第2网络结构与第1网络结构交织。第1网络结构包含通过第1交联剂交联的聚合物。第2网络结构包含通过第2交联剂交联的聚合物。第1交联剂中的、50mol％以上不含降解性键。第2交联剂中的、50mol％以上不含降解性键。(The hydrogel has a 1 st network structure and a 2 nd network structure. The 2 nd network structure is interleaved with the 1 st network structure. The 1 st network structure comprises a polymer crosslinked by the 1 st crosslinking agent. The 2 nd network structure comprises a polymer crosslinked by the 2 nd crosslinker. 50 mol% or more of the first crosslinking agent does not contain a degradable bond. 50 mol% or more of the second crosslinking agent does not contain a degradable bond.)

1. A hydrogel, comprising:

a 1 st network fabric, and a 2 nd network fabric interleaved with the 1 st network fabric,

the 1 st network structure comprises a polymer crosslinked by a 1 st crosslinking agent,

the 2 nd network structure comprises a polymer crosslinked by a 2 nd crosslinking agent,

50 mol% or more of the first crosslinking agent does not contain a degradable bond,

50 mol% or more of the 2 nd crosslinking agent does not contain a degradable bond.

2. The hydrogel of claim 1, wherein,

the main chain constituting the 1 st network structure and the main chain constituting the 2 nd network structure do not contain a degradable bond.

3. The hydrogel according to claim 1 or 2, wherein,

in the 1 st and 2 nd crosslinking agents, the degradable bonds each independently include 1 or more selected from an amide bond, an ester bond, and a thioester bond.

4. The hydrogel according to any one of claims 1 to 3, wherein,

the 1 st cross-linking agent and the 2 nd cross-linking agent containing the degradable bond each independently contain 1 or more selected from the group of N, N' -methylenebisacrylamide, and ethylene glycol dimethacrylate.

5. The hydrogel according to any one of claims 1 to 4,

the 1 st crosslinking agent and the 2 nd crosslinking agent not containing the degradable bond each independently contain 1 or more selected from the group of divinylbenzene, divinylpyridine, divinylbiphenyl, and divinylsulfone.

6. The hydrogel according to any one of claims 1 to 5, wherein,

an initial elastic modulus ratio X defined by the following formula (1) is 50% or more,

formula (1) X ═ E2/E1 × 100

In the formula (1), E2 represents the elastic modulus of the hydrogel after the treatment of immersing the hydrogel in an aqueous hydrochloric acid solution having a hydrochloric acid concentration of 0.05mol/L and a temperature of 60 ℃ for 72 hours, and E1 represents the elastic modulus of the hydrogel before the treatment.

7. A process for producing a hydrogel, which comprises a step of forming a hydrogel,

the manufacturing method is carried out as follows:

polymerizing the 1 st monomer, crosslinking by the 1 st crosslinking agent, to form a 1 st network structure,

introducing a 2 nd monomer and a 2 nd cross-linking agent into the 1 st network structure,

polymerizing the 2 nd monomer, crosslinking by the 2 nd crosslinking agent, thereby forming a 2 nd network structure interlaced with the 1 st network structure,

50 mol% or more of the first crosslinking agent does not contain a degradable bond,

50 mol% or more of the 2 nd crosslinking agent does not contain a degradable bond.

8. The method for producing a hydrogel according to claim 7, wherein,

in the 1 st and 2 nd crosslinking agents, the degradable bonds each independently include 1 or more selected from the group consisting of an amide bond, an ester bond, and a thioester bond.

Technical Field

The present disclosure relates to hydrogels and methods of making hydrogels.

Background

Conventionally, hydrogels having a 1 st network structure and a 2 nd network structure are known. The 2 nd network structure is interleaved with the 1 st network structure. The 1 st network structure and the 2 nd network structure are formed by polymerizing and crosslinking monomers, respectively. Patent document 1 discloses a hydrogel.

Disclosure of Invention

Problems to be solved by the invention

Conventional hydrogels tend to have a decreased elastic modulus and strength under acidic conditions. In one aspect of the present disclosure, it is preferable to provide a hydrogel in which the elastic modulus and strength are not easily decreased under acidic conditions, and a method for producing the hydrogel.

Means for solving the problems

One aspect of the present disclosure is a hydrogel, which includes: a 1 st network structure and a 2 nd network structure interlaced with the 1 st network structure, wherein the 1 st network structure contains a polymer crosslinked by a 1 st crosslinking agent, the 2 nd network structure contains a polymer crosslinked by a 2 nd crosslinking agent, 50 mol% or more of the 1 st crosslinking agent does not contain a degradable bond, and 50 mol% or more of the 2 nd crosslinking agent does not contain a degradable bond.

The hydrogel as one aspect of the present disclosure is also less likely to cause hydrolysis of the crosslinking points under acidic conditions. Therefore, the hydrogel according to one aspect of the present disclosure is less likely to decrease in elastic modulus and strength under acidic conditions.

Another aspect of the present disclosure is a method of making a hydrogel by: a1 st monomer is polymerized and crosslinked by a 1 st crosslinking agent to form a 1 st network structure, a 2 nd monomer and a 2 nd crosslinking agent are introduced into the 1 st network structure, the 2 nd monomer is polymerized, and the 2 nd crosslinking agent is crosslinked to form a 2 nd network structure interlaced with the 1 st network structure, wherein 50 mol% or more of the 1 st crosslinking agent does not contain a degradable bond, and 50 mol% or more of the 2 nd crosslinking agent does not contain a degradable bond.

The hydrogel produced by the method for producing a hydrogel according to another aspect of the present disclosure is less likely to cause hydrolysis of the crosslinking points under acidic conditions. Therefore, the hydrogel produced by the method for producing a hydrogel according to another aspect of the present disclosure is less likely to decrease in elastic modulus and strength under acidic conditions.

Drawings

FIG. 1 is a graph showing the initial elastic modulus ratio X in the hydrogels of examples and comparative examples_TGraph of the measurement results of (1).

FIG. 2 is a graph showing the initial elastic modulus ratio X in the hydrogels of example 1 and comparative example 2_TGraph of relationship to T。

Detailed Description

Exemplary embodiments of the present disclosure are explained.

1. Hydrogels

The hydrogel of the present disclosure has a 1 st network structure and a 2 nd network structure. The 2 nd network structure is interleaved with the 1 st network structure.

The 1 st network structure and the 2 nd network structure each comprise a polymer formed by polymerizing a monomer. The monomer constituting the 1 st network structure is referred to as the 1 st monomer. In addition, the monomer constituting the 2 nd network structure is referred to as the 2 nd monomer.

Examples of the 1 st monomer and the 2 nd monomer include monomers having an electric charge. Examples of the monomer having a charge include 2-acrylamido-2-methylpropanesulfonic acid, acrylic acid, methacrylic acid, and salts thereof.

Examples of the 1 st monomer and the 2 nd monomer include those which are electrically neutral. Examples of the monomer having charge neutrality include acrylamide, N-dimethylacrylamide, N-isopropylacrylamide, vinylpyridine, styrene, methyl methacrylate, a fluorine-containing unsaturated monomer, hydroxyethyl acrylate, and vinyl acetate. Examples of the fluorine-containing unsaturated monomer include trifluoroethyl acrylate and the like.

The 1 st and 2 nd monomers may be different kinds of monomers from each other, or may be the same kind of monomers.

In the case of the 1 st and 2 nd monomers being different kinds of monomers from each other, for example, one of the 1 st and 2 nd monomers is a monomer having a charge, and the other of the 1 st and 2 nd monomers is a monomer having electric neutrality. In addition, the 1 st monomer and the 2 nd monomer may be both monomers having electric charges. In the case where the 1 st monomer and the 2 nd monomer are both monomers having electric charges, monomers different from each other may be selected from 2-acrylamido-2-methylpropanesulfonic acid, acrylic acid, methacrylic acid, and salts thereof. In addition, both the 1 st and 2 nd monomers may be electrically neutral. In the case where the 1 st monomer and the 2 nd monomer are both electrically neutral, the monomers may be selected from acrylamide, N-dimethylacrylamide, N-isopropylacrylamide, vinylpyridine, styrene, methyl methacrylate, fluorine-containing unsaturated monomers, hydroxyethyl acrylate, and vinyl acetate, which are different from each other.

In the 1 st network structure, the 1 st monomer polymerizes to form a polymer. The polymer is crosslinked by a 1 st crosslinking agent to form a 1 st network structure. 50 mol% or more of the 1 st crosslinking agent is a crosslinking agent containing no degradable bond. This also makes it difficult to cause hydrolysis of the crosslinking points under acidic conditions. Since hydrolysis of the crosslinking points is not easily caused under acidic conditions, the hydrogel of the present disclosure is not easily reduced in elastic modulus and strength under acidic conditions. Preferably, 60 mol% or more of the 1 st crosslinking agent is a crosslinking agent containing no degradable bond, and more preferably 75 mol% or more of the 1 st crosslinking agent is a crosslinking agent containing no degradable bond. The higher the ratio of the crosslinking agent having no degradable bond in the 1 st crosslinking agent is, the lower the elastic modulus and strength of the hydrogel of the present disclosure under acidic conditions is.

In the 2 nd network structure, the 2 nd monomer is polymerized to form a polymer. The polymer is crosslinked by a 2 nd crosslinking agent to form a 2 nd network structure. 50 mol% or more of the 2 nd crosslinking agent is a crosslinking agent containing no degradable bond. This also makes it difficult to cause hydrolysis of the crosslinking points under acidic conditions. Since hydrolysis of the crosslinking points is not easily caused under acidic conditions, the hydrogel of the present disclosure is not easily reduced in elastic modulus and strength under acidic conditions. Preferably, 60 mol% or more of the 2 nd crosslinking agent is a crosslinking agent containing no degradable bond, and more preferably 75 mol% or more of the 2 nd crosslinking agent is a crosslinking agent containing no degradable bond. The higher the ratio of the crosslinking agent having no degradable bond in the 2 nd crosslinking agent is, the lower the elastic modulus and strength of the hydrogel of the present disclosure under acidic conditions is. As the 2 nd crosslinking agent, the same one as the 1 st crosslinking agent can be used.

In the 1 st and 2 nd crosslinking agents, the degradable bond means a bond which is easily hydrolyzed under acidic conditions. Examples of the degradable bond include an ester bond, an amide bond, and a thioester bond. Examples of the 1 st crosslinking agent not having a degradable bond and the 2 nd crosslinking agent not having a degradable bond include, independently of each other, divinylbenzene, divinylpyridine, divinylbiphenyl, and divinylsulfone. All of the 1 st crosslinking agent may be a crosslinking agent containing no degradable bond, and a part of the 1 st crosslinking agent may be a crosslinking agent containing a degradable bond. All of the 2 nd crosslinking agent may be a crosslinking agent containing no degradable bond, and a part of the 2 nd crosslinking agent may be a crosslinking agent containing a degradable bond. Among the 1 st crosslinking agent and the 2 nd crosslinking agent, examples of the crosslinking agent containing a degradable bond include N, N' -methylenebisacrylamide, ethylene glycol dimethacrylate, and the like. The 1 st crosslinking agent and the 2 nd crosslinking agent may be the same crosslinking agent as each other or different crosslinking agents.

The main chains constituting the 1 st network structure and the 2 nd network structure preferably do not contain degradable bonds. The main chain means a main chain of a polymer formed from the 1 st monomer or a main chain of a polymer formed from the 2 nd monomer. In the case where the main chains constituting the 1 st network structure and the 2 nd network structure do not contain degradable bonds, the main chains are less likely to be hydrolyzed under acidic conditions. The main chain is less likely to be hydrolyzed under acidic conditions, and as a result, the elastic modulus and strength of the hydrogel of the present disclosure are less likely to be further reduced under acidic conditions.

In the hydrogel of the present disclosure, the initial elastic modulus ratio X defined by the following formula (1) is preferably 50% or more.

Formula (1) X ═ E2/E1 × 100

(in the formula (1), E2 represents the elastic modulus of the hydrogel after the treatment of immersing the hydrogel in an aqueous hydrochloric acid solution having a hydrochloric acid concentration of 0.05mol/L and a temperature of 60 ℃ for 72 hours; E1 represents the elastic modulus of the hydrogel before the treatment.)

When the initial elastic modulus ratio X is 50% or more, the elastic modulus and strength of the hydrogel of the present disclosure are not likely to be further reduced under acidic conditions.

The degree of crosslinking in the 1 st network structure is preferably in the range of, for example, 0.1 to 50 mol%. The crosslinking degree is a value representing the ratio of the molar concentration of the crosslinking agent to the input molar concentration of the monomer in percentage units. The monomer that does not actually participate in polymerization and the crosslinking agent that does not participate in crosslinking may be present in a trace amount, but in the above case, the crosslinking degree in the present specification is also defined as described above. The degree of crosslinking in the 2 nd network structure is preferably in the range of 0.001 to 20 mol%, for example. In the case where the degree of crosslinking in the 1 st network structure and the 2 nd network structure is within the above range, the mechanical strength of the hydrogel of the present disclosure is further increased.

Preferably, the 1 st network structure is of high stiffness and the 2 nd network structure is of high expandability. The strength of the hydrogels of the present disclosure is further increased where the 1 st network structure is of high stiffness and the 2 nd network structure is of high expandability.

The degree of crosslinking in the 2 nd network structure is preferably less than the degree of crosslinking in the 1 st network structure. When the degree of crosslinking in the 2 nd network structure is smaller than that in the 1 st network structure, the 1 st network structure has high hardness and the 2 nd network structure has high expandability. As a result, the strength of the hydrogel of the present disclosure is further increased.

The component amount of the 1 st monomer in the hydrogel of the present disclosure was M1 (mol). The component amount of the 2 nd monomer in the hydrogel of the present disclosure was M2 (mol). The molar ratio of M1 to M2 (hereinafter referred to as M1: M2) is preferably 1: 2-1: 100, more preferably 1: 3-1: 50, particularly preferably 1: 3-1: 30, or less. M1: with M2 in the above range, the mechanical strength of the hydrogel of the present disclosure can be further improved.

The water content of the hydrogel is preferably 10-99.9%. The hydrogel of the present disclosure preferably has a compressive stress at break of 1 to 100 MPa. The tensile breaking stress of the hydrogel is preferably 0.1-100 MPa.

Examples of applications of the hydrogel of the present disclosure include artificial cartilage, artificial joints, artificial organs, cell culture substrates, Drug Delivery Systems (DDS), contact lenses, artificial lenses, hollow fibers, drug delivery vehicles, soft smart actuators used for sensors for specific substances or distal ends of catheters, stabilizers for preventing decubitus ulcers and bedsores, mats, lubricants, lotions and the like, thickeners, materials for fuel cells, battery separators, diapers, sanitary products, sustained release agents, civil engineering materials, building materials, and the like. Examples of the artificial organ include an artificial blood vessel and an artificial skin.

2. Method for producing hydrogel

In the method of manufacturing the hydrogel of the present disclosure, the 1 st network structure is formed. The 1 st network structure may be formed, for example, as follows. A1 st polymerization solution including a 1 st monomer, a 1 st crosslinking agent, and a polymerization initiator is prepared. Subsequently, the 1 st monomer is polymerized and crosslinked by the 1 st crosslinking agent to form the 1 st network structure.

Next, a 2 nd network structure is formed. The 2 nd network structure may be formed as follows, for example. Preparing a 2 nd polymerization solution comprising a 2 nd monomer, a 2 nd crosslinking agent, and a polymerization initiator. Next, the gel having the 1 st network structure is immersed in the 2 nd polymerization solution and stored in the immersed state. At this time, the 2 nd monomer and the 2 nd crosslinking agent are introduced into the 1 st network structure, and diffused and permeated. Next, the gel having the 1 st network structure is taken out of the 2 nd polymerization solution. Subsequently, the 2 nd monomer introduced into the 1 st network structure is polymerized and crosslinked by the 2 nd crosslinking agent. As a result, a 2 nd network structure interlaced with the 1 st network structure is formed.

The 1 st crosslinking agent and the 2 nd crosslinking agent used in the method for producing a hydrogel of the present disclosure are as described in the aforementioned item "1. hydrogel". Therefore, the hydrogel produced by the method for producing a hydrogel according to the present disclosure is less likely to cause hydrolysis of the crosslinking points under acidic conditions. Since hydrolysis of the crosslinking points is not easily caused under acidic conditions, the hydrogel produced by the method for producing a hydrogel according to the present disclosure is not easily reduced in elastic modulus and strength under acidic conditions.

The polymerization initiator contained in the 1 st polymerization solution and the 2 nd polymerization solution is not particularly limited, and may be appropriately selected depending on the kind of the monomer. When the monomer is thermally polymerized, examples of the polymerization initiator include a water-soluble thermal catalyst such as potassium persulfate, a redox initiator such as potassium persulfate-sodium thiosulfate, Azobisisobutyronitrile (AIBN), Benzoyl Peroxide (BPO), and the like. When the monomer is photopolymerized, for example, 2-oxoglutaric acid, benzophenone, hydrogen peroxide, or the like can be used as a polymerization initiator.

The solvent in the 1 st polymerization solution and the 2 nd polymerization solution is not particularly limited and may be appropriately selected. Examples of the solvent include water, an organic solvent, and a mixed solvent of water and an organic solvent. Examples of the organic solvent include dimethyl sulfoxide, 2-methyl-2-propanol, and tetrahydrofuran. The solvent in the 1 st polymerization solution and the solvent in the 2 nd polymerization solution are preferably the same. In the case where the solvent in the 1 st polymerization solution and the solvent in the 2 nd polymerization solution are the same, the 1 st network structure and the 2 nd network structure are likely to further interlace.

Examples of the method of polymerizing the 1 st monomer include thermal polymerization and photopolymerization. Examples of the light used for photopolymerization include ultraviolet rays. Examples of the method of crosslinking the polymer formed from the 1 st monomer with the 1 st crosslinking agent include thermal crosslinking and photocrosslinking. Examples of the light used for photocrosslinking include ultraviolet rays. The polymerization of the 1 st monomer and the crosslinking with the 1 st crosslinking agent may be carried out simultaneously, or the crosslinking may be carried out after the polymerization.

Examples of the method for polymerizing the 2 nd monomer include thermal polymerization and photopolymerization. Examples of the light used for photopolymerization include ultraviolet rays. Examples of the method of crosslinking the polymer formed from the 2 nd monomer with the 2 nd crosslinking agent include thermal crosslinking and photocrosslinking. Examples of the light used for photocrosslinking include ultraviolet rays. The polymerization of the 2 nd monomer and the crosslinking with the 2 nd crosslinking agent may be carried out simultaneously, or the crosslinking may be carried out after the polymerization.