JPH0414124B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a novel hydrogel that is insoluble in water and highly hydrophilic, and is mainly used as a medical material. Prior Art In recent years, the application of polymeric materials to the medical field has been actively studied. Among them, hydrogels, which are insoluble in water and highly hydrophilic, are permeable to substances (gases, ions, molecules, etc.) and water-retaining, and have attracted attention for having functions similar to human tissues.
It has come to be used as catheters, soft contact lenses, blood storage containers, cell culture substrates, blood flow circuits, and embedding materials for oxygen and pharmaceuticals. For this purpose, hydrogels using hydrophilic monomers such as 2-hydroxyethyl methacrylate, (meth)acrylic acid, (meth)acrylamide, and N-vinylpyrrolidone have been used so far. However, these hydrogels suffer from rapid decreases in mechanical strength and loss of transparency when attempting to increase permeability to substances, and are not as compatible with living tissues, blood, and body fluids as originally thought. It has become clear that there are problems such as poor performance. In order to improve this problem, for example, the following general formula n is an integer of 5 or more, R ₁ is H or CH ₃ , R ₂ is a hydroxyl group, a C _{1 to C 4} alkoxy group, or a macromonomer (macromer) where φ is a phenyl group is used. It is proposed that the compatibility be improved. However, when using such macromers, due to the low concentration of polymerizable double bonds in the monomers, the degree of polymerization of such macromer polymers is low and therefore some of the mechanical properties required for hydrogels are not obtained. However, it has been found that there is a problem in that it is not possible to obtain products with particularly excellent elongation. Purpose of the Invention As a result of extensive research into hydrogels, the present inventors discovered a novel hydrogel that is highly compatible with living organisms and has excellent mechanical properties. Structure of the Invention In other words, the present invention provides: A having a polymerizable double bond at both ends and having a molecular weight of
1,500 to 500,000 polyethylene glycol or 95 to 40 parts of poly(ethylene glycol-propylene glycol) copolymer and B: a hydrophobic monomer having a polymerizable double bond and a hydrophobic monomer having a polymerizable double bond in the molecule It is a hydrogel consisting of a polymerization reaction product with 5 to 60 parts of a polymer. Component A is a component that imparts hydrophilicity to the hydrogel of the present invention and is given by the following general formula. Here, m is a positive integer, n is 0 or a positive integer, and m and n are selected such that the molecular weight is in the range of 1,500 to 500,000. _R1 is

【formula】

【formula】

【formula】

【formula】

[Formula], and R ₂ is H or CH ₃ . Methods for producing polyethylene glycol or poly(ethylene glycol-propylene glycol) copolymers having polymerizable double bonds at both ends are known; for example, when R ₁ is

[Formula] The compound of formula (1) where n = 0 can be obtained by reacting the hydroxyl groups at both ends of polyethylene glycol with a large excess of (meth)acrylic acid chloride and (meth)acrylic acid. I can do it. In the present invention, the molecular weight of component A is from 1500 to
Must be in the range of 500000. molecular weight
If it is less than 1500, the mechanical properties, especially The elongation at break decreases significantly. molecular weight
If it is 1500 or more, excellent elongation at break can be obtained due to the high molecular weight effect of the polyethylene glycol chain or poly(ethylene glycol-propylene glycol) chain. On the other hand, if the molecular weight exceeds 500,000, a uniform hydrogel cannot be obtained due to decreased solubility. The hydrogel of the present invention may contain one or more of these A components. The hydrophobic monomer having a polymerizable double bond and the hydrophobic polymer having a polymerizable double bond in the molecule as component B are used to reinforce the strength of the hydrogel of the present invention. . A hydrophobic monomer having a polymerizable double bond is one that gives a water-insoluble polymer when polymerized, and is an unsaturated monomer such as (meth)acrylic acid alkyl ester or (meth)acrylonitrile. One or more monomers are selected from the group of monomers such as aromatic olefins such as nitrile and styrene, and vinyl compounds such as vinyl chloride and vinyl acetate. Further, as the polymer having a polymerizable double bond in the molecule, one or more types are selected from the following polymer groups. (1) A polymer obtained by copolymerizing a (meth)acrylic acid alkyl ester with, for example, 2-hydroxyethyl (meth)acrylate or glycidyl (meth)acrylate, and (meth)acrylic acid chloride or (meth)acrylic acid chloride. A polymer with a polymerizable double bond in its side chain, obtained by reacting with an acid. (2) A polymer of the above hydrophobic monomer having a polymerizable double bond at one end. The manufacturing method of this polymer is known. For example, polystyrene having a polymerizable double bond at one end is produced by living polymerizing styrene with sec-butyllithium, stopping the polymerization reaction with ethylene oxide, and then using methacrylic acid chloride. It can be obtained by reacting. For example, polymethyl methacrylate having a polymerizable double bond at one end can be produced by adding thioglycolic acid to methyl methacrylate to perform radical polymerization, and then reacting it with glycidyl (meth)acrylate. Obtainable. (3) Polyvinyl chloride with a dithiocarbamate group as a photofunctional group. These hydrophobic monomers and hydrophobic polymers having polymerizable double bonds in their molecules are selected depending on the physical properties required of the hydrogel. For example, when high mechanical strength is required, it is desirable to use a hydrophobic monomer that provides a polymer with a high glass transition temperature or a hydrophobic polymer with a high glass transition temperature. Component B is a combination of a hydrophobic monomer and a hydrophobic polymer. The ratio of component A to component B in the hydrogel of the present invention is 95:5 to 40:60 on a weight basis. If the proportion of A component exceeds 95%, the mechanical properties will be markedly reduced, while if the proportion of A component is less than 40%, the water content will decrease, and material permeability and affinity with living organisms will decrease, so this is preferable. do not have. Copolymerization of component A and component B in such a ratio,
It is carried out by solution polymerization, bulk polymerization, etc., using means such as heat, light, and radiation. Due to the properties of the component A, the hydrogel of the present invention is flexible or brittle when dried, and it is extremely difficult to obtain a desired shape from the copolymer, such as a rod shape. A method that obtains the following is preferably carried out. As for the method of molding at the same time as polymerization,
For example, a method for polymerizing by injecting raw materials into a mold, a method for performing polymerization in a rotary mold, a method for applying the material to a rod, etc.
Examples include a method of pulling out a rod after polymerization is completed.
If a polymerization initiator is required during polymerization, benzoyl peroxide, di-t-butyl peroxide, 2,4-dichlorobenzoyl peroxide, t-butyl hydroperoxide, ammonium persulfate, etc. Organic peroxides such as azobisisobutyronitrile, azobiscyclohexanecarbonitrile, phenyl azoisobutyronitrile, and azobisdimethylvaleronitrile are used. Furthermore, the solvent for solution polymerization may be any solvent as long as it dissolves components A and B well to give a clear liquid and does not inhibit polymerization, but dimethyl sulfoxide, N-methyl-2-
pyrrolidone, N,N-dimethylacetamide,
N,N-dimethylformamide, tetrahydrofuran, 1,4 dioxane and the like are preferably used alone or as a mixture. The hydrogel of the present invention may contain suitable monomers other than both components A and B. This third monomer or monomer mixture is introduced for the purpose of improving processability and handling when the hydrogel is dried. Examples of monomers that can be used include polyethylene glycol mono(meth)acrylate, alkoxypolyethylene glycol mono(meth)acrylate, N-vinyl lactams such as N-vinylpyrrolidone and N-vinylpiperidone, (meth)acrylic acid, Hydrophilic monomers such as hydroxyalkyl (meth)acrylates such as hydroxyethyl or hydroxypropyl esters of (meth)acrylic acid, (meth)acrylamide, and mono(meth)acrylate of glycerin. In this case, the range of addition amount is A
Up to the same amount as the ingredients. In addition, like ordinary hydrogels, it may contain a crosslinking agent. Examples of crosslinking agents that can be used include di- or tri-acrylates such as ethylene glycol di(meth)acrylate, hexamethylene bismaleimide, divinylbenzene, N,N'-methylenebisacrylamide, and trimethylolpropane tri(meth)acrylate. −
Vinyl compounds, allyl compounds such as diallyl succinate, diethylene glycol bisallyl carbonate, triallyl isocyanurate, allyl vinyl compounds such as allyl (meth)acrylate, vinyl (meth)acrylate, etc., and are 0.01 to 2% by weight based on the total raw material. It is preferable to add %. Effects of the Invention The hydrogel obtained by the present invention has the following excellent properties. (1) Contains highly hydrophilic high molecular weight polyethylene glycol or a derivative of poly(ethylene glycol-propylene glycol) copolymer, so it has a high water content and has excellent permeability to substances and compatibility with living organisms. (2) Excellent mechanical properties, especially elongation at break. This is because high molecular weight polyethylene glycol or poly(ethylene glycol-propylene glycol) copolymer derivatives are used.
This is because the distance between crosslinking points is long and a high molecular weight effect appears. The hydrogel of the present invention takes advantage of the above properties,
Soft contact lenses, catheters, cell culture substrates, blood flow circuits, embedding materials for oxygen and pharmaceuticals,
It can be preferably used for various separation membranes. The effects of the present invention will be explained below with reference to Examples. Example 1 40 parts of methyl methacrylate, 60 parts of methyl acrylate
1 part, 2-hydroxyethyl methacrylate was dissolved in dimethyl sulfoxide and heated at 70°C using azobisisobutyronitrile as a polymerization initiator.
After polymerization, the polymer was poured into a methanol-water mixture, reprecipitated and recovered, and dried under reduced pressure to obtain a polymer.
This polymer was dissolved in 1,4-dioxane and reacted with methacrylic acid chloride to obtain a hydrophobic polymer having a polymerizable double bond in the side chain. Furthermore, a methacrylic acid diester of polyethylene glycol having an average molecular weight of 4000 was obtained by the following method. Polyethylene glycol with an average molecular weight of 4000 was dissolved in 1,4-dioxane and reacted with a large excess of methacrylic acid chloride using pyridine as a catalyst to obtain a methacrylic acid diester having polymerizable double bonds at both ends. . Using these compounds, the following composition was thoroughly stirred and mixed to obtain a transparent stock solution. 70 parts of the above methacrylic diester of polyethylene glycol with an average molecular weight of 4000 30 parts of the above hydrophobic polymer having a polymerizable double bond in the side chain Methyl methacrylate 25 parts Dimethyl sulfoxide 233 parts Azobisdimethylvaleronitrile 0.15 parts The stock solution was placed in a nitrogen stream between glass plates using a polyethylene terephthalate film as a spacer and fixed with a fastener, and then polymerization was carried out in an electric furnace capable of continuous temperature rise. The polymerization conditions were: heating at 40℃ for 8 hours, then raising the temperature from 40℃ to 60℃ over 4 hours,
Increase temperature from 60℃ to 80℃ over 3 hours, from 80℃ to 90℃
The temperature was raised to ℃ over 1 hour. After the polymerization was completed, the produced polymer film was peeled off from the glass plate, immersed in pure water, boiled for 30 minutes, cooled and replaced three times to obtain a hydrogel film in a water-containing state. The water content was 62% and the transparency was good. The breaking strength is 34Kg/cm ² and the breaking elongation is 165.
It was %. Example 2 Polymerization of a stock solution consisting of the following composition was carried out in the same manner as in Example 1, using methoxypolyethylene glycol monomethacrylate as the third monomer. Diester of polyethylene glycol methacrylate with an average molecular weight of 20,000 30 parts Methyl methacrylate 40 parts Methoxypolyethylene glycol monomethacrylate (Shin Nakamura Chemical M23G) 30 parts Triethylene glycol dimethacrylate
0.5 part dimethyl sulfoxide 233 parts azobisdimethylvaleronitrile 0.1 part After the polymerization was completed, a hydrogel film in a water-containing state was obtained in the same manner as in Example 1. The water content was 75% and the transparency was good. Also, the breaking strength is 23
Kg/cm ² and elongation at break were 230%, which were very excellent. Comparative Example 1 A methacrylic acid diester of polyethylene glycol having an average molecular weight of 1000 was obtained in the same manner as in Example 1. This methacrylic acid diester of polyethylene glycol with an average molecular weight of 1000 is
A hydrogel film in a water-containing state was obtained in exactly the same manner as in Example 1, except that polyethylene glycol 4000 was used instead of diester methacrylate. Despite the low moisture content of 46%, the breaking strength is 19
Kg/cm ² , the elongation at break was 70%, and the mechanical properties were poor.

Claims (1)

[Scope of Claims] 1 A: 95 to 40 parts of polyethylene glycol or poly(ethylene glycol-propylene glycol) copolymer having a molecular weight of 1,500 to 500,000 and having polymerizable double bonds at both ends, and B: a polymerizable double bond. A hydrogel comprising a polymerization reaction product of a hydrophobic monomer having a bond and 5 to 60 parts of a hydrophobic polymer having a polymerizable double bond in the molecule.