WO2017033892A1 - Method for producing hydrogel - Google Patents

Method for producing hydrogel Download PDF

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Publication number
WO2017033892A1
WO2017033892A1 PCT/JP2016/074388 JP2016074388W WO2017033892A1 WO 2017033892 A1 WO2017033892 A1 WO 2017033892A1 JP 2016074388 W JP2016074388 W JP 2016074388W WO 2017033892 A1 WO2017033892 A1 WO 2017033892A1
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Prior art keywords
hydrogel
vinyl
pva
polymerization
water
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PCT/JP2016/074388
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French (fr)
Japanese (ja)
Inventor
小原田　明信
佳弘 木村
和明 松村
智世 阪口
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日本酢ビ・ポバール株式会社
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Publication of WO2017033892A1 publication Critical patent/WO2017033892A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F16/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical
    • C08F16/02—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical by an alcohol radical
    • C08F16/04—Acyclic compounds
    • C08F16/06—Polyvinyl alcohol ; Vinyl alcohol
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels

Definitions

  • the present invention relates to a method for producing a hydrogel having excellent mechanical strength such as strength and elastic modulus, and more particularly to a hydrogel that can be used as a biocompatible material such as an artificial joint cartilage material.
  • a hydrogel using a polyvinyl alcohol (hereinafter abbreviated as PVA) resin has a high water content, a high flexibility and a high mechanical strength, and a high affinity with a living body. It is a useful material and is widely used in the medical materials field, the environment field, and daily goods.
  • PVA polyvinyl alcohol
  • Examples of the medical material field include artificial articular cartilage material. Artificial joints are often used for articular cartilage damage due to rheumatism or accidents, but artificial joints are a major operation that removes healthy femurs and bone heads and replaces them with titanium artificial joints. . Also, due to the wear of the sliding part, it has a life of approximately 20 years or less and may require re-operation. However, as it is understood from the fact that more than 1.5 million cases are performed annually worldwide, this is a highly necessary operation. For this reason, recently, a technique using friction and wear reduction technology has been reported, for example, an artificial joint having a hydrophilic polymer attached to the surface of a sliding portion has been released (Patent Document 1).
  • Non-Patent Document 1 Japanese Patent Document 1
  • a high-strength hydrogel can be produced by dissolving a high-concentration solution by heating and compressing polyvinyl alcohol and water and then releasing the pressure. It has become clear (Non-Patent Document 2).
  • Non-Patent Document 1 is toxic to dimethyl sulfoxide (DMSO) used at the time of hydrogel preparation, and also has the effect of accelerating the absorption of other harmful substances by DMSO. It becomes a problem. Although a certain level of DMSO can be removed by desolvation, it is difficult to completely remove DMSO. Furthermore, it is desired to increase the water content while maintaining the mechanical strength of the hydrogel. However, since the water content and the strength are inversely proportional, if the water content is increased, the material is not suitable as cartilage.
  • DMSO dimethyl sulfoxide
  • Non-Patent Document 2 the mechanical strength of the hydrogel obtained in Non-Patent Document 2 is not sufficiently satisfactory, and a long time is required until gelation, which is not an industrially advantageous method.
  • the objective of this invention is providing the hydrogel excellent in mechanical strength, and its manufacturing method. Another object of the present invention is to provide a hydrogel having no toxicity problem in vivo and a method for producing the hydrogel. Furthermore, another object of the present invention is to provide a hydrogel that can be produced by an industrially advantageous method and a method for producing the hydrogel.
  • the present invention relates to the following hydrogel production methods and the like.
  • a polyvinyl alcohol resin (A) having a syndiotacticity of 32% or more in triad display is swollen in water (B), dissolved under heat compression conditions of 1 to 50 MPa and 90 to 160 ° C., and then released.
  • a hydrogel can be produced by gelation in a short time, and the productivity is excellent. Further, according to the present invention, PVA with high syndiotacticity can be dissolved in water at a high concentration (for example, a concentration of 40% by mass or more), and a hydrogel suitable for the purpose can be produced. Further, according to the present invention, a hydrogel having a high water content and high strength can be produced. Furthermore, according to the present invention, a hydrogel having high mechanical strength can be produced without using an organic solvent that is toxic to living organisms such as DMSO, which is suitable for biomaterials such as artificial joint cartilage. Hydrogels can be provided.
  • PVA with high syndiotacticity has poor solubility in not only water but also an organic solvent, gelation itself is difficult with the conventional gelation method.
  • PVA with high syndiotacticity can be dissolved in water (and dissolved at a high concentration) without using an organic solvent, and a hydrogel having excellent mechanical strength can be obtained in a short time. The effect of the present invention that it can be achieved is surprising.
  • FIG. 2 is a photograph of the hydrogel of Example 1. It is a time-dependent change of the elution rate to the water of the hydrogel of Example 1 and Comparative Example 1. It is a time-dependent change of the X-ray small angle scattering spectrum of the hydrogel of Example 1.
  • FIG. It is a time-dependent change of the X-ray small angle scattering spectrum of the hydrogel of the comparative example 1.
  • the syndiotacticity used in the present invention is a syndiotacticity based on triad display in which the polyvinyl alcohol resin (A) having a triad display of 32% or more (hereinafter sometimes abbreviated as St-PVA (A)) is used. Is, for example, 32 to 40%, preferably 33% or more (for example, 33 to 39%), more preferably 34% or more (for example, 34 to 38%), and still more preferably 36% or more (for example, 36 to 36%). 38%).
  • the triad-syntacticity can be obtained from a hydroxyl peak measured by proton NMR measurement by dissolving a polyvinyl alcohol-based resin in heavy DMSO.
  • the production method of St-PVA (A) used in the present invention is not particularly limited as long as the syndiotacticity by triad display is 32% or more, and a vinyl ester polymer obtained by a conventionally known method is saponified. Obtained by the method.
  • the method for producing the vinyl ester polymer is not particularly limited as long as it is a method for polymerizing a vinyl ester monomer, and may be a conventionally known method. In the polymerization, any known method may be used for the shape of the polymerization vessel, the type of the polymerization stirrer, the polymerization temperature, the pressure in the polymerization vessel, and the like.
  • polymerization method conventionally known various polymerization methods such as bulk polymerization, solution polymerization, suspension polymerization, and emulsion polymerization are possible.
  • solution polymerization using alcohol as a solvent or suspension polymerization using water or water and alcohol as a dispersion medium are preferable, but are not limited thereto. It is not a thing.
  • vinyl ester monomer examples include vinyl esters such as fatty acid vinyl esters and non-fatty acid vinyl esters (for example, vinyl formate, aromatic carboxylic acid vinyl esters, etc.), but have high syndiotacticity.
  • C 3-15 fatty acid vinyl ester for example, linear or branched C 3-15 fatty acid vinyl ester such as vinyl propionate, vinyl butyrate, vinyl pivalate, etc., preferably C 3-10 Fatty acid vinyl esters (eg, linear or branched C 3-10 fatty acid vinyl esters, etc.)]
  • C 3-15 fatty acid vinyl esters having a substituent (eg, halogen group) eg, vinyl trifluoroacetate, vinyl trichloroacetate Etc.
  • vinyl formate and the like examples include vinyl esters such as fatty acid vinyl esters and non-fatty acid vinyl esters (for example, vinyl formate, aromatic carboxylic acid vinyl esters, etc.), but have high syndiotacticity.
  • St-PVA (A) can be produced by polymerizing vinyl esters such as vinyl propionate, vinyl butyrate and vinyl pivalate having bulky side chains and then saponifying with an alkali catalyst, formic acid, Examples include a method of polymerizing a highly polar vinyl ester such as vinyl, vinyl trifluoroacetate or vinyl trichloroacetate and then saponifying with an alkali catalyst. Of these, vinyl pivalate is preferably used, but vinyl propionate and vinyl butyrate may be copolymerized.
  • the vinyl ester content may be, for example, 20 to 100% by mass, 30 to 100% by mass, 40 to 100% by mass, or the like.
  • the vinyl ester content may be, for example, 220 to 100 mol%, preferably 30 to 100 mol%, more preferably 40 to 100 mol%.
  • the content of vinyl pivalate in the total vinyl ester component of St-PVA (A) is, for example, 40 to 100% by mass (for example, 45 to 100% by mass), preferably 50 to It is 100% by mass (for example, 55 to 100% by mass), more preferably 60 to 100% by mass (for example, 65 to 100% by mass).
  • the vinyl pivalate content in the total vinyl ester component of St-PVA (A) is, for example, 60 to 100 mol% (for example, 65 to 95 mol%), preferably It is 70 to 100 mol% (for example, 75 to 95 mol%), more preferably 80 to 100 mol% (for example, 85 to 95 mol%).
  • the vinyl ester polymer may be copolymerized with another unsaturated monomer copolymerizable with the vinyl ester as long as the effects of the present invention are not impaired.
  • unsaturated monomers include carboxyl group-containing unsaturated monomers ⁇ eg, unsaturated monocarboxylic acids [eg, (meth) acrylic acid, etc.], unsaturated dicarboxylic acids (eg, maleic acid, fumaric acid, etc.).
  • (Meth) acrylic acid esters for example, methyl (meth) acrylate, ethyl (meth) acrylate, 2-ethylhexyl acrylate, n-butyl acrylate, etc.], vinyl Nylsilanes (eg, trimethoxyvinylsilane, tributylvinylsilane, diphenylmethylvinylsilane, etc.), polyoxyalkylene (meth) acrylates [eg, polyoxyethylene (meth) acrylate, polyoxypropylene (meth) acrylate, etc.), polyoxyalkylene (Meth) acrylic acid amides [eg, polyoxyethylene (meth) acrylic acid amide, polyoxypropylene (meth) acrylic acid amide, etc.], polyoxyalkylene vinyl ethers (eg, polyoxyethylene vinyl ether, polyoxypropylene vinyl ether, etc.
  • Polyoxyalkylene alkyl vinyl ethers for example, polyoxyethylene allyl ether, polyoxypropylene allyl ether, polyoxyethylene bityl vinyl) Ether, polyoxypropylene butyl vinyl ether, etc.
  • ⁇ -olefins eg, ethylene, propylene, 1-butenes (eg, 3,4-dihydroxy-1-butene, 3,4-diacyloxy-1-butene, 3- Acyloxy-4-hydroxy-1-butene, 4-acyloxy-3-hydroxy-1-butene, 3,4-diacyloxy-2-methyl-1-butene), 1-pentenes (for example, 4,5-dihydroxy -1-pentene, 4,5-diasiloxy-1-pentene, 4,5-dihydroxy-3-methyl-1-pentene, 4,5-diasiloxy-3-methyl-1-pentene, etc.), 1-hexene ( For example, 5,6-dihydroxy-1-hexen
  • the other monomer is, for example, 20% by mass or less (for example, 0.1 to 20% by mass, preferably 1 to 10% by mass) with respect to the vinyl ester. Can be used.
  • the other monomer is, for example, 20 mol% or less (for example, 0.1 to 20 mol%, 1 to 10 mol%, etc.) with respect to the vinyl ester. be able to.
  • the alcohol solvent used for the polymerization of the vinyl ester is not particularly limited, and examples thereof include alcohols such as methanol, ethanol, n-propanol, 2-propanol, etc. Among them, methanol is industrially preferable.
  • the polymerization initiator is not particularly limited, and examples thereof include percarbonate compounds (for example, diisopropyl peroxydicarbonate, di-2-ethylhexyl peroxydicarbonate, diethoxyethyl peroxydicarbonate, etc.), peroxyester compounds ( For example, t-butylperoxyneodecanoate, t-hexylperoxyneodecanoate, t-hexylperoxypivalate, ⁇ -cumylperoxyneodecanoate, t-hexylneohexanoate, 2, 4,4-trimethylpentyl-2-peroxy-2-neodecanoate, etc.), azo compounds [eg, azobis (2,4-dimethylvaleronitrile), azobisisobutyronitrile, etc.], peroxide compounds (eg, lauryl percarbonate, di-2-ethylhexyl peroxydicarbonate
  • a chain transfer agent may be used for the purpose of adjusting the degree of polymerization of the resulting vinyl ester polymer.
  • the chain transfer agent include, but are not limited to, aldehydes such as acetaldehyde, propionaldehyde, butyraldehyde, and benzaldehyde; ketones such as acetone, methyl ethyl ketone, hexanone, and cyclohexanone; mercaptans such as 2-hydroxyethanethiol and dodecyl mercaptan.
  • chain transfer agents such as carbon tetrachloride, trichlorethylene and perchloroethylene, among which aldehydes and ketones are preferably used.
  • chain transfer agents can be used alone or in combination of two or more.
  • the addition amount of the chain transfer agent is determined according to the chain transfer constant of the chain transfer agent to be added and the degree of polymerization of the target vinyl ester polymer, but is generally 0.1% relative to the vinyl ester monomer. ⁇ 10% by mass is desirable.
  • St-PVA (A) can be produced by saponifying the vinyl ester polymer obtained as described above.
  • the saponification reaction method of the vinyl ester polymer is not particularly limited and may be a conventionally known method.
  • a conventionally known basic catalyst such as sodium hydroxide, potassium hydroxide, sodium methoxide, hydrochloric acid,
  • An alcoholysis or hydrolysis reaction using an acidic catalyst such as sulfuric acid or p-toluenesulfonic acid can be applied.
  • Examples of the solvent used in the saponification reaction include alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; ketones such as acetone and methyl ethyl ketone; aromatic hydrocarbons such as benzene and toluene; These can be used alone or in combination of two or more.
  • the method for drying and pulverizing the saponified product there are no particular restrictions on the method for drying and pulverizing the saponified product, and a known method may be used.
  • a polymerization terminator can be used.
  • the polymerization terminator is not particularly limited, and examples thereof include m-dinitrobenzene.
  • the saponification degree of St-PVA (A) is preferably 90 mol% or more (for example, 90 to 99.99 mol%), more preferably 98 mol% or more (for example, 98. to 99.95 mol%). More preferably, it is 99 mol% or more (for example, 99 to 99.93 mol%).
  • the saponification degree of St-PVA (A) can be determined by measuring 1 H-NMR in a heavy DMSO solution.
  • the degree of polymerization of St-PVA (A) is preferably 100 to 10000, more preferably 500 to 8000, still more preferably 1000 to 5000, and is relatively easy to handle.
  • the resulting hydrogel is sticky. From the standpoints that it can be made less and can be made excellent in strength and water resistance, it is particularly preferably 1000 to 3000.
  • the degree of polymerization of St-PVA (A) may be, for example, 1000 to 2000, preferably 2000 to 3000, more preferably 3000 to 4000, and still more preferably 4000 to 5000. If the degree of polymerization is 100 or more, it is easy to produce an aqueous gel having high resin strength and shape retention.
  • the degree of polymerization is a degree of polymerization in terms of polyvinyl acetate at 30 ° C. in a benzene solution described in JIS K6725.
  • St-PVA (A) preferably contains a unit derived from a fatty acid vinyl ester (or also referred to as a fatty acid vinyl ester unit; hereinafter the same in the same expression). That is, it is preferable that the PVA resin remains a fatty acid vinyl ester unit copolymerized without being saponified.
  • the content of the fatty acid vinyl ester unit in St-PVA (A) is, for example, 25% by mass or less (for example, 0.01 to 25% by mass), preferably 10% by mass or less (for example, 0.01 to 10% by mass). More preferably, it is 0.01 to 2% by mass, and still more preferably 0.01 to 1% by mass.
  • the content of the fatty acid vinyl ester unit in St-PVA (A) is, for example, 10 mol% or less (for example, 0.01 to 10 mol) with respect to the entire monomer-derived unit constituting St-PVA (A). %), Preferably 0.01 to 2 mol%, more preferably 0.01 to 1 mol%.
  • St-PVA (A) preferably contains vinyl pivalate units among fatty acid vinyl ester units.
  • the content of vinyl pivalate units in St-PVA (A) is, for example, 25% by mass or less (for example, 0.01 to 25% by mass), preferably 10% by mass or less (for example, 0.01 to 10% by mass). More preferably, it is 0.01 to 2% by mass, and still more preferably 0.01 to 1% by mass.
  • the content of vinyl pivalate units in St-PVA (A) is, for example, 10 mol% or less (for example, 0.01 to 10 mol%) with respect to the entire monomer-derived units constituting St-PVA (A). ), Preferably 0.01 to 2 mol%, more preferably 0.01 to 1 mol%.
  • St-PVA (A) may be post-modified by reactions such as acetalization, urethanization, etherification, grafting, phosphoric esterification, acetoacetylation, cationization, etc., as long as the effects of the present invention are not impaired. Good.
  • the hydrogel of the present invention can be obtained by making St-PVA (A) and water (B) into a solution by heat compression and then allowing to cool.
  • the heat compression is usually carried out after St-PVA (A) is swollen in water (B).
  • the heat compression conditions are not particularly limited as long as St-PVA (A) is dissolved in water.
  • the temperature for heat compression is preferably 90 to 160 ° C.
  • the pressure for heat compression is preferably 1 to 50 MPa, more preferably 1.5 to 40 MPa, and still more preferably 2 to 30 MPa.
  • the heat compression time can be appropriately changed depending on the temperature and pressure of heat compression, and is, for example, 1 minute to 2 hours, 1 minute to 1 hour, or the like.
  • the ratio (mass ratio) of St-PVA (A) and water (B) to be subjected to heat compression is not particularly limited, but is, for example, 90/10 to 20/80, preferably 80/20 to 25/75. More preferably, it is 70/30 to 30/70.
  • the ratio of St-PVA (A) and water (B) may be, for example, 90/10 to 40/60, preferably 80/20 to 45/55.
  • the cooling temperature is, for example, ⁇ 30 to 40 ° C., and may be room temperature such as 25 to 35 ° C.
  • the cooling time can be appropriately adjusted according to the cooling temperature, and is not particularly limited, but may be, for example, 30 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • a hot press machine As an apparatus used for heat compression, for example, a hot press machine can be used. St-PVA (A) and water (B) can be easily made into a solution by heating and compressing using a hot press machine.
  • St-PVA (A) constituting the hydrogel of the present invention may contain, for example, 0.01 to 25% by mass of a vinyl ester unit (or 0.01 to 10 mol% in terms of monomer unit).
  • St-PVA (A) constituting the hydrogel preferably contains a fatty acid vinyl ester unit among vinyl ester units, and among the fatty acid vinyl ester units, the water gel has excellent water resistance. From the viewpoint, it is particularly preferable that vinyl pivalate units are contained, but non-fatty acid vinyl esters may be contained.
  • the content of St-PVA (A) and water contained in the hydrogel usually reflects the ratio of St-PVA (A) and water (B) used for heat compression as they are. That is, the ratio of St-PVA (A) and water contained in the hydrogel is, for example, 90/10 to 20/80, preferably 80/20 to 25/75, more preferably 70, by mass ratio. / 30 to 30/70.
  • the aqueous gel of the present invention may contain St-PVA (A) and other components as necessary, but St-PVA (A) preferably consists essentially of PVA. .
  • PVA other than St-PVA (A) eg, PVA having a syndiotacticity of 31% or less
  • starches eg, starch, modified starch, etc.
  • cellulose derivatives eg, Methyl cellulose, carboxymethyl cellulose, etc.
  • polyacrylic acid and its derivatives other polymer compounds (eg, gelatin, agar, carrageenan, sodium alginate, etc.), inorganic fillers (eg, thickener, clay, kaolin, talc, silica) , Calcium carbonate, etc.), plasticizers (eg, glycerin, ethylene glycol, propylene glycol, sorbitol, etc.), antifoaming agents, chelating agents, pH adjusters, surfactants, organic solvents, etc
  • the aqueous gel of the present invention is excellent in strength even though it is a hydrogel containing PVA resin as a constituent component.
  • the Young's modulus of the aqueous gel of the present invention is, for example, 2 to 100 MPa, preferably 2 to 80 MPa, more preferably 2 to 30 MPa.
  • the Young's modulus can be determined using, for example, the method described in the examples described later.
  • the aqueous gel of the present invention is excellent in water resistance despite the PVA resin as a constituent component. Furthermore, the aqueous gel of the present invention is excellent in water resistance even when the water content is increased.
  • the water elution rate of the aqueous gel of the present invention is, for example, 0.01 to 5%, preferably 0.01 to 0.5%. In addition, the elution rate of water can be calculated
  • the hydrogel of the present invention can be produced without using an organic solvent that is toxic to the living body, and further has excellent mechanical strength, so that it can be used as a biocompatible material such as an artificial joint cartilage material. can do.
  • the method for forming the hydrogel of the present invention on an artificial joint cartilage material is not particularly limited. For example, after producing a hydrogel, it can be formed into an artificial joint cartilage material by leaving it in an artificial joint cartilage type container and leaving it out. The temperature and time for leaving are not particularly limited, and can be performed at room temperature. Moreover, when producing the hydrogel of this invention, you may form the hydrogel for artificial joint cartilage materials by making it melt
  • IP detector Target Cu K ⁇ ray (0.154 nm)
  • Output 45kV-60mA
  • Beam stopper ⁇ 2.5mm
  • Camera length 960mm
  • the elution rate measurement result of the obtained hydrogel is shown in FIG.
  • the elution rate was already 0% 15 minutes after the production, and was also 0% 48 hours after the production. Thus, it was confirmed that the hydrogel obtained in Example 1 is excellent in water resistance.
  • a hydrogel was prepared in the same manner as in Example 1 except that atactic PVA having a syndiotacticity of 30.8%, a saponification degree of 99.1 mol%, and a polymerization degree of 1920 was used.
  • the hydrogel was soft and could not be taken out from the silicon mold for several hours (3 hours) after preparation.
  • the measurement result of the elution rate of the obtained hydrogel is shown in FIG. In this case, the dissolution rate after standing for 48 hours after preparation was 23%.
  • the time-dependent change of the microstructure of the hydrogel produced in Example 1 and Comparative Example 1 was measured by X-ray small angle scattering (SAXS).
  • SAXS X-ray small angle scattering
  • Comparative Example 1 As described above, the gelation was not immediately after production (0 hours after gel production), and the gel was finally formed as a gel 20 hours after production, and the Young's modulus was 120 hours after production. It was 1.3 MPa, and it was not strong enough to be used as a gel. On the other hand, as shown in Table 1, the gel of Example 1 had a Young's modulus of 2.6 MPa even immediately after gel preparation (0 hours after gel preparation), and a high Young's modulus of 4.4 MPa after 20 hours of preparation, After 170 hours of preparation, the gel became 4.8 MPa.
  • Example 1 immediately after preparation was placed in an artificial articular cartilage-type container, allowed to stand at room temperature for 12 hours and then taken out, whereby a gel for artificial joint cartilage could be formed.
  • the production method of the hydrogel of the present invention is industrially advantageous because a gel can be produced at a high concentration and the gel can be obtained in a relatively short time.
  • the obtained hydrogel is mechanically strong. Since it is excellent, it is particularly useful as a biomaterial such as artificial joint cartilage.

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Abstract

The purpose of the present invention is to provide a hydrogel that has excellent mechanical strength and that does not present problems in terms of toxicity to living organisms, and a method for producing the same. This hydrogel is produced by allowing a polyvinyl alcohol-based resin (A) having a syndiotacticity of 32% or more, expressed as triads, to swell in water (B), dissolve under thermocompression conditions, and then cool.

Description

ハイドロゲルの製造方法Method for producing hydrogel
　本発明は、強度、弾性率などの機械的強度に優れたハイドロゲルの製造方法に関するもので、特に人工関節軟骨材料などの生体適合性材料として利用可能なハイドロゲルに関する。 The present invention relates to a method for producing a hydrogel having excellent mechanical strength such as strength and elastic modulus, and more particularly to a hydrogel that can be used as a biocompatible material such as an artificial joint cartilage material.
　ポリビニルアルコール（以下、ＰＶＡと略記する）系樹脂を用いたハイドロゲルは、含水率が高いこと、成形物の柔軟性が高く機械的強度が高いこと、生体との親和性が高いこと等の点で有用な素材であり、医療材料分野、環境分野、日用雑貨等に幅広く利用されている。 A hydrogel using a polyvinyl alcohol (hereinafter abbreviated as PVA) resin has a high water content, a high flexibility and a high mechanical strength, and a high affinity with a living body. It is a useful material and is widely used in the medical materials field, the environment field, and daily goods.
　医療材料分野としては、例えば人工関節軟骨材料用などが挙げられる。リウマチや事故などの理由による関節軟骨の損傷で人工関節を用いることが多いが、人工関節の施術は健全な大腿骨、骨頭を除去し、チタン製の人工関節に置き換える大きな手術であり負担が大きい。また摺動部の摩耗により大体２０年以下の寿命しかなく、再手術も必要となることがある。ただ、世界的には年間１５０万例以上行われていることからわかる様に必要性が高い手術である。このため最近では、親水性高分子を摺動部表面に付けた人工関節が発売されるなど、摩擦や摩耗の低減技術を用いた技術が報告されている（特許文献１）。 Examples of the medical material field include artificial articular cartilage material. Artificial joints are often used for articular cartilage damage due to rheumatism or accidents, but artificial joints are a major operation that removes healthy femurs and bone heads and replaces them with titanium artificial joints. . Also, due to the wear of the sliding part, it has a life of approximately 20 years or less and may require re-operation. However, as it is understood from the fact that more than 1.5 million cases are performed annually worldwide, this is a highly necessary operation. For this reason, recently, a technique using friction and wear reduction technology has been reported, for example, an artificial joint having a hydrophilic polymer attached to the surface of a sliding portion has been released (Patent Document 1).
　また、人工関節の摺動部にあたる軟骨のみを置換するような開発も行われており、これまで人工関節軟骨としてポリビニルアルコールハイドロゲルを用いる研究もなされている（非特許文献１）。 Also, development has been made to replace only the cartilage corresponding to the sliding portion of the artificial joint, and research using polyvinyl alcohol hydrogel as the artificial joint cartilage has been made (Non-Patent Document 1).
　一方、水のみで機械的強度の高いゲルを作製する方法として、ポリビニルアルコールと水を加熱圧縮により高濃度の溶液を溶解し、その後圧を解放することで高強度のハイドロゲルが作製できる事も明らかとなっている（非特許文献２）。 On the other hand, as a method of producing a gel having high mechanical strength only with water, a high-strength hydrogel can be produced by dissolving a high-concentration solution by heating and compressing polyvinyl alcohol and water and then releasing the pressure. It has become clear (Non-Patent Document 2).
特許第５１０００２３号Patent No. 5100023
　しかしながら、非特許文献１で得られるハイドロゲルは、ハイドロゲル作製時に使用するジメチルスルホキシド（ＤＭＳＯ）に毒性があり、また、ＤＭＳＯによって他の有害物質の吸収を早める効果もあり生体内での使用時に問題となる。また、脱溶媒によって一定レベルのＤＭＳＯの除去は可能だが、完全に除去することが難しい。さらには、ハイドロゲルの機械的強度を維持したまま含水率を高くしたいが、含水率と強度が反比例するため、含水率を高くすると軟骨として適した材料とならない。 However, the hydrogel obtained in Non-Patent Document 1 is toxic to dimethyl sulfoxide (DMSO) used at the time of hydrogel preparation, and also has the effect of accelerating the absorption of other harmful substances by DMSO. It becomes a problem. Although a certain level of DMSO can be removed by desolvation, it is difficult to completely remove DMSO. Furthermore, it is desired to increase the water content while maintaining the mechanical strength of the hydrogel. However, since the water content and the strength are inversely proportional, if the water content is increased, the material is not suitable as cartilage.
　また、非特許文献２で得られるハイドロゲルの機械的強度も十分に満足できるものではなく、ゲル化までに長時間を必要とすることから工業的に有利な方法ではなかった。 Further, the mechanical strength of the hydrogel obtained in Non-Patent Document 2 is not sufficiently satisfactory, and a long time is required until gelation, which is not an industrially advantageous method.
　本発明の目的は、機械的強度に優れたハイドロゲル及びその製造方法を提供することにある。
　また、本発明の別の目的は、生体内での毒性の問題がないハイドロゲル及びその製造方法を提供することにある。
　さらに、本発明の別の目的は、工業的に有利な方法で製造できるハイドロゲル及びその製造方法を提供することにある。 The objective of this invention is providing the hydrogel excellent in mechanical strength, and its manufacturing method.
Another object of the present invention is to provide a hydrogel having no toxicity problem in vivo and a method for producing the hydrogel.
Furthermore, another object of the present invention is to provide a hydrogel that can be produced by an industrially advantageous method and a method for producing the hydrogel.
　本発明者らは、上記課題を解決するために鋭意研究を重ねた結果、立体規則性の高いポリビニルアルコール（具体的には、シンジオタクティシティがトライアッド表示で３２％以上のポリビニルアルコール）を水と混合し、加熱圧縮してハイドロゲルを製造することにより上記課題を解決出来ることを見出し、さらに検討を重ねて本発明を完成した。 As a result of intensive research in order to solve the above problems, the present inventors have obtained highly stereoregular polyvinyl alcohol (specifically, polyvinyl alcohol having a syndiotacticity of 32% or more in triad display). It was found that the above-mentioned problems can be solved by mixing and heating and compressing to produce a hydrogel, and further studies were completed to complete the present invention.
　すなわち、以下のハイドロゲルの製造方法等に関する。
［１］シンジオタクティシティがトライアッド表示で３２％以上のポリビニルアルコール系樹脂（Ａ）を水（Ｂ）に膨潤させ、１～５０ＭＰａ、９０～１６０℃の加熱圧縮条件下で溶解し、その後放冷するハイドロゲルの製造方法。
［２］前記ポリビニルアルコール系樹脂（Ａ）および水（Ｂ）の割合が、質量比で９０／１０～２０／８０である前記［１］記載のハイドロゲルの製造方法。
［３］ホットプレス機を用いて溶解する前記［１］又は［２］に記載のハイドロゲルの製造方法。
［４］前記［１］～［３］のいずれかに記載の製造方法を用いて得られるハイドロゲル。
［５］前記［４］記載のハイドロゲルで形成された人工関節軟骨材料。 That is, the present invention relates to the following hydrogel production methods and the like.
[1] A polyvinyl alcohol resin (A) having a syndiotacticity of 32% or more in triad display is swollen in water (B), dissolved under heat compression conditions of 1 to 50 MPa and 90 to 160 ° C., and then released. A method for producing a cooled hydrogel.
[2] The method for producing a hydrogel according to [1], wherein the ratio of the polyvinyl alcohol-based resin (A) and water (B) is 90/10 to 20/80 by mass ratio.
[3] The method for producing a hydrogel according to [1] or [2], wherein the hydrogel is dissolved using a hot press.
[4] A hydrogel obtained using the production method according to any one of [1] to [3].
[5] An artificial joint cartilage material formed of the hydrogel according to [4].
　本発明によれば、短時間でのゲル化によりハイドロゲルを製造することができ、生産性に優れる。
　また、本発明によれば、シンジオタクティシティの高いＰＶＡを高濃度（例えば４０質量％以上等の濃度）で水に溶解することができ、目的に応じたハイドロゲルの作製が可能である。
　また、本発明によれば、高含水率で強度の高いハイドロゲルを作製出来る。
　さらに、本発明によれば、ＤＭＳＯなどの生体に対して毒性のある有機溶媒を使用することなく、機械的強度の高いハイドロゲルを作製することが出来るため、人工関節軟骨などの生体材料に適したハイドロゲルを提供することができる。 According to the present invention, a hydrogel can be produced by gelation in a short time, and the productivity is excellent.
Further, according to the present invention, PVA with high syndiotacticity can be dissolved in water at a high concentration (for example, a concentration of 40% by mass or more), and a hydrogel suitable for the purpose can be produced.
Further, according to the present invention, a hydrogel having a high water content and high strength can be produced.
Furthermore, according to the present invention, a hydrogel having high mechanical strength can be produced without using an organic solvent that is toxic to living organisms such as DMSO, which is suitable for biomaterials such as artificial joint cartilage. Hydrogels can be provided.
　尚、シンジオタクティシティが高いＰＶＡは、水だけでなく有機溶媒に対しても溶解性が悪いため、従来のゲル化方法では、ゲル化自体が困難であった。
　一方、有機溶媒を使用しなくともシンジオタクティシティの高いＰＶＡを水に溶解（さらには、高濃度で溶解）することができ、さらに、優れた機械的強度を有するハイドロゲルが短時間で得られるという本願発明の効果は、驚くべきものである。 In addition, since PVA with high syndiotacticity has poor solubility in not only water but also an organic solvent, gelation itself is difficult with the conventional gelation method.
On the other hand, PVA with high syndiotacticity can be dissolved in water (and dissolved at a high concentration) without using an organic solvent, and a hydrogel having excellent mechanical strength can be obtained in a short time. The effect of the present invention that it can be achieved is surprising.
実施例１のハイドロゲルの写真である。2 is a photograph of the hydrogel of Example 1. 実施例１及び比較例１のハイドロゲルの、水への溶出率の経時変化である。It is a time-dependent change of the elution rate to the water of the hydrogel of Example 1 and Comparative Example 1. 実施例１のハイドロゲルの、Ｘ線小角散乱スペクトルの経時変化である。It is a time-dependent change of the X-ray small angle scattering spectrum of the hydrogel of Example 1. FIG. 比較例１のハイドロゲルの、Ｘ線小角散乱スペクトルの経時変化である。It is a time-dependent change of the X-ray small angle scattering spectrum of the hydrogel of the comparative example 1.
　以下、本発明について具体的に説明する。
　まず、本発明で使用されるポリビニルアルコール系樹脂（Ａ）について説明する。
［ポリビニルアルコール系樹脂（Ａ）］
　本発明で使用されるシンジオタクティシティがトライアッド表示で３２％以上のポリビニルアルコール系樹脂（Ａ）（以下、Ｓｔ－ＰＶＡ（Ａ）と略記する場合がある）は、トライアッド表示によるシンジオタクティシティが、例えば３２～４０％であり、好ましくは３３％以上（例えば、３３～３９％）、より好ましくは３４％以上（例えば、３４～３８％）、さらに好ましくは３６％以上（例えば、３６～３８％）である。尚、トライアッド表示のシンジオタクティシティは、ポリビニルアルコール系樹脂を重ＤＭＳＯに溶解し、プロトンＮＭＲ測定による水酸基のピークより求める事ができる。 Hereinafter, the present invention will be specifically described.
First, the polyvinyl alcohol resin (A) used in the present invention will be described.
[Polyvinyl alcohol resin (A)]
The syndiotacticity used in the present invention is a syndiotacticity based on triad display in which the polyvinyl alcohol resin (A) having a triad display of 32% or more (hereinafter sometimes abbreviated as St-PVA (A)) is used. Is, for example, 32 to 40%, preferably 33% or more (for example, 33 to 39%), more preferably 34% or more (for example, 34 to 38%), and still more preferably 36% or more (for example, 36 to 36%). 38%). The triad-syntacticity can be obtained from a hydroxyl peak measured by proton NMR measurement by dissolving a polyvinyl alcohol-based resin in heavy DMSO.
　本発明で使用されるＳｔ－ＰＶＡ（Ａ）の製法は、トライアッド表示によるシンジオタクティシティが３２％以上になれば特に限定されず、従来公知の方法で得られたビニルエステル重合体を鹸化する方法により得られる。
　ビニルエステル重合体の製造方法としては、ビニルエステル系単量体を重合する方法であれば特に限定されず、従来公知の方法に従って良い。
　重合の際には、重合容器の形状、重合攪拌機の種類、さらには重合温度や、重合容器内の圧力等いずれも公知の方法を使用してかまわない。重合方法としては、従来から公知のバルク重合、溶液重合、懸濁重合、乳化重合等の各種の重合方法が可能である。重合度の制御や重合後に行うケン化反応のこと等を考慮すると、アルコールを溶媒とした溶液重合、あるいは、水又は水及びアルコールを分散媒とする懸濁重合が好ましいが、これらに限定されるものではない。 The production method of St-PVA (A) used in the present invention is not particularly limited as long as the syndiotacticity by triad display is 32% or more, and a vinyl ester polymer obtained by a conventionally known method is saponified. Obtained by the method.
The method for producing the vinyl ester polymer is not particularly limited as long as it is a method for polymerizing a vinyl ester monomer, and may be a conventionally known method.
In the polymerization, any known method may be used for the shape of the polymerization vessel, the type of the polymerization stirrer, the polymerization temperature, the pressure in the polymerization vessel, and the like. As the polymerization method, conventionally known various polymerization methods such as bulk polymerization, solution polymerization, suspension polymerization, and emulsion polymerization are possible. In consideration of the control of the degree of polymerization and the saponification reaction performed after the polymerization, solution polymerization using alcohol as a solvent or suspension polymerization using water or water and alcohol as a dispersion medium are preferable, but are not limited thereto. It is not a thing.
　ビニルエステル系単量体としては、例えば、脂肪酸ビニルエステル、非脂肪酸系ビニルエステル（例えば、蟻酸ビニル、芳香族カルボン酸ビニルエステル等）等のビニルエステル等が挙げられるが、シンジオタクティシティが高いＰＶＡが得られる等の観点から、Ｃ３―１５脂肪酸ビニルエステル［例えば、プロピオン酸ビニル、酪酸ビニル、ピバリン酸ビニル等の直鎖又は分岐Ｃ３―１５脂肪酸ビニルエステル、好ましくは、Ｃ３―１０脂肪酸ビニルエステル（例えば、直鎖又は分岐Ｃ３―１０脂肪酸ビニルエステル等）等］、置換基（例えば、ハロゲン基）を有するＣ３―１５脂肪酸ビニルエステル［例えば、トリフルオロ酢酸ビニル、トリクロロ酢酸ビニル等］、蟻酸ビニル等が挙げられる。これらのビニルエステルは、１種又は２種以上を使用することができる。 Examples of the vinyl ester monomer include vinyl esters such as fatty acid vinyl esters and non-fatty acid vinyl esters (for example, vinyl formate, aromatic carboxylic acid vinyl esters, etc.), but have high syndiotacticity. From the viewpoint of obtaining PVA and the like, C 3-15 fatty acid vinyl ester [for example, linear or branched C 3-15 fatty acid vinyl ester such as vinyl propionate, vinyl butyrate, vinyl pivalate, etc., preferably C 3-10 Fatty acid vinyl esters (eg, linear or branched C 3-10 fatty acid vinyl esters, etc.)], C 3-15 fatty acid vinyl esters having a substituent (eg, halogen group) [eg, vinyl trifluoroacetate, vinyl trichloroacetate Etc.], vinyl formate and the like. These vinyl esters can use 1 type (s) or 2 or more types.
　Ｓｔ－ＰＶＡ（Ａ）の製法としては、具体的には、嵩高い側鎖を有するプロピオン酸ビニル、酪酸ビニル、ピバリン酸ビニルなどのビニルエステルを重合した後、アルカリ触媒により鹸化する方法や、蟻酸ビニル、トリフルオロ酢酸ビニル、トリクロロ酢酸ビニルなどの高極性のビニルエステルを重合した後、アルカリ触媒により鹸化する方法が挙げられる。中でもピバリン酸ビニルが好適に用いられるが、プロピオン酸ビニル、酪酸ビニルを共重合しても構わない。 Specifically, St-PVA (A) can be produced by polymerizing vinyl esters such as vinyl propionate, vinyl butyrate and vinyl pivalate having bulky side chains and then saponifying with an alkali catalyst, formic acid, Examples include a method of polymerizing a highly polar vinyl ester such as vinyl, vinyl trifluoroacetate or vinyl trichloroacetate and then saponifying with an alkali catalyst. Of these, vinyl pivalate is preferably used, but vinyl propionate and vinyl butyrate may be copolymerized.
　Ｓｔ－ＰＶＡ（Ａ）の構成成分において、ビニルエステルの含有量は、例えば２０～１００質量％、３０～１００質量％、４０～１００質量％等であってよい。
　また、Ｓｔ－ＰＶＡ（Ａ）の構成成分において、ビニルエステルの含有量は、例えば２２０～１００モル％、好ましくは３０～１００モル％、より好ましくは４０～１００モル％等であってよい。 In the constituent component of St-PVA (A), the vinyl ester content may be, for example, 20 to 100% by mass, 30 to 100% by mass, 40 to 100% by mass, or the like.
In the constituent component of St-PVA (A), the vinyl ester content may be, for example, 220 to 100 mol%, preferably 30 to 100 mol%, more preferably 40 to 100 mol%.
　ピバリン酸ビニルを使用する場合、Ｓｔ－ＰＶＡ（Ａ）の全ビニルエステル成分において、ピバリン酸ビニルの含有量は、例えば４０～１００質量％（例えば、４５～１００質量％等）、好ましくは５０～１００質量％（例えば、５５～１００質量％等）、より好ましくは６０～１００質量％（例えば、６５～１００質量％等）である。 When vinyl pivalate is used, the content of vinyl pivalate in the total vinyl ester component of St-PVA (A) is, for example, 40 to 100% by mass (for example, 45 to 100% by mass), preferably 50 to It is 100% by mass (for example, 55 to 100% by mass), more preferably 60 to 100% by mass (for example, 65 to 100% by mass).
　また、ピバリン酸ビニルを使用する場合、Ｓｔ－ＰＶＡ（Ａ）の全ビニルエステル成分において、ピバリン酸ビニルの含有量は、例えば６０～１００モル％（例えば、６５～９５モル％等）、好ましくは７０～１００モル％（例えば、７５～９５モル％等）、より好ましくは８０～１００モル％（例えば、８５～９５モル％等）である。 When vinyl pivalate is used, the vinyl pivalate content in the total vinyl ester component of St-PVA (A) is, for example, 60 to 100 mol% (for example, 65 to 95 mol%), preferably It is 70 to 100 mol% (for example, 75 to 95 mol%), more preferably 80 to 100 mol% (for example, 85 to 95 mol%).
　また、ビニルエステル重合体には、上記したビニルエステルの他に、本発明の効果を阻害しない範囲で、ビニルエステルと共重合可能な他の不飽和単量体を共重合してもよい。
　他の不飽和単量体としては、例えば、カルボキシル基含有不飽和単量体｛例えば、不飽和モノカルボン酸［例えば、（メタ）アクリル酸等］、不飽和ジカルボン酸（例えば、マレイン酸、フマル酸、イタコン酸、クロトン酸、ウンデシレン酸等）又はその無水物（例えば、無水マレイン酸等）等｝、不飽和ジカルボン酸モノアルキルエステル類（例えば、マレイン酸モノメチル、イタコン酸モノメチル等）、アミド基含有不飽和単量体［例えば、アクリルアミド類（例えば、アクリルアミド、ジメチルアクリルアミド、ジメチルアミノエチルアクリルアミド、ジエチルアクリルアミド、ジメチルアミノプロピルアクリルアミド、イソプロピルアクリルアミド、Ｎ－メチロールアクリルアミド等）、アセトアミド類（例えば、Ｎ－ビニルアセトアミド等）］、ハロゲン化ビニル類（例えば、塩化ビニル、フッ化ビニル等）、グリシジル基を有する不飽和単量体（例えば、アリルグリシジルエーテル、グリシジルメタクリレート等）、２－ピロリドン環含有不飽和単量体（例えば、Ｎ－ビニル－２－ピロリドン、Ｎ－ビニル－３－プロピル－２－ピロリドン、Ｎ－ビニル－５－メチル－２－ピロリドン、Ｎ－ビニル－５，５－ジメチル－２－ピロリドン、Ｎ－ビニル－３，５－ジメチル－２－ピロリドン、Ｎ－アリル－２－ピロリドン等）、アルキルビニルエーテル類（例えば、メチルビニルエーテル、ｎ－プロピルビニルエーテル、ｉ－プロピルビニルエーテル、ｎ－ブチルビニルエーテル、ｉ－ブチルビニルエーテル、ｔ－ブチルビニルエーテル、ラウリルビニルエーテル、ドデシルビニルエーテル、ステアリルビニルエーテル等）、ニトリル類（例えば、アクリロニトリル、メタアクリロニトリル等）、水酸基含有不飽和単量体［例えば、不飽和アルコール類（例えば、アリルアルコール、ジメチルアリルアルコール、イソプロペニルアリルアルコール等）、ヒドロキシアルキルビニルエーテル類（例えば、ヒドロキシエチルビニルエーテル、ヒドロキシブチルビニルエーテル等）等］、アセチル基含有不飽和単量体［例えば、アリルアセテート類（例えば、アリルアセテート、ジメチルアリルアセテート、イソプロペニルアリルアセテート等）等］、（メタ）アクリル酸エステル類［例えば、（メタ）アクリル酸メチル、（メタ）アクリル酸エチル、アクリル酸－２－エチルヘキシル、アクリル酸－ｎ－ブチル等］、ビニルシラン類（例えば、トリメトキシビニルシラン、トリブチルビニルシラン、ジフェニルメチルビニルシラン等）、ポリオキシアルキレン（メタ）アクリレート類［例えば、ポリオキシエチレン（メタ）アクリレート、ポリオキシプロピレン（メタ）アクリレート等］、ポリオキシアルキレン（メタ）アクリル酸アミド類［例えば、ポリオキシエチレン（メタ）アクリル酸アミド、ポリオキシプロピレン（メタ）アクリル酸アミド等］、ポリオキシアルキレンビニルエーテル類（例えば、ポリオキシエチレンビニルエーテル、ポリオキシプロピレンビニルエーテル等）、ポリオキシアルキレンアルキルビニルエーテル類（例えば、ポリオキシエチレンアリルエーテル、ポリオキシプロピレンアリルエーテル、ポリオキシエチレンビチルビニルエーテル、ポリオキシプロピレンブチルビニルエーテル等）、α－オレフィン類［例えば、エチレン、プロピレン、１－ブテン類（例えば、３，４－ジヒドロキシ－１－ブテン、３，４－ジアシロキシ－１－ブテン、３－アシロキシ－４－ヒドロキシ－１－ブテン、４－アシロキシ－３－ヒドロキシ－１－ブテン、３，４－ジアシロキシ－２－メチル－１－ブテン等）、１－ペンテン類（例えば、４，５－ジヒドロキシ－１－ペンテン、４，５－ジアシロキシ－１－ペンテン、４，５－ジヒドロキシ－３－メチル－１－ペンテン、４，５－ジアシロキシ－３－メチル－１－ペンテン等）、１－ヘキセン類（例えば、５，６－ジヒドロキシ－１－ヘキセン、５，６－ジアシロキシ－１－ヘキセン等）等］、アミン系不飽和単量体［例えば、Ｎ，Ｎ－ジメチルアリルアミン、Ｎ－アリルピペラジン、３－ピペリジンアクリル酸エチルエステル、２－ビニルピリジン、４－ビニルピリジン、２－メチル－６－ビニルピリジン、５－エチル－２－ビニルピリジン、５－ブテニルピリジン、４－ペンテニルピリジン、２－（４－ピリジル）アリルアルコール等］、第四アンモニウム化合物を有する不飽和単量体（例えば、ジメチルアミノエチルアクリレート塩化メチル４級塩、Ｎ，Ｎ－ジメチルアミノプロピルアクリルアミド塩化メチル４級塩、Ｎ，Ｎ－ジメチルアミノプロピルアクリルアミドメチルベンゼンスルホン酸４級塩等）、芳香族系不飽和単量体（例えば、スチレン等）、スルホン酸基を含有する不飽和単量体（例えば、２－アクリルアミド－２－メチルプロパンスルホン酸、２－アクリルアミド－１－メチルプロパンスルホン酸、２－メタクリルアミド－２－メチルプロパンスルホン酸、ビニルスルホン酸、アリルスルホン酸、メタアリルスルホン酸等）又はその塩（例えば、アルカリ金属塩、アンモニウム塩又は有機アミン塩等）、グリセリンモノアリルエーテル、グリセリンモノビニルエーテル、グリセリンモノイソプロペニルエーテル、２，３－ジアセトキシ－１－アリルオキシプロパン、２－アセトキシ－１－アリルオキシ－３－ヒドロキシプロパン、３－アセトキシ－１－アリルオキシ－３－ヒドロキシプロパン、３－アセトキシ－１－アリルオキシ－２－ヒドロキシプロパン、アクリロイルモルホリン、ビニルエチレンカーボネート等から選ばれる１種以上と共重合したものであってもよい。 In addition to the above vinyl ester, the vinyl ester polymer may be copolymerized with another unsaturated monomer copolymerizable with the vinyl ester as long as the effects of the present invention are not impaired.
Examples of other unsaturated monomers include carboxyl group-containing unsaturated monomers {eg, unsaturated monocarboxylic acids [eg, (meth) acrylic acid, etc.], unsaturated dicarboxylic acids (eg, maleic acid, fumaric acid, etc.). Acid, itaconic acid, crotonic acid, undecylenic acid etc.) or anhydrides thereof (eg maleic anhydride etc.)}, unsaturated dicarboxylic acid monoalkyl esters (eg monomethyl maleate, monomethyl itaconic acid etc.), amide groups Containing unsaturated monomers [eg, acrylamides (eg, acrylamide, dimethylacrylamide, dimethylaminoethylacrylamide, diethylacrylamide, dimethylaminopropylacrylamide, isopropylacrylamide, N-methylolacrylamide, etc.), acetamides (eg, N-vinylacetate, etc.) Amide)], vinyl halides (eg, vinyl chloride, vinyl fluoride, etc.), unsaturated monomers having a glycidyl group (eg, allyl glycidyl ether, glycidyl methacrylate, etc.), 2-pyrrolidone ring-containing unsaturated monomers Mer (eg N-vinyl-2-pyrrolidone, N-vinyl-3-propyl-2-pyrrolidone, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone) N-vinyl-3,5-dimethyl-2-pyrrolidone, N-allyl-2-pyrrolidone, etc.), alkyl vinyl ethers (for example, methyl vinyl ether, n-propyl vinyl ether, i-propyl vinyl ether, n-butyl vinyl ether, i -Butyl vinyl ether, t-butyl vinyl ether, lauryl vinyl ether, dodecy Vinyl ether, stearyl vinyl ether, etc.), nitriles (eg, acrylonitrile, methacrylonitrile, etc.), hydroxyl group-containing unsaturated monomers [eg, unsaturated alcohols (eg, allyl alcohol, dimethylallyl alcohol, isopropenyl allyl alcohol, etc.), Hydroxyalkyl vinyl ethers (eg, hydroxyethyl vinyl ether, hydroxybutyl vinyl ether, etc.)], acetyl group-containing unsaturated monomers [eg, allyl acetates (eg, allyl acetate, dimethylallyl acetate, isopropenyl allyl acetate, etc.), etc. ], (Meth) acrylic acid esters [for example, methyl (meth) acrylate, ethyl (meth) acrylate, 2-ethylhexyl acrylate, n-butyl acrylate, etc.], vinyl Nylsilanes (eg, trimethoxyvinylsilane, tributylvinylsilane, diphenylmethylvinylsilane, etc.), polyoxyalkylene (meth) acrylates [eg, polyoxyethylene (meth) acrylate, polyoxypropylene (meth) acrylate, etc.), polyoxyalkylene (Meth) acrylic acid amides [eg, polyoxyethylene (meth) acrylic acid amide, polyoxypropylene (meth) acrylic acid amide, etc.], polyoxyalkylene vinyl ethers (eg, polyoxyethylene vinyl ether, polyoxypropylene vinyl ether, etc. ), Polyoxyalkylene alkyl vinyl ethers (for example, polyoxyethylene allyl ether, polyoxypropylene allyl ether, polyoxyethylene bityl vinyl) Ether, polyoxypropylene butyl vinyl ether, etc.), α-olefins [eg, ethylene, propylene, 1-butenes (eg, 3,4-dihydroxy-1-butene, 3,4-diacyloxy-1-butene, 3- Acyloxy-4-hydroxy-1-butene, 4-acyloxy-3-hydroxy-1-butene, 3,4-diacyloxy-2-methyl-1-butene), 1-pentenes (for example, 4,5-dihydroxy -1-pentene, 4,5-diasiloxy-1-pentene, 4,5-dihydroxy-3-methyl-1-pentene, 4,5-diasiloxy-3-methyl-1-pentene, etc.), 1-hexene ( For example, 5,6-dihydroxy-1-hexene, 5,6-diasiloxy-1-hexene, etc.)], an amine unsaturated monomer [for example, N, N-dimethylallylamine, N-allylpiperazine, 3-piperidineacrylic acid ethyl ester, 2-vinylpyridine, 4-vinylpyridine, 2-methyl-6-vinylpyridine, 5-ethyl-2-vinylpyridine, 5-butenylpyridine, 4-pentenylpyridine, 2- (4-pyridyl) allyl alcohol, etc.], unsaturated monomers having a quaternary ammonium compound (for example, dimethylaminoethyl acrylate methyl chloride quaternary salt, N, N-dimethylaminopropylacrylamide chloride) Methyl quaternary salts, N, N-dimethylaminopropylacrylamide methylbenzene sulfonic acid quaternary salts, etc.), aromatic unsaturated monomers (eg styrene etc.), unsaturated monomers containing sulfonic acid groups ( For example, 2-acrylamido-2-methylpropanesulfonic acid, 2- Kurylamido-1-methylpropanesulfonic acid, 2-methacrylamideamido-2-methylpropanesulfonic acid, vinylsulfonic acid, allylsulfonic acid, methallylsulfonic acid, etc.) or salts thereof (for example, alkali metal salts, ammonium salts or organic amines) Salt), glycerol monoallyl ether, glycerol monovinyl ether, glycerol monoisopropenyl ether, 2,3-diacetoxy-1-allyloxypropane, 2-acetoxy-1-allyloxy-3-hydroxypropane, 3-acetoxy-1- It may be copolymerized with at least one selected from allyloxy-3-hydroxypropane, 3-acetoxy-1-allyloxy-2-hydroxypropane, acryloylmorpholine, vinylethylene carbonate and the like.
　前記他の単量体を使用する場合は、他の単量体は、ビニルエステルに対して、例えば２０質量％以下（例えば０．１～２０質量％、好ましくは１～１０質量％等）を使用することができる。
　前記他の単量体を使用する場合は、他の単量体は、ビニルエステルに対して、例えば２０モル％以下（例えば０．１～２０モル％、１～１０モル％等）を使用することができる。 When the other monomer is used, the other monomer is, for example, 20% by mass or less (for example, 0.1 to 20% by mass, preferably 1 to 10% by mass) with respect to the vinyl ester. Can be used.
When the other monomer is used, the other monomer is, for example, 20 mol% or less (for example, 0.1 to 20 mol%, 1 to 10 mol%, etc.) with respect to the vinyl ester. be able to.
　ビニルエステルの重合に使用されるアルコール溶媒としては、特に限定されないが、例えば、メタノール、エタノール、ｎ－プロパノール、２－プロパノール等のアルコール類が挙げられ、中でもメタノールが工業的に好ましい。 The alcohol solvent used for the polymerization of the vinyl ester is not particularly limited, and examples thereof include alcohols such as methanol, ethanol, n-propanol, 2-propanol, etc. Among them, methanol is industrially preferable.
　また、重合において重合開始剤を使用してもよい。
　重合開始剤としては、特に限定されず、例えば、パーカーボネート化合物（例えば、ジイソプロピルパーオキシジカーボネート、ジ－２－エチルヘキシルパーオキシジカーボネート、ジエトキシエチルパーオキシジカーボネート等）、パーオキシエステル化合物（例えば、ｔ－ブチルパーオキシネオデカノエート、ｔ－ヘキシルパーオキシネオデカノエート、ｔ－ヘキシルパーオキシピバレート、α－クミルパーオキシネオデカノエート、ｔ－ヘキシルネオヘキサノエート、２，４，４－トリメチルペンチル－２－パーオキシ－２－ネオデカノエート等）、アゾ化合物［例えば、アゾビス（２，４－ジメチルバレロニトリル）、アゾビスイソブチロニトリル等］、パーオキシド化合物（例えば、ラウリルパーオキシド、ベンゾイルパーオキシド、クメンハイドロパーオキシド、２，４，４－トリメチルペンチル－２－パーオキシフェノキシアセテート等）等が挙げられる。 Moreover, you may use a polymerization initiator in superposition | polymerization.
The polymerization initiator is not particularly limited, and examples thereof include percarbonate compounds (for example, diisopropyl peroxydicarbonate, di-2-ethylhexyl peroxydicarbonate, diethoxyethyl peroxydicarbonate, etc.), peroxyester compounds ( For example, t-butylperoxyneodecanoate, t-hexylperoxyneodecanoate, t-hexylperoxypivalate, α-cumylperoxyneodecanoate, t-hexylneohexanoate, 2, 4,4-trimethylpentyl-2-peroxy-2-neodecanoate, etc.), azo compounds [eg, azobis (2,4-dimethylvaleronitrile), azobisisobutyronitrile, etc.], peroxide compounds (eg, lauryl peroxide) Benzoyl peroxy , Cumene hydroperoxide, 2,4,4-trimethylpentyl-2-peroxy phenoxy acetate, and the like) and the like.
　また、重合おいて、得られるビニルエステル系重合体の重合度を調節すること等を目的として、連鎖移動剤を使用してもよい。
　連鎖移動剤としては、特に限定されないが、例えば、アセトアルデヒド、プロピオンアルデヒド、ブチルアルデヒド、ベンズアルデヒド等のアルデヒド類；アセトン、メチルエチルケトン、ヘキサノン、シクロヘキサノン等のケトン類；２－ヒドロキシエタンチオール、ドデシルメルカプタン等のメルカプタン類；四塩化炭素、トリクロロエチレン、パークロロエチレン等の有機ハロゲン類が挙げられ、中でもアルデヒド類及びケトン類が好適に用いられる。これらの連鎖移動剤は１種又は２種以上使用することができる。
　連鎖移動剤の添加量は、添加する連鎖移動剤の連鎖移動定数及び目的とするビニルエステル系重合体の重合度に応じて決定されるが、一般にビニルエステル系単量体に対して０．１～１０質量％が望ましい。 In the polymerization, a chain transfer agent may be used for the purpose of adjusting the degree of polymerization of the resulting vinyl ester polymer.
Examples of the chain transfer agent include, but are not limited to, aldehydes such as acetaldehyde, propionaldehyde, butyraldehyde, and benzaldehyde; ketones such as acetone, methyl ethyl ketone, hexanone, and cyclohexanone; mercaptans such as 2-hydroxyethanethiol and dodecyl mercaptan. And organic halogens such as carbon tetrachloride, trichlorethylene and perchloroethylene, among which aldehydes and ketones are preferably used. These chain transfer agents can be used alone or in combination of two or more.
The addition amount of the chain transfer agent is determined according to the chain transfer constant of the chain transfer agent to be added and the degree of polymerization of the target vinyl ester polymer, but is generally 0.1% relative to the vinyl ester monomer. ~ 10% by mass is desirable.
　上述のようにして得られたビニルエステル系重合体をケン化反応することにより、Ｓｔ－ＰＶＡ（Ａ）を製造することができる。
　ビニルエステル系重合体のケン化反応方法は、特に限定されず、従来公知の方法に従ってよいが、例えば、従来公知の水酸化ナトリウム、水酸化カリウム、ナトリウムメトキシド等の塩基性触媒、又は塩酸、硫酸、ｐ－トルエンスルホン酸等の酸性触媒を用いた、加アルコール分解ないし加水分解反応が適用できる。
　ケン化反応に用いられる溶媒としては、メタノール、エタノール等のアルコール類；酢酸メチル、酢酸エチル等のエステル類；アセトン、メチルエチルケトン等のケトン類；ベンゼン、トルエン等の芳香族炭化水素等が挙げられ、これらは単独で又は２種以上を組合せて用いることができる。 St-PVA (A) can be produced by saponifying the vinyl ester polymer obtained as described above.
The saponification reaction method of the vinyl ester polymer is not particularly limited and may be a conventionally known method. For example, a conventionally known basic catalyst such as sodium hydroxide, potassium hydroxide, sodium methoxide, hydrochloric acid, An alcoholysis or hydrolysis reaction using an acidic catalyst such as sulfuric acid or p-toluenesulfonic acid can be applied.
Examples of the solvent used in the saponification reaction include alcohols such as methanol and ethanol; esters such as methyl acetate and ethyl acetate; ketones such as acetone and methyl ethyl ketone; aromatic hydrocarbons such as benzene and toluene; These can be used alone or in combination of two or more.
　また、鹸化物の乾燥、粉砕方法も特に制限はなく、公知の方法を使用してもかまわない。重合の終了には、特に限定されないが、重合停止剤を使用することができる。重合停止剤は、特に限定されず、例えば、ｍ－ジニトロベンゼン等が挙げられる。 Also, there are no particular restrictions on the method for drying and pulverizing the saponified product, and a known method may be used. Although the polymerization is not particularly limited, a polymerization terminator can be used. The polymerization terminator is not particularly limited, and examples thereof include m-dinitrobenzene.
　Ｓｔ－ＰＶＡ（Ａ）の鹸化度は、好ましくは９０モル％以上（例えば、９０～９９．９９モル％）であり、より好ましくは９８モル％以上（例えば、９８．～９９．９５モル％）、さらに好ましくは９９モル％以上（例えば、９９～９９．９３モル％）である。尚、Ｓｔ－ＰＶＡ（Ａ）の鹸化度は、重ＤＭＳＯ溶液中で１Ｈ－ＮＭＲを測定し求めることができる。 The saponification degree of St-PVA (A) is preferably 90 mol% or more (for example, 90 to 99.99 mol%), more preferably 98 mol% or more (for example, 98. to 99.95 mol%). More preferably, it is 99 mol% or more (for example, 99 to 99.93 mol%). The saponification degree of St-PVA (A) can be determined by measuring 1 H-NMR in a heavy DMSO solution.
　Ｓｔ－ＰＶＡ（Ａ）の重合度は、好ましくは１００～１００００であり、より好ましくは５００～８０００であり、さらに好ましくは１０００～５０００であり、ハンドリングが比較的容易で、得られるハイドロゲルをべたつきが少ないものとでき、強度や耐水性に優れたものとできる等の観点から、特に好ましくは１０００～３０００である。また、Ｓｔ－ＰＶＡ（Ａ）の重合度は、例えば１０００～２０００、好ましくは２０００～３０００、より好ましくは３０００～４０００、さらに好ましくは４０００～５０００等であってもよい。重合度が１００以上であれば、樹脂強度が強く、保形性のある水性ゲルが作製しやすい。重合度が１００００以下であれば、水溶液粘度が取り扱い易い。なお、重合度はＪＩＳＫ６７２５記載のベンゼン溶液、３０℃におけるポリ酢酸ビニル換算の重合度である。 The degree of polymerization of St-PVA (A) is preferably 100 to 10000, more preferably 500 to 8000, still more preferably 1000 to 5000, and is relatively easy to handle. The resulting hydrogel is sticky. From the standpoints that it can be made less and can be made excellent in strength and water resistance, it is particularly preferably 1000 to 3000. The degree of polymerization of St-PVA (A) may be, for example, 1000 to 2000, preferably 2000 to 3000, more preferably 3000 to 4000, and still more preferably 4000 to 5000. If the degree of polymerization is 100 or more, it is easy to produce an aqueous gel having high resin strength and shape retention. If the degree of polymerization is 10,000 or less, the aqueous solution viscosity is easy to handle. The degree of polymerization is a degree of polymerization in terms of polyvinyl acetate at 30 ° C. in a benzene solution described in JIS K6725.
　Ｓｔ－ＰＶＡ（Ａ）は、脂肪酸ビニルエステル由来の単位（又は、脂肪酸ビニルエステル単位ともいう。以下、同様の表現において同じ）を含むことが好ましい。すなわち、ＰＶＡ樹脂は、ケン化されずに共重合された脂肪酸ビニルエステル単位が残存することが好ましい。
　Ｓｔ－ＰＶＡ（Ａ）における脂肪酸ビニルエステル単位の含有量は、例えば２５質量％以下（例えば、０．０１～２５質量％）、好ましくは１０質量％以下（例えば、０．０１～１０質量％）、より好ましくは０．０１～２質量％、さらに好ましくは０．０１～１質量％である。
　また、Ｓｔ－ＰＶＡ（Ａ）中の脂肪酸ビニルエステル単位の含有量は、Ｓｔ－ＰＶＡ（Ａ）を構成するモノマー由来単位全体に対して、例えば１０モル％以下（例えば、０．０１～１０モル％）、好ましくは０．０１～２モル％、より好ましくは０．０１～１モル％である。 St-PVA (A) preferably contains a unit derived from a fatty acid vinyl ester (or also referred to as a fatty acid vinyl ester unit; hereinafter the same in the same expression). That is, it is preferable that the PVA resin remains a fatty acid vinyl ester unit copolymerized without being saponified.
The content of the fatty acid vinyl ester unit in St-PVA (A) is, for example, 25% by mass or less (for example, 0.01 to 25% by mass), preferably 10% by mass or less (for example, 0.01 to 10% by mass). More preferably, it is 0.01 to 2% by mass, and still more preferably 0.01 to 1% by mass.
In addition, the content of the fatty acid vinyl ester unit in St-PVA (A) is, for example, 10 mol% or less (for example, 0.01 to 10 mol) with respect to the entire monomer-derived unit constituting St-PVA (A). %), Preferably 0.01 to 2 mol%, more preferably 0.01 to 1 mol%.
　Ｓｔ－ＰＶＡ（Ａ）は、脂肪酸ビニルエステル単位の中でも、ピバリン酸ビニル単位を含むことが好ましい。
　Ｓｔ－ＰＶＡ（Ａ）におけるピバリン酸ビニル単位の含有量は、例えば２５質量％以下（例えば、０．０１～２５質量％）、好ましくは１０質量％以下（例えば、０．０１～１０質量％）、より好ましくは０．０１～２質量％、さらに好ましくは０．０１～１質量％である。
　また、Ｓｔ－ＰＶＡ（Ａ）におけるピバリン酸ビニル単位の含有量は、Ｓｔ－ＰＶＡ（Ａ）を構成するモノマー由来単位全体に対して、例えば１０モル％以下（例えば、０．０１～１０モル％）、好ましくは０．０１～２モル％、より好ましくは０．０１～１モル％である。 St-PVA (A) preferably contains vinyl pivalate units among fatty acid vinyl ester units.
The content of vinyl pivalate units in St-PVA (A) is, for example, 25% by mass or less (for example, 0.01 to 25% by mass), preferably 10% by mass or less (for example, 0.01 to 10% by mass). More preferably, it is 0.01 to 2% by mass, and still more preferably 0.01 to 1% by mass.
The content of vinyl pivalate units in St-PVA (A) is, for example, 10 mol% or less (for example, 0.01 to 10 mol%) with respect to the entire monomer-derived units constituting St-PVA (A). ), Preferably 0.01 to 2 mol%, more preferably 0.01 to 1 mol%.
　Ｓｔ－ＰＶＡ（Ａ）は、本発明の効果を阻害しない範囲で、アセタール化、ウレタン化、エーテル化、グラフト化、リン酸エステル化、アセトアセチル化、カチオン化等の反応によって後変性したものでもよい。 St-PVA (A) may be post-modified by reactions such as acetalization, urethanization, etherification, grafting, phosphoric esterification, acetoacetylation, cationization, etc., as long as the effects of the present invention are not impaired. Good.
［ハイドロゲルの製造方法］
　次に、ハイドロゲルの製造方法について説明する。
　本発明のハイドロゲルは、Ｓｔ－ＰＶＡ（Ａ）および水（Ｂ）を、加熱圧縮により溶液化させ、その後放冷することにより得られる。尚、加熱圧縮は、通常、Ｓｔ－ＰＶＡ（Ａ）を水（Ｂ）に膨潤させてから行う。 [Production method of hydrogel]
Next, the manufacturing method of hydrogel is demonstrated.
The hydrogel of the present invention can be obtained by making St-PVA (A) and water (B) into a solution by heat compression and then allowing to cool. The heat compression is usually carried out after St-PVA (A) is swollen in water (B).
　加熱圧縮の条件は、Ｓｔ－ＰＶＡ（Ａ）が水に溶解する条件であれば特に限定されない。
　加熱圧縮の温度は、好ましくは９０～１６０℃である。
　加熱圧縮の圧力は、好ましくは１～５０ＭＰａ、より好ましくは１．５～４０ＭＰａ、さらに好ましくは２～３０ＭＰａである。
　加熱圧縮の時間は、加熱圧縮の温度や圧力によって適宜変更できるが、例えば、１分～２時間、１分～１時間等である。 The heat compression conditions are not particularly limited as long as St-PVA (A) is dissolved in water.
The temperature for heat compression is preferably 90 to 160 ° C.
The pressure for heat compression is preferably 1 to 50 MPa, more preferably 1.5 to 40 MPa, and still more preferably 2 to 30 MPa.
The heat compression time can be appropriately changed depending on the temperature and pressure of heat compression, and is, for example, 1 minute to 2 hours, 1 minute to 1 hour, or the like.
　また、加熱圧縮に供するＳｔ－ＰＶＡ（Ａ）および水（Ｂ）の割合（質量比）は、特に限定されないが、例えば９０／１０～２０／８０であり、好ましくは８０／２０～２５／７５であり、より好ましくは７０／３０～３０／７０である。また、Ｓｔ－ＰＶＡ（Ａ）および水（Ｂ）の割合は、例えば９０／１０～４０／６０、好ましくは８０／２０～４５／５５等であってもよい。 The ratio (mass ratio) of St-PVA (A) and water (B) to be subjected to heat compression is not particularly limited, but is, for example, 90/10 to 20/80, preferably 80/20 to 25/75. More preferably, it is 70/30 to 30/70. The ratio of St-PVA (A) and water (B) may be, for example, 90/10 to 40/60, preferably 80/20 to 45/55.
　放冷温度は、例えば－３０～４０℃であり、２５～３５℃等の室温であってもよい。
　また、放冷時間は、放冷温度によって適宜調整することができ、特に限定されないが、例えば３０分～２４時間、好ましくは３０分～１２時間等であってよい。 The cooling temperature is, for example, −30 to 40 ° C., and may be room temperature such as 25 to 35 ° C.
The cooling time can be appropriately adjusted according to the cooling temperature, and is not particularly limited, but may be, for example, 30 minutes to 24 hours, preferably 30 minutes to 12 hours.
　加熱圧縮に使用する装置としては、例えば、ホットプレス機を用いることができる。ホットプレス機を用いて加熱圧縮にすることで、Ｓｔ－ＰＶＡ（Ａ）および水（Ｂ）を容易に溶液化させることができる。 As an apparatus used for heat compression, for example, a hot press machine can be used. St-PVA (A) and water (B) can be easily made into a solution by heating and compressing using a hot press machine.
［ハイドロゲル］
　本発明のハイドロゲルを構成するＳｔ－ＰＶＡ（Ａ）は、ビニルエステル単位を、例えば０．０１～２５質量％（又は、モノマー単位換算で０．０１～１０モル％）含有していてもよい。ハイドロゲルを構成するＳｔ－ＰＶＡ（Ａ）中には、ビニルエステル単位の中でも、脂肪酸ビニルエステル単位が含有されていることが好ましく、脂肪酸ビニルエステル単位の中でも、水性ゲルの耐水性が優れる等の観点から、特に、ピバリン酸ビニル単位が含有されていることが好ましいが、非脂肪酸系ビニルエステルが含有されていてもよい。 [Hydrogel]
St-PVA (A) constituting the hydrogel of the present invention may contain, for example, 0.01 to 25% by mass of a vinyl ester unit (or 0.01 to 10 mol% in terms of monomer unit). . St-PVA (A) constituting the hydrogel preferably contains a fatty acid vinyl ester unit among vinyl ester units, and among the fatty acid vinyl ester units, the water gel has excellent water resistance. From the viewpoint, it is particularly preferable that vinyl pivalate units are contained, but non-fatty acid vinyl esters may be contained.
　また、ハイドロゲルに含まれるＳｔ－ＰＶＡ（Ａ）および水の含有量は、通常、加熱圧縮に供するＳｔ－ＰＶＡ（Ａ）および水（Ｂ）の割合をそのまま反映している。すなわち、ハイドロゲルに含まれるＳｔ－ＰＶＡ（Ａ）および水の割合は、質量比で、例えば９０／１０～２０／８０であり、好ましくは８０／２０～２５／７５であり、より好ましくは７０／３０～３０／７０である。 In addition, the content of St-PVA (A) and water contained in the hydrogel usually reflects the ratio of St-PVA (A) and water (B) used for heat compression as they are. That is, the ratio of St-PVA (A) and water contained in the hydrogel is, for example, 90/10 to 20/80, preferably 80/20 to 25/75, more preferably 70, by mass ratio. / 30 to 30/70.
　本発明の水性ゲルには、必要に応じて、Ｓｔ－ＰＶＡ（Ａ）および以外の他の成分が含有されていてもよいが、Ｓｔ－ＰＶＡ（Ａ）は、実質ＰＶＡのみからなることが好ましい。
　他の成分としては、例えば、Ｓｔ－ＰＶＡ（Ａ）以外のＰＶＡ［例えば、シンジオタクティシティが３１％以下のＰＶＡ等］、デンプン類（例えば、デンプン、変性デンプン等）、セルロース誘導体（例えば、メチルセルロース、カルボキシメチルセルロース等）、ポリアクリル酸及びその誘導体、他の高分子化合物（例えば、ゼラチン、寒天、カラギーナン、アルギン酸ナトリウム等）、無機充填剤（例えば、増粘剤、クレー、カオリン、タルク、シリカ、炭酸カルシウム等）、可塑剤（例えば、グリセリン、エチレングリコール、プロピレングリコール、ソルビトール等）、消泡剤、キレート剤、ｐＨ調整剤、界面活性剤、有機溶剤等を本発明の効果を損なわない範囲で配合することができる。
　上記他の成分を含有する場合、他の成分の含有量は、ＰＶＡ樹脂および水性溶媒に対して、例えば、０．１～２０質量％等であってよい。 The aqueous gel of the present invention may contain St-PVA (A) and other components as necessary, but St-PVA (A) preferably consists essentially of PVA. .
Examples of other components include PVA other than St-PVA (A) [eg, PVA having a syndiotacticity of 31% or less], starches (eg, starch, modified starch, etc.), cellulose derivatives (eg, Methyl cellulose, carboxymethyl cellulose, etc.), polyacrylic acid and its derivatives, other polymer compounds (eg, gelatin, agar, carrageenan, sodium alginate, etc.), inorganic fillers (eg, thickener, clay, kaolin, talc, silica) , Calcium carbonate, etc.), plasticizers (eg, glycerin, ethylene glycol, propylene glycol, sorbitol, etc.), antifoaming agents, chelating agents, pH adjusters, surfactants, organic solvents, etc. Can be blended.
When the other component is contained, the content of the other component may be, for example, 0.1 to 20% by mass with respect to the PVA resin and the aqueous solvent.
　本発明の水性ゲルは、ＰＶＡ樹脂を構成成分とした含水ゲルであるにもかかわらず、強度に優れたものである。
　本発明の水性ゲルのヤング率は、例えば２～１００ＭＰａ、好ましくは２～８０ＭＰａ、より好ましくは２～３０ＭＰａである。尚、ヤング率は、例えば後述の実施例に記載の方法を用いて求めることができる。 The aqueous gel of the present invention is excellent in strength even though it is a hydrogel containing PVA resin as a constituent component.
The Young's modulus of the aqueous gel of the present invention is, for example, 2 to 100 MPa, preferably 2 to 80 MPa, more preferably 2 to 30 MPa. The Young's modulus can be determined using, for example, the method described in the examples described later.
　本発明の水性ゲルは、ＰＶＡ樹脂を構成成分とするにもかかわらず、耐水性に優れたものである。さらに、本発明の水性ゲルは、水の含有量を多くしても、耐水性に優れる。
　本発明の水性ゲルの水の溶出率は、例えば０．０１～５％、好ましくは０．０１～０．５％である。尚、水の溶出率は、例えば後述の実施例に記載の方法を用いて求めることができる。 The aqueous gel of the present invention is excellent in water resistance despite the PVA resin as a constituent component. Furthermore, the aqueous gel of the present invention is excellent in water resistance even when the water content is increased.
The water elution rate of the aqueous gel of the present invention is, for example, 0.01 to 5%, preferably 0.01 to 0.5%. In addition, the elution rate of water can be calculated | required, for example using the method as described in the below-mentioned Example.
　また、本発明のハイドロゲルは、生体に対して毒性のある有機溶剤を使用せずに製造することができ、さらには機械的強度に優れるため、人工関節軟骨材料などの生体適合性材料として使用することができる。
　本発明のハイドロゲルを人工関節軟骨材料に形成する方法は、特に限定されない。
　例えば、ハイドロゲルを作製した後に、人工関節軟骨型の容器に入れて放置してから取り出すことにより、人工関節軟骨材料に形成することができる。放置の温度や時間は、特に限定されず、室温で行うことができる。また、本発明のハイドロゲルを作製する際に、人工関節軟骨型の容器内で溶解及び／又は放冷させることにより、人工関節軟骨材料用のハイドロゲルを形成してもよい。 In addition, the hydrogel of the present invention can be produced without using an organic solvent that is toxic to the living body, and further has excellent mechanical strength, so that it can be used as a biocompatible material such as an artificial joint cartilage material. can do.
The method for forming the hydrogel of the present invention on an artificial joint cartilage material is not particularly limited.
For example, after producing a hydrogel, it can be formed into an artificial joint cartilage material by leaving it in an artificial joint cartilage type container and leaving it out. The temperature and time for leaving are not particularly limited, and can be performed at room temperature. Moreover, when producing the hydrogel of this invention, you may form the hydrogel for artificial joint cartilage materials by making it melt | dissolve and / or cool in an artificial joint cartilage type container.
　次に、実施例を挙げて本発明をさらに具体的に説明するが、本発明はこれらの実施例により何ら限定されるものではなく、多くの変形が本発明の技術的思想内で当分野において通常の知識を有する者により可能である。なお、例中の「部」および「％」は、特に指定しない限り「質量部」および「質量％」を示す。
　また、実施例及び比較例中の物性評価は以下の方法で行なった。 EXAMPLES Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples at all, and many variations are within the technical idea of the present invention. This is possible by those with ordinary knowledge. In the examples, “parts” and “%” indicate “parts by mass” and “% by mass” unless otherwise specified.
Moreover, the physical property evaluation in an Example and a comparative example was performed with the following method.
（１）トライアッド表示のシンジオタクティシティ
　ｄ６－ＤＭＳＯ溶液中で１Ｈ－ＮＭＲを測定しトライアッド表示のシンジオタクティシティ（％）を求めた。 (1) Syndiotacticity indicated by triads 1 H-NMR was measured in a d 6 -DMSO solution to obtain syndiotacticity (%) indicated by triads.
（２）鹸化度
　ｄ６－ＤＭＳＯ溶液中で１Ｈ－ＮＭＲを測定し鹸化度（モル％）を求めた。 (2) Saponification degree 1 H-NMR was measured in a d 6 -DMSO solution to determine the saponification degree (mol%).
（３）重合度
　ＪＩＳＫ６７２５記載のベンゼン溶液、３０℃におけるポリ酢酸ビニル換算の重合度を測定した。 (3) Degree of polymerization The degree of polymerization in terms of polyvinyl acetate at 30 ° C. was measured using a benzene solution described in JIS K6725.
（４）溶出率
　加熱圧縮にて作製したゲル（２０×２０ｍｍ２）を、室温下、乾燥しないように密閉した状態で、純水中に２日間浸漬した。純水中に溶出したＰＶＡ重量（Ｗｅｌｕ）を経過時間ごとに測定し、浸漬後の試験片を乾燥させることにより測定した残存ＰＶＡ重量（Ｗｇｅｌ）から、以下の式を用いて溶解度を算出した。
　　溶解度［％］＝Ｗｅｌｕ／（Ｗｅｌｕ＋Ｗｇｅｌ）×１００ (4) Elution rate A gel (20 × 20 mm 2 ) prepared by heat compression was immersed in pure water for 2 days in a sealed state so as not to be dried at room temperature. The PVA weight (W elu ) eluted in pure water is measured every elapsed time, and the solubility is calculated using the following equation from the residual PVA weight (W gel ) measured by drying the test piece after immersion. did.
Solubility [%] = W elu / (W elu + W gel ) × 100
（５）Ｘ線小角散乱
　本研究では、ゲル化過程の進行度と微結晶間の間隔を測定するため、圧縮法で作製したＳｔ－ＰＶＡゲルとアタクティックＰＶＡゲルについて、経時的にＳＡＸＳの測定を行った。ゲルはカプトンフィルムにくるみ、乾燥を避けるために恒湿度下で１２時間Ｘ線を照射し測定を行った。測定は、株式会社リガク製ナノスケールＸ線構造評価装置ＮＡＮＯ－Ｖｉｅｗｅｒを用いて行った。試験条件を以下に示す。
（ＳＡＸＳの試験条件）
　　ＩＰ検出器
　　ターゲット：Ｃｕ　Ｋα線（０．１５４ｎｍ）
　　出力：４５ｋＶ－６０ｍＡ
　　ビームストッパー：φ２．５ｍｍ
　　カメラ長：９６０ｍｍ
　　露光時間：１２時間
　　スリット：１stスリット＝０．２０ｍｍ、２ｎｄスリット＝０．１０ｍｍ、３ｒｄスリット＝０．２５ｍｍ (5) Small-angle X-ray scattering In this study, SAXS was measured over time for the St-PVA gel and the atactic PVA gel prepared by the compression method in order to measure the progress of the gelation process and the spacing between the microcrystals. Went. The gel was wrapped in a Kapton film and measured by irradiating with X-rays at constant humidity for 12 hours to avoid drying. The measurement was performed using a nanoscale X-ray structure evaluation apparatus NANO-Viewer manufactured by Rigaku Corporation. Test conditions are shown below.
(SAXS test conditions)
IP detector Target: Cu Kα ray (0.154 nm)
Output: 45kV-60mA
Beam stopper: φ2.5mm
Camera length: 960mm
Exposure time: 12 hours Slit: 1st slit = 0.20 mm, 2nd slit = 0.10 mm, 3rd slit = 0.25 mm
（６）力学的強度
　Ｓｔ－ＰＶＡゲルおよびアタクティックＰＶＡゲルを圧縮法で作製した後、時間経過ごとのゲルの弾性率を、引張試験により求めた。引張試験は島津製作所製オートグラフＡＧＳ－Ｊを用いて、試験片形状ＪＩＳダンベル７型、初期加重０．５Ｎ、引張速度５ｍｍ／ｍｉｎとした。また、今回の引張試験では、測定を簡略化するため、すべての試料において標点間距離をつかみ部間の距離とした。 (6) Mechanical strength After the St-PVA gel and the atactic PVA gel were prepared by the compression method, the elastic modulus of the gel over time was determined by a tensile test. In the tensile test, an autograph AGS-J manufactured by Shimadzu Corporation was used, and a test piece shape JIS dumbbell 7 type, an initial load of 0.5 N, and a tensile speed of 5 mm / min were used. In this tensile test, in order to simplify the measurement, the distance between the gauge points was used as the distance between the gripping parts in all the samples.
［合成例１］
　攪拌機、温度計、滴下ロ－ト及び還流冷却器を取り付けたフラスコ中に、ピバリン酸ビニル８００部、メタノール１９０部を仕込み、系内の窒素置換を行った後加熱し、還流が発生した時点で２，２－アゾビスイソブチリロニトリル０．０７部をメタノール１０部に溶解した溶液を添加し重合を開始し、６時間後に重合停止剤としてｍ－ジニトロベンゼン０．００８部を添加し、重合を停止した。重合収率は７０％であった。
　得られた反応物からメタノール、ピバリン酸ビニルを除去後、ポリピバリン酸ビニルの２０％アセトン溶液を得た。
　このアセトン溶液２５０部に水酸化カリウムの２５％メタノール溶液１１５部とを加えてよく混合し、５０℃で２．５時間鹸化反応を行った。得られたゲル状物を粉砕し、アセトン１５０部、水酸化カリウムの２５％メタノール溶液３８０部中でさらに５０℃で４時間鹸化反応を行った。反応後酢酸で中和し、固液分離を行い、メタノール、水で洗浄、乾燥後、Ｓｔ－ＰＶＡを得た。得られたＳｔ－ＰＶＡの重合度は１２００であり、ケン化度は９９．９２モル％であった。またシンジオタクティシティは３７．０％であった。 [Synthesis Example 1]
In a flask equipped with a stirrer, thermometer, dropping funnel, and reflux condenser, charge 800 parts of vinyl pivalate and 190 parts of methanol, and after replacing the nitrogen in the system and heating, when refluxing occurred A solution in which 0.07 part of 2,2-azobisisobutyronitrile was dissolved in 10 parts of methanol was added to initiate polymerization, and after 6 hours, 0.008 part of m-dinitrobenzene was added as a polymerization terminator, and polymerization was performed. Stopped. The polymerization yield was 70%.
After removing methanol and vinyl pivalate from the obtained reaction product, a 20% acetone solution of polyvinyl polypivalate was obtained.
To 250 parts of this acetone solution, 115 parts of a 25% potassium hydroxide solution in methanol was added and mixed well, and a saponification reaction was carried out at 50 ° C. for 2.5 hours. The obtained gel-like material was pulverized and saponified in 150 parts of acetone and 380 parts of a 25% potassium hydroxide solution in methanol at 50 ° C. for 4 hours. After the reaction, the reaction solution was neutralized with acetic acid, separated into solid and liquid, washed with methanol and water and dried to obtain St-PVA. The resulting St-PVA had a polymerization degree of 1200 and a saponification degree of 99.92 mol%. Syndiotacticity was 37.0%.
　合成例１で得られたＳｔ－ＰＶＡを８部秤量し、水１２部と混合し、膨潤させた。この膨潤体をシリコンシートで作製した５ｃｍ×５ｃｍ×２ｍｍの型に入れ、テフロン（登録商標）シートを上から重ね、真鍮板で挟んであらかじめ１３０℃に熱しておいたホットプレス機にセットした。５ＭＰａ程度の圧を加え、５分程度サンプル内部まで温度が安定させた。その後、９０℃に設定温度を下げ、５分後に１０ＭＰａまで圧をかけた。続いて１５分後に２０ＭＰａとし、３０分後に圧縮機から取り出し、型から外し、室温で１時間冷却させた。このゲルは作製直後より取り出し可能で、ゲル化が早いことが示された。そのときのハイドロゲルの写真を図１に示すが、透明なゲルが出来ていることが見て取れる。 8 parts of St-PVA obtained in Synthesis Example 1 was weighed, mixed with 12 parts of water, and swollen. This swollen body was put into a 5 cm × 5 cm × 2 mm mold made of a silicon sheet, and a Teflon (registered trademark) sheet was stacked from above, and was set in a hot press machine that had been heated to 130 ° C. in advance by being sandwiched between brass plates. A pressure of about 5 MPa was applied to stabilize the temperature up to the inside of the sample for about 5 minutes. Thereafter, the set temperature was lowered to 90 ° C., and pressure was applied to 10 MPa after 5 minutes. Subsequently, the pressure was set to 20 MPa after 15 minutes, and after 30 minutes, the product was taken out from the compressor, removed from the mold, and cooled at room temperature for 1 hour. This gel can be taken out immediately after preparation, and it was shown that gelation is quick. A photograph of the hydrogel at that time is shown in FIG. 1, and it can be seen that a transparent gel is formed.
　また、得られたハイドロゲルの溶出率測定結果を図２に示す。実施例１で得られたハイドロゲルでは、作製後１５分で既に溶出率は０％であり、作製後４８時間後も０％であった。このように、実施例１で得られたハイドロゲルは、耐水性に優れることが確認された。 Moreover, the elution rate measurement result of the obtained hydrogel is shown in FIG. In the hydrogel obtained in Example 1, the elution rate was already 0% 15 minutes after the production, and was also 0% 48 hours after the production. Thus, it was confirmed that the hydrogel obtained in Example 1 is excellent in water resistance.
比較例１Comparative Example 1
　シンジオタクティシティ３０．８％、鹸化度９９．１モル％、重合度１９２０のアタクティックＰＶＡを用いる以外は実施例１と同様にハイドロゲルを作製した。この場合、作製後数時間（３時間）はハイドロゲルが柔らかくシリコン型から取り出すことが出来なかった。
　また、得られたハイドロゲルの溶出率の測定結果を、図２に示す。この場合、作製後４８時間放置後の溶出率は２３％あった。 A hydrogel was prepared in the same manner as in Example 1 except that atactic PVA having a syndiotacticity of 30.8%, a saponification degree of 99.1 mol%, and a polymerization degree of 1920 was used. In this case, the hydrogel was soft and could not be taken out from the silicon mold for several hours (3 hours) after preparation.
Moreover, the measurement result of the elution rate of the obtained hydrogel is shown in FIG. In this case, the dissolution rate after standing for 48 hours after preparation was 23%.
　また、実施例1および比較例１で作製したハイドロゲルの微小構造の経時変化を、エックス線小角散乱（ＳＡＸＳ）にて測定した。結果を図３に示す。
　実施例１から得られたハイドロゲルでは、作製1日目より微小ではあるがピーク（２θ＝０．４°）が見られ、作製1日目の周期構造が２３．２ｎｍであることが分かった。これは２３．２ｎｍ以下の微小な結晶が形成され、架橋点を形成しゲル化していることを示す。また、１日目以降は経時的にピークが広角側にシフトしていることから、結晶が経時的に成長している事が示唆される。
　一方で、比較例１で得られたハイドロゲルの場合、作製３０日後でようやくピークが観測でき、微結晶の形成が明らかに遅いことが確認された。 Moreover, the time-dependent change of the microstructure of the hydrogel produced in Example 1 and Comparative Example 1 was measured by X-ray small angle scattering (SAXS). The results are shown in FIG.
In the hydrogel obtained from Example 1, a peak (2θ = 0.4 °) was observed although it was finer from the first day of production, and it was found that the periodic structure of the first day of production was 23.2 nm. . This indicates that a fine crystal of 23.2 nm or less is formed and a cross-linking point is formed and gelled. In addition, since the peak shifts to the wide-angle side with time after the first day, it is suggested that the crystal grows with time.
On the other hand, in the case of the hydrogel obtained in Comparative Example 1, a peak was finally observed 30 days after production, and it was confirmed that the formation of microcrystals was clearly slow.
　また、比較例１では、上記したように作製直後（ゲル作製０時間後）ではゲル化しておらず、作製２０時間後にやっとゲルとしての形をなした程度で、作製１２０時間後でもヤング率が１．３ＭＰａでありゲルとして十分に使用できる強度のものではなかった。
　一方、表１に示すように、実施例１のゲルは、ゲル作製直後（ゲル作製０時間後）でもヤング率が２．６ＭＰａであり、作製２０時間後には４．４ＭＰａと高いヤング率となり、作製１７０時間後には４．８ＭＰａのさらに強固なゲルとなった。 In Comparative Example 1, as described above, the gelation was not immediately after production (0 hours after gel production), and the gel was finally formed as a gel 20 hours after production, and the Young's modulus was 120 hours after production. It was 1.3 MPa, and it was not strong enough to be used as a gel.
On the other hand, as shown in Table 1, the gel of Example 1 had a Young's modulus of 2.6 MPa even immediately after gel preparation (0 hours after gel preparation), and a high Young's modulus of 4.4 MPa after 20 hours of preparation, After 170 hours of preparation, the gel became 4.8 MPa.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　また、作製直後の実施例１のハイドロゲルを、人工関節軟骨型の容器に入れ、室温で１２時間放置してから取り出すことにより、人工関節軟骨用のゲルを形成することができた。 Also, the hydrogel of Example 1 immediately after preparation was placed in an artificial articular cartilage-type container, allowed to stand at room temperature for 12 hours and then taken out, whereby a gel for artificial joint cartilage could be formed.
　本発明のハイドロゲルの製造方法は、高濃度でのゲル作製が可能であり、かつ比較的短時間でゲルが得られるため工業的に有利であり、また、得られるハイドロゲルは機械的強度に優れるため特に人工関節軟骨等の生体材料として有用である。 The production method of the hydrogel of the present invention is industrially advantageous because a gel can be produced at a high concentration and the gel can be obtained in a relatively short time. The obtained hydrogel is mechanically strong. Since it is excellent, it is particularly useful as a biomaterial such as artificial joint cartilage.

Claims (5)

  1. 　シンジオタクティシティがトライアッド表示で３２％以上のポリビニルアルコール系樹脂（Ａ）を水（Ｂ）に膨潤させ、１～５０ＭＰａ、９０～１６０℃の加熱圧縮条件下で溶解し、その後放冷するハイドロゲルの製造方法。 Hydro with a syndiotacticity of 32% or more in triad format and swollen in water (B), dissolved under heat and compression conditions of 1 to 50 MPa and 90 to 160 ° C., and then allowed to cool A method for producing a gel.
  2. 　前記ポリビニルアルコール系樹脂（Ａ）および水（Ｂ）の割合が、質量比で９０／１０～２０／８０である請求項１記載のハイドロゲルの製造方法。 The method for producing a hydrogel according to claim 1, wherein a ratio of the polyvinyl alcohol-based resin (A) and water (B) is 90/10 to 20/80 in mass ratio.
  3. 　ホットプレス機を用いて溶解する請求項１又は２に記載のハイドロゲルの製造方法。 The method for producing a hydrogel according to claim 1, wherein the hydrogel is dissolved using a hot press machine.
  4. 　請求項１～３のいずれかに記載の製造方法を用いて得られるハイドロゲル。 A hydrogel obtained by using the production method according to any one of claims 1 to 3.
  5. 　請求項４記載のハイドロゲルで形成された人工関節軟骨材料。 An artificial joint cartilage material formed of the hydrogel according to claim 4.
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