WO2024034610A1

WO2024034610A1 - Frozen and thawed hydrogel, production method therefor, ophthalmic medical device, and contact lens

Info

Publication number: WO2024034610A1
Application number: PCT/JP2023/028930
Authority: WO
Inventors: 修作万代; 千津子風呂; 祐哉金森; 潤磯部
Original assignee: 三菱ケミカル株式会社
Priority date: 2022-08-08
Filing date: 2023-08-08
Publication date: 2024-02-15

Abstract

This frozen and thawed hydrogel comprises a modified polyvinyl alcohol, and a drug. This method for producing a frozen and thawed hydrogel comprises: executing, at least twice, a freezing and thawing cycle in which a composition containing water, a modified polyvinyl alcohol, and a drug is cooled to a temperature of at most -5°C to be frozen, and the frozen composition is heated to a temperature of at least 5°C to be thawed.

Description

Freeze-thaw hydrogel, its manufacturing method, ophthalmological medical instruments and contact lenses

The present invention relates to a freeze-thaw hydrogel, a method for producing the same, an ophthalmic medical device, and a contact lens.
This application claims priority based on Japanese Patent Application No. 2022-126533 filed in Japan on August 8, 2022 and Japanese Patent Application No. 2023-050956 filed in Japan on March 28, 2023. , the contents of which are incorporated herein.

A contact lens with sustained drug release properties has been studied so that the drug can be delivered to the affected area of the eye over a long period of time by wearing a contact lens containing a therapeutic drug (Patent Document 1).

Chemically cross-linked hydrogel is used in contact lenses. When such a contact lens contains a drug, it is necessary to impregnate the crosslinked hydrogel formed into the contact lens with the drug. However, hydrogels with sustained release properties have a problem in that they are difficult to impregnate with drugs.

On the other hand, by repeatedly freezing and thawing an aqueous solution of polyvinyl alcohol, polyvinyl alcohol can be physically crosslinked to form a hydrogel (Patent Document 2).

Special Publication No. 2008-539837 Japanese Patent Application Publication No. 8-239538

By adding the drug to an aqueous solution of polyvinyl alcohol in advance, a hydrogel containing the drug can be created, and there is no need to impregnate the crosslinked hydrogel with the drug.
However, in conventional hydrogels using polyvinyl alcohol, even if a drug is contained, the drug existing near the surface will elute, but the drug existing inside the hydrogel will not elute, resulting in a sustained release. There is a problem with being inferior.

An object of the present invention is to provide a hydrogel, an ophthalmological medical device, and a contact lens that exhibit excellent sustained drug release properties, and a manufacturing method that yields a hydrogel that exhibits excellent sustained drug release properties.

Polyvinyl alcohol hydrogels produced by the conventional freeze-thaw method have problems such as a portion of the polyvinyl alcohol eluting even in water heated to around body temperature, and the hydrogel becoming cloudy after the freeze-thaw process, resulting in decreased transparency. It was difficult to form a high-quality hydrogel, making it unsuitable for use as a contact lens.

Another object of the present invention is to provide a hydrogel with low elution and high transparency, an ophthalmic medical device, and a contact lens, and a manufacturing method that yields a hydrogel with low elution and high transparency.

As a result of intensive studies, the present inventors discovered the following.
By using modified polyvinyl alcohol, the amount of physical crosslinking points can be controlled and a freeze-thaw hydrogel with excellent sustained drug release properties can be obtained.

In differential scanning calorimetry, the onset temperature of the absorption peak on the low temperature side is -5°C or lower in the range where the melting point of water in the gel is 0°C or lower when measured at a heating rate of 10°C/min. The freeze-thaw hydrogel becomes a highly transparent freeze-thaw hydrogel with less elution. In addition, after the aqueous solution of polyvinyl alcohol is made into a hydrogel by the first freeze-thaw treatment, the water content of the hydrogel is reduced to 75% or less, and then the second freeze-thaw treatment is performed to reduce elution and make it transparent. A polyvinyl alcohol hydrogel with excellent properties can be obtained.

The present invention has the following aspects.
[1] Freeze-thaw hydrogel containing modified polyvinyl alcohol and drug.
[2] The freeze-thaw hydrogel according to [1], wherein the average degree of saponification of the modified polyvinyl alcohol is 95 mol% or more.
[3] The freeze-thaw hydrogel according to [1] or [2], wherein the 4% by mass aqueous solution of the modified polyvinyl alcohol has a viscosity of 5 to 100 mPa·s at 20°C.
[4] The freeze-thaw hydrogel according to any one of [1] to [3], wherein the modified polyvinyl alcohol has at least one type selected from the group consisting of cationic groups, anionic groups, and nonionic groups.
[5] The freeze-thaw hydrogel according to any one of [1] to [4], wherein the amount of modification of the modified polyvinyl alcohol is 0.1 to 30 mol%.
[6] The freeze-thaw hydrogel according to any one of [1] to [5], which has a saturated moisture content of 50 to 90% by mass.
[7] The freeze-thaw hydrogel according to any one of [1] to [6], which has a compressive modulus of elasticity at 37°C of 0.001 to 0.5 MPa.
[8] The modified polyvinyl alcohol has a cationic group,
The freeze-thaw hydrogel according to any one of [1] to [7], wherein the drug includes an anionic drug.
[9] The modified polyvinyl alcohol has an anionic group,
The freeze-thaw hydrogel according to any one of [1] to [7], wherein the drug includes a cationic drug.
[10] In the following sustained release test, the cumulative dissolution rate of the drug after 1 hour is 80% by mass or less of the cumulative dissolution rate after 24 hours, according to any one of [1] to [9]. Freeze-thaw hydrogel.
Sustained release test:
The frozen and thawed hydrogel was placed in a 24-well cell culture plate, 1000 μL of phosphate buffered saline was added, and after standing at 37°C for 15 minutes, the entire amount of the phosphate buffered saline was collected, and then freshly After adding 1000 μL of phosphate buffered saline and allowing it to stand at 37°C for 15 minutes (30 minutes in total), the entire amount of the phosphate buffered saline was collected, and then 1000 μL of fresh phosphate buffered saline was added. After adding physiological saline and allowing it to stand at 37° C. for 30 minutes (1 hour in total), the entire amount of the phosphate buffered saline is collected. Repeat this and measure the phosphate buffered saline collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after adding the phosphate buffered saline for the first time. The elution amount of the drug is determined as a sample, and the cumulative elution rate at each time is calculated.
[11] Prepare a composition containing water, modified polyvinyl alcohol, and a drug,
A method for producing a freeze-thaw hydrogel, comprising repeating a cycle of lowering the temperature of the composition to a temperature of -5°C or lower, freezing it, and raising the temperature of the frozen composition to a temperature of 5°C or higher to melt it, twice or more.
[12] An ophthalmic medical device comprising the freeze-thaw hydrogel according to any one of [1] to [10].
[13] A contact lens comprising the freeze-thaw hydrogel according to any one of [1] to [10].

[14] A freeze-thaw hydrogel of polyvinyl alcohol, which exhibits an endothermic peak observed in the range of 0°C or less in differential scanning calorimetry under the conditions of -50°C to 150°C and a heating rate of 10°C/min. A polyvinyl alcohol freeze-thaw hydrogel with a set temperature of -5°C or lower.
[15] The freeze-thaw hydrogel according to [14], wherein the polyvinyl alcohol is modified polyvinyl alcohol.
[16] The freeze-thaw hydrogel according to [14] or [15], which contains a drug.
[17] An ophthalmological medical device comprising the freeze-thaw hydrogel according to any one of [14] to [16].
[18] A contact lens comprising the freeze-thaw hydrogel according to any one of [14] to [16].
[19] Freezing and thawing of polyvinyl alcohol, after turning an aqueous solution of polyvinyl alcohol into a hydrogel through a first-stage freeze-thaw treatment, reducing the water content of the hydrogel to 75% by mass or less, and then performing a second-stage freeze-thaw treatment Method for producing hydrogel.

According to one aspect of the present invention, it is possible to provide a hydrogel, an ophthalmological medical device, and a contact lens that exhibit excellent sustained drug release properties, and a manufacturing method that yields a hydrogel that exhibits excellent sustained drug release properties.

According to another aspect of the present invention, it is possible to provide a hydrogel with low elution and excellent transparency, an ophthalmic medical device and a contact lens, and a manufacturing method that yields a hydrogel with low elution and excellent transparency.

1 is a graph showing the sustained release test results of the hydrogels of Examples A1 to A5. Figure 2 is a graph of the endothermic peaks of the PVOH freeze-thaw hydrogel of Example B1 obtained by differential scanning calorimetry.

As used herein, "hydrogel" is a structure that has a network structure formed by physically or chemically crosslinking polymer molecular chains, and that swells by incorporating water into this network structure. be.
"Freeze-thaw hydrogel" is a hydrogel in which physical crosslinking points are formed between the molecular chains of polyvinyl alcohol (hereinafter also referred to as "PVOH") by hydrogen bonds. It is a hydrogel formed by repeatedly freezing and thawing (thawing) an aqueous solution. When an aqueous solution of PVOH is repeatedly frozen and thawed, physical crosslinking points are formed between molecular chains of PVOH by hydrogen bonds, resulting in a hydrogel. Freeze-thaw hydrogels can be redissolved at high temperatures, and are different from chemically crosslinked hydrogels obtained by using crosslinking agents or irradiating with energy rays. Conditions for redissolution include, for example, 1 hour at 100°C.
"~" indicating a numerical range means that the numerical values written before and after it are included as lower and upper limits.

[Freeze-thaw hydrogel]
≪First embodiment≫
The freeze-thaw hydrogel according to the first embodiment of the present invention includes modified PVOH and a drug.

<Modified PVOH>
Modified PVOH is PVOH having a modifying group.
PVOH is a polymer containing vinyl alcohol units, and is typically a saponified product of a polymer containing vinyl ester monomer units. PVOH may be a polymer containing vinyl ester monomer units.
Modified PVOH typically includes vinyl alcohol units and units with modifying groups. The unit having a modifying group is a unit other than vinyl alcohol units and vinyl ester monomer units. The modified PVOH may contain vinyl ester monomer units.
Modified PVOH can be produced by saponifying a polymer of a vinyl ester monomer and another unsaturated monomer or by post-modifying PVOH.

The modifying group is preferably at least one selected from the group consisting of cationic groups, anionic groups, and nonionic groups. Examples of the cationic group include quaternary ammonium bases such as diallyldimethylammonium base, (3-methacrylamidopropyl)trimethylammonium base, [2-(methacryloyloxy)ethyl]trimethylammonium chloride, sulfonium group, oxonium group, and phosphonium group. Examples include groups. Examples of anionic groups include carboxy groups and salts thereof, sulfo groups and salts thereof, and phosphoric acid groups and salts thereof. Examples of the nonionic group include an acetoacetate group, an acetal group, a urethane group, an ether group, a phosphate group, an oxyalkylene group, an alkylene group, an amide group, a silanol group, an epoxy group, an olefin group, and a diol group. .
When an anionic drug is used as the drug, a cationic group is preferred as the modifying group because it has a high affinity with the anionic drug and provides good sustained release properties of the anionic drug. When a cationic drug is used as the drug, an anionic group is preferable as the modifying group because it has a high affinity with the cationic drug and provides good sustained release properties of the cationic drug.
Modified PVOH having a cationic group is also referred to as cationically modified PVOH. Modified PVOH having an anionic group is also referred to as anion-modified PVOH.

An example of modified PVOH is copolymerized modified PVOH.
Copolymerized modified PVOH is produced by copolymerizing a vinyl ester monomer and another unsaturated monomer that can be copolymerized with the vinyl ester monomer, and saponifying the resulting copolymer. can be manufactured.
Examples of vinyl ester monomers include vinyl acetate, vinyl formate, vinyl propionate, vinyl valerate, vinyl caprate, vinyl laurate, vinyl stearate, vinyl benzoate, vinyl pivalate, and vinyl versatate. However, vinyl acetate is preferred from the viewpoint of stable polymerization.

Other unsaturated monomers copolymerizable with the vinyl ester monomer include unsaturated monomers having at least one modification group selected from the group consisting of cationic groups, anionic groups, and nonionic groups. An unsaturated monomer having a cationic group or an unsaturated monomer having an anionic group is particularly preferred.
Examples of the unsaturated monomer having a cationic group include N-acrylamidomethyltrimethylammonium chloride, allyltrimethylammonium chloride, and diallyltrimethylammonium chloride.
Examples of unsaturated monomers having an anionic group include unsaturated carboxylic acids or salts thereof such as acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itaconic acid, and undecylenic acid; maleic acid, itaconic acid; , esters in which part of the carboxyl group of polycarboxylic acids such as fumaric acid is esterified (monoalkyl esters of unsaturated dicarboxylic acids, etc.); Olefin sulfonic acids such as ethylene sulfonic acid, allyl sulfonic acid, meta-allylsulfonic acid, etc. or a salt thereof;
Examples of unsaturated monomers having a nonionic group include olefins such as ethylene, propylene, isobutylene, α-octene, α-dodecene, and α-octadecene; acrylic acid, methacrylic acid, crotonic acid, maleic acid, and maleic anhydride. esters in which all the carboxy groups of unsaturated carboxylic acids such as itaconic acid and undecylenic acid are esterified (dialkyl esters of unsaturated dicarboxylic acids, etc.); Nitriles such as acrylonitrile and methacrylonitrile; diacetone acrylamide, acrylamide , amides such as methacrylamide; alkyl vinyl ethers; dimethylallyl vinyl ketone; N-vinylpyrrolidone; vinyl chloride; vinylidene chloride; polyoxyalkylenes such as polyoxyethylene (meth)allyl ether, polyoxypropylene (meth)allyl ether, etc. (meth)allyl ether; polyoxyalkylene (meth)acrylate such as polyoxyethylene (meth)acrylate, polyoxypropylene (meth)acrylate; polyoxy such as polyoxyethylene (meth)acrylamide, polyoxypropylene (meth)acrylamide, etc. Alkylene (meth)acrylamide; polyoxyethylene (1-(meth)acrylamide-1,1-dimethylpropyl) ester; polyoxyalkylene vinyl ether such as polyoxyethylene vinyl ether, polyoxypropylene vinyl ether; polyoxyethylene allylamine, polyoxypropylene Polyoxyalkylene allylamine such as allylamine; polyoxyalkylene vinylamine such as polyoxyethylene vinylamine, polyoxypropylene vinylamine; 3-buten-1-ol, 4-penten-1-ol, 5-hexen-1-ol hydroxy group-containing α-olefins such as or acylated products thereof, vinyl ethylene carbonate; 2,2-dialkyl-4-vinyl-1,3-dioxolane; glycerin monoallyl ether; 3,4-diacetoxy-1-butene, etc. Vinyl compounds; isopropenyl acetate; substituted vinyl acetates such as 1-methoxyvinyl acetate, 1,4-diacetoxy-2-butene, vinylene carbonate, vinyl acetoacetate, and the like.
These unsaturated monomers may be used alone or in combination of two or more.
Among the above, diallyldimethylammonium chloride and monomethyl maleate are preferred.

The ratio of other unsaturated monomers to the total of 100 mol% of the vinyl ester monomer and other unsaturated monomers is preferably 0.2 to 20 mol%, and 0.4 to 10 mol%. More preferred. If the proportion of other unsaturated monomers is within the above range, the amount of modification of the modified PVOH is likely to be within the preferred range described below. The proportion of other unsaturated monomers may be 0.5 to 20 mol%, or 0.8 to 10 mol%.

Copolymerization can be performed by any known polymerization method, such as solution polymerization, suspension polymerization, emulsion polymerization, etc. Among these, it is preferable to carry out solution polymerization under reflux because it can efficiently remove the heat of reaction. As a solvent for solution polymerization, alcohol is usually used, preferably a lower alcohol having 1 to 3 carbon atoms.
Also for saponification of the obtained copolymer, known saponification methods can be employed. That is, the copolymer can be dissolved in alcohol or a water/alcohol solvent using an alkali catalyst or an acid catalyst.
As the alkali catalyst, for example, alkali metal hydroxides or alcoholates such as potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate, potassium methylate, and lithium methylate can be used.
Usually, a transesterification reaction using an alkali catalyst in an anhydrous alcohol solvent is preferably used from the viewpoint of reaction rate and the ability to reduce impurities such as fatty acid salts.
The reaction temperature of the saponification reaction is usually 20 to 60°C. If the reaction temperature is too low, the reaction rate tends to be low and the reaction efficiency is reduced; if it is too high, the temperature may exceed the boiling point of the reaction solvent, which tends to reduce safety in production. In addition, when saponifying under high pressure using a column-type continuous saponification tower with high pressure resistance, it is possible to saponify at a higher temperature, for example, 80 to 150°C, and a small amount of saponification catalyst is used. It is also possible to obtain a product with a high degree of saponification in a short period of time.

After saponification, the obtained copolymerized modified PVOH is preferably washed with a washing liquid.
Examples of the cleaning liquid include alcohols such as methanol, ethanol, isopropyl alcohol, butanol, and methanol is preferred from the viewpoint of cleaning efficiency and drying efficiency.
Although a continuous method may be used as the cleaning method, a batch method is usually adopted. The bath ratio (mass of cleaning liquid/mass of copolymerization-modified PVOH) is usually 1 to 30, preferably 2 to 20. If the bath ratio is too large, a large cleaning device will be required, which tends to increase costs, and if the bath ratio is too small, the cleaning effect will decrease and the number of cleanings will tend to increase.
The temperature during washing is usually 10 to 80°C, preferably 20 to 70°C. If the temperature is too high, the amount of volatilization of the cleaning liquid increases, which tends to require reflux equipment. If the temperature is too low, cleaning efficiency tends to decrease.
Washing time is typically 5 minutes to 12 hours. If the cleaning time is too long, production efficiency tends to decrease, and if the cleaning time is too short, cleaning tends to be insufficient. Further, the number of times of washing is usually 1 to 10 times, particularly preferably 1 to 5 times. If the number of washings is too large, productivity tends to deteriorate and costs increase.

The washed copolymerized modified PVOH is dried with hot air or the like in a continuous or batch manner.
The drying temperature is usually 50 to 150°C. If the drying temperature is too high, the copolymerized modified PVOH tends to be thermally degraded, and if the drying temperature is too low, the drying tends to take a long time.
Drying time is typically 1 to 48 hours. If the drying time is too long, the copolymerized modified PVOH tends to be thermally degraded, and if the drying time is too short, the drying tends to be insufficient or high temperature drying is required.
The content of the solvent contained in the copolymerized modified PVOH after drying is usually 0 to 10% by mass, preferably 0.1 to 5% by mass, and more preferably 0.1 to 1% by mass.

The resulting copolymerized modified PVOH usually contains an alkali metal salt of acetic acid derived from the alkali catalyst used during saponification. The content of the alkali metal salt is usually 0.001 to 2% by mass, preferably 0.005 to 1% by mass, and more preferably 0.01 to 0.1% by mass based on the total mass of the copolymerized modified PVOH. It is.
Examples of methods for adjusting the content of the alkali metal salt include a method of adjusting the amount of an alkali catalyst used during saponification, and a method of washing the copolymerized modified PVOH with alcohol such as ethanol and methanol.
Examples of methods for quantifying alkali metal salts include dissolving copolymerized modified PVOH powder in water, using methyl orange as an indicator, and performing neutralization titration with hydrochloric acid to determine the content of alkali metal salts. .

Other examples of modified PVOH include post-modified PVOH.
Post-modified PVOH can be produced by post-modifying unmodified PVOH. Unmodified PVOH consists only of vinyl alcohol units, or consists of vinyl alcohol units and vinyl ester monomer units before saponification. In post-modification, a modifying group is typically introduced into the OH group of the vinyl alcohol unit of unmodified PVOH.
Examples of post-modification methods include methods in which unmodified PVOH is subjected to acetoacetic acid esterification, acetalization, urethanization, etherification, phosphoric acid esterification, oxyalkylenization, or dehydration condensation with an acid. Examples of the method for acetoacetate esterification include a method in which a hydroxyl group of unmodified PVOH and acetoacetate are subjected to a transesterification reaction, a method in which unmodified PVOH and diketene are reacted, and the like.
As the post-modified PVOH, acetoacetic esterified modified PVOH is preferable from the viewpoint of solubility in water.

As the modified PVOH, any one of the above-mentioned modified PVOH may be used alone, or a mixture of two or more may be used. Further, as the modified PVOH, a mixture of one or more of the above-mentioned modified PVOH and unmodified PVOH may be used.

The amount of modification of modified PVOH varies depending on the nature of the modifying group, but is preferably 0.1 to 30 mol%, more preferably 0.3 to 20 mol%, and 0.5 to 10 mol%. It is more preferable that If the amount of modification is above the lower limit, the crosslinking density of the freeze-thaw hydrogel will be low, and not only the drug present near the surface of the freeze-thaw hydrogel but also the drug present inside the freeze-thaw hydrogel will tend to be easily eluted. There is. If the amount of denaturation is below the upper limit, rapid elution of the drug immediately after applying the freeze-thaw hydrogel to the affected area tends to be suppressed. The amount of modification of the modified PVOH may be 0.5 to 20 mol%, or 1 to 10 mol%.
The amount of modification is the ratio of the modifying group to 100 mol% of the total units constituting the modified PVOH. The amount of modification is measured by NMR or titration.
Note that the amount of denaturation of the denatured PVOH does not change before and after forming it into a freeze-thaw hydrogel. By redissolving the freeze-thawed hydrogel, the amount of denaturation of the denatured PVOH can be measured. A method for redissolving a freeze-thawed hydrogel includes dissolution at high temperature and high pressure.

The average saponification degree of the modified PVOH is preferably 95 mol% or more, more preferably 96 mol% or more, even more preferably 97 mol% or more, and may be 100 mol%. If the average degree of saponification is equal to or higher than the lower limit, gelation tends to occur easily and the gel elution rate tends to be reduced.
The average degree of saponification is measured according to 3.5 of JIS K 6726:1994.
Note that the average degree of saponification of the modified PVOH does not change before and after it is made into a freeze-thaw hydrogel. By redissolving the freeze-thawed hydrogel, the average degree of saponification of the modified PVOH can be measured.

The average degree of polymerization of modified PVOH can generally be expressed by the viscosity of an aqueous solution.
The viscosity at 20° C. of a 4% by mass aqueous solution of modified PVOH is preferably 5 to 100 mPa·s, more preferably 13 to 70 mPa·s, and even more preferably 17 to 40 mPa·s. If the viscosity is above the above lower limit, gelation tends to occur easily and the dissolution rate of the gel can be reduced. On the other hand, if the viscosity is below the above upper limit, the PVOH aqueous solution is easier to handle and the release of the drug is improved. It tends to be better.
The viscosity is measured according to 3.11.2 of JIS K 6726:1994.
Note that the average degree of polymerization of the modified PVOH does not change before and after forming it into a freeze-thaw hydrogel. By redissolving the freeze-thaw hydrogel, the average degree of polymerization of the modified PVOH can be measured.

<Drug>
The drug is not particularly limited and can be appropriately selected from known drugs depending on the disease to be treated.
The agent may be, for example, a nucleic acid, a protein, a carbohydrate (such as a polysaccharide), another organic compound, an inorganic compound, or a combination of two or more thereof.

Examples of drugs applied to ophthalmological diseases include, but are not limited to, anti-infective agents (antibacterial agents, anti-viral agents, anti-fungal agents, antiprotozoal agents, etc.), angiogenesis inhibitors (anti-vascular endothelial agents, etc.) Cell growth factor (VEGF) agents, etc.), anti-inflammatory agents, intraocular hypotensive agents, antineoplastic agents, anesthetics, autonomic nerve agents, steroids (corticosteroids, etc.), antihistamines, mast cell stabilizers, immunosuppressants , mitosis inhibitors, and the like.

Non-limiting examples of antimicrobial agents include bacitracin, chloramphenicol, ciprofloxacin, erythromycin, moxifloxacin, gatifloxacin, gentamicin, levofloxacin, sulfacetamide, polymyxin B, vancomycin, tobramycin, or the like. Examples include combinations.
Non-limiting examples of antiviral agents include trifluridine, vidarabine, acyclovir, valacyclovir, famciclovir, foscarnet, ganciclovir, formivirsen, cidofovir, or combinations thereof.
Non-limiting examples of antifungal agents include amphotericin B, natamycin, fluconazole, itraconazole, ketoconazole, miconazole, or combinations thereof.
Non-limiting examples of antiprotozoal agents include polymyxin B, neomycin, clotrimazole, miconazole, ketoconazole, propamidine, polyhexamethylene biguanide, chlorhexidine, itraconazole, or combinations thereof.

Non-limiting examples of anti-inflammatory agents include any known steroidal anti-inflammatory drugs (SAIDs), any known non-steroidal anti-inflammatory drugs (NSAIDs), or combinations thereof. Non-limiting examples of SAIDs include glucocorticoids such as dexamethasone, prednisolone, fluorometholone, loteprednol, medrysone, rimexolone, and the like. Non-limiting examples of NSAIDs include diclofenac, flurbiprofen, ketorolac, bromofenac, nepafenac, or combinations thereof.

Non-limiting examples of antineoplastic agents include chemotherapeutic agents well known in the art.
Non-limiting examples of anesthetics include aminoamides, aminoesters, or combinations thereof. Non-limiting examples of aminoamides include lidocaine, prilocaine, mepivacaine, ropivacaine, or combinations thereof. Non-limiting examples of possible amino esters include benzocaine, procaine, proparacaine, tetracaine, or combinations thereof.

Non-limiting examples of autonomic agents include acetylcholine, carbachol, pilocarpine, physostigmine, ecothiophate, atropine, scopolamine, homotrapine, cyclopentolate, tropicamide, dipivefrin, epinephrine, phenylephrine, apraclonidine, brimonidine, cocaine, hydroxy Included are amphetamine, naphazoline, tetrahydrozoline, dapiprazole, betaxolol, carteolol, levobunolol, methiplanolol, timolol, bepotastine besylate, or combinations thereof.

Non-limiting examples of antihistamines include pheniramine, antazoline, naphazoline, emedastine, levocarbastine, cromolyn, or combinations thereof.
Non-limiting examples of mast cell stabilizers include lodoxamide, pemirolast, nedocromil, olopatadine, ketotifen, azelastine, epinastine, or combinations thereof.

The drug is preferably an anionic drug, an amphoteric drug, or a cationic drug because it is easily adsorbed to the gel and its release can be easily controlled.
Anionic drugs are drugs that have an anionic group and exhibit a negative charge in water.
Non-limiting examples of anionic agents include nucleic acids, tranilast, acitazanolast hydrate, sodium cromoglycate, glutathione, pranoprofen, bromfenac sodium, diclofenac sodium, or combinations thereof.
Examples of nucleic acids used as drugs include antisense oligonucleotides. Antisense oligonucleotides are also referred to as antisense nucleic acids, and contain a base sequence that can hybridize (i.e., are complementary) to a transcript of a target gene or at least a portion of a target transcript, and are mainly used for antisense oligonucleotides. Refers to a single-stranded oligonucleotide whose effect is to suppress the expression of a target gene transcript or the level of a target transcript.
The target gene or target transcript whose expression is suppressed, altered, or modified by the antisense effect is not particularly limited, but includes, for example, a gene derived from an organism into which the nucleic acid complex is introduced, for example, its expression in various diseases. Examples include genes with an increased number of genes. Furthermore, the transcription product of the target gene is mRNA transcribed from genomic DNA encoding the target gene, and further includes unbase-modified mRNA, unprocessed mRNA precursor, and the like. Target transcripts can include not only mRNA but also non-coding RNA (ncRNA) such as miRNA. More generally, a transcription product may be any RNA synthesized by a DNA-dependent RNA polymerase. In one embodiment, the target transcript is, for example, metastasis associated lung adenocarcinoma transcript 1 (malat1) non-coding RNA, scavenger receptor B1 (SR-B1) mRNA or DMPK (dystrophia myotonica-protein kinase) mRNA may be used. The base sequences of genes and transcripts can be obtained from known databases such as the NCBI (National Center for Biotechnology Information) database.
Anionic drugs and other drugs may be used in combination.

Amphoteric drugs are drugs that have an anionic group and a cationic group and have zero charge in water. The ophthalmic drug olopatadine has a single positively charged tertiary amine group and a single negatively charged carboxylic acid group and is therefore considered to have a net charge of zero.
Non-limiting examples of amphoteric drugs include levocabastine hydrochloride, amlexanox, olopatadine, lomefloxacin hydrochloride, ofloxacin, norfloxacin, levofloxacin, tosufloxacin, pirenoxine, rapamycin, or combinations thereof.
Amphoteric drugs may be used in combination with other drugs.

A cationic drug is a drug that has a cationic group and exhibits a positive charge in water.
In one example, the cationic drug is a polymer. Exemplary cationic polymers include epsilon polylysine (εPLL), polyquat, and the like, which are antimicrobial peptides containing multiple arginine and/or lysine groups.
In another example, a cationic drug is a positively charged group that includes a central carbon atom covalently bonded to three nitrogen atoms and has a double bond between one nitrogen atom and the central carbon. Contains a guanidium group. Typical useful agents for ophthalmic use containing at least one guanidinium group include antihistamines such as epinastine and emedastine; glaucoma drugs such as apraclonidine and brimonidine; guanine derivative antivirals such as ganciclovir and valganciclovir; arginine Containing antimicrobial peptides such as defensins and indolicidin; and biguanide antimicrobials such as chlorhexidine, alexidine, and polyhexamethylene biguanide (PHMB).
Other cationic drugs for ophthalmic use include ketotifen, cationic steroids, neostigmine methyl sulfate, oxybuprocaine hydrochloride, naphazoline nitrate, sodium chondroitin sulfate, pilocarpine hydrochloride, distigmine bromide, ecothiopate iodide, epinepherine, Examples include epinepherine bitartrate, carteolol hydrochloride, befunolol hydrochloride, and ripasudil hydrochloride hydrate.
A cationic drug and another drug may be used in combination.

The freeze-thaw hydrogel may further contain other components other than the modified PVOH and the drug, if necessary, to the extent that the effects of the present invention are not significantly impaired.
For example, when the freeze-thaw hydrogel is used to treat an ophthalmological disease, it may contain known components other than drugs in formulations for ophthalmological diseases (eye drops, etc.).
For example, when a freeze-thaw hydrogel is used for a contact lens, it can contain known ingredients (antioxidants, stabilizers, preservatives, osmotic pressure regulators, etc.) as compounded ingredients other than drugs in the contact lens. .
The other components may be used alone or in combination of two or more.

In the freeze-thaw hydrogel, the content of modified PVOH is preferably 5 to 50% by mass, more preferably 10 to 40% by mass, based on the total mass of the freeze-thaw hydrogel. If the content of modified PVOH is at least the lower limit, the strength of the lens tends to be better. If the content of modified PVOH is below the upper limit, oxygen permeability tends to be better.

In the freeze-thaw hydrogel, the content of the drug is determined by taking into consideration the dosage, release amount, etc. of the drug.
The content of the drug is not particularly limited, but can be set, for example, in the range of 0.1 to 20% by mass based on the total mass of the freeze-thaw hydrogel. Further, it can be set in a range of 0.2 to 80% by mass based on modified PVOH.

The saturated moisture content of the freeze-thaw hydrogel is preferably 50 to 90% by mass, more preferably 60 to 88% by mass. When the saturated moisture content is equal to or higher than the lower limit, oxygen permeability tends to be better. If the saturated moisture content is below the upper limit, the gel strength tends to be better.
The saturated moisture content of the freeze-thaw hydrogel is the water content of the freeze-thaw hydrogel immersed in purified water at 37° C. for 24 hours. The saturated moisture content is measured by the dry weight method and calculated using the following formula. The freeze-thaw hydrogel is dried at 140° C. for 1 hour.
Saturated moisture content = {(mass after immersion) - (mass after drying)}/(mass after immersion) x 100

The compressive modulus of the freeze-thaw hydrogel at 37°C is preferably 0.001 to 0.5 MPa, more preferably 0.005 to 0.4 MPa, and more preferably 0.01 to 0.3 MPa. is even more preferable. If the compressive elastic modulus is equal to or higher than the lower limit value, the wearing feeling tends to be better. If the compressive elastic modulus is below the upper limit, the wearing comfort tends to be better.
Compressive modulus is measured by thermomechanical analysis (TMA method).
The compressive elastic modulus of the freeze-thaw hydrogel can be adjusted by the number of repetitions of the freeze-thaw cycle, the degree of saponification of modified PVOH, the degree of polymerization, etc., which will be described later. For example, as the number of repeated freeze-thaw cycles increases, the compressive modulus tends to increase.

In the sustained release test below, the freeze-thaw hydrogel preferably has a cumulative dissolution rate of the drug after 1 hour of 90% by mass or less, and preferably 80% by mass or less of the cumulative dissolution rate after 24 hours. is more preferable, and even more preferably 70% by mass or less. If the cumulative dissolution rate after 1 hour is below the upper limit, sustained release properties are excellent.

Sustained release test:
The frozen and thawed hydrogel was placed in a 24-well cell culture plate, 1000 μL of phosphate buffered saline (hereinafter also referred to as "PBS") was added, and after standing at 37°C for 15 minutes, the entire amount of the PBS was collected. Next, 1000 μL of new PBS was added, and after standing at 37°C for 15 minutes (30 minutes in total), the entire amount of the PBS was collected. After standing for a minute (1 hour in total), the entire amount of the PBS is collected. Repeat this, and use the PBS collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after the first addition of PBS as a measurement sample to determine the elution amount of the drug, Calculate the cumulative elution percentage at each time.
Here, the "cumulative elution ratio" is the mass percentage of the "total amount of drugs eluted by each time" relative to the "drug content of the freeze-thaw hydrogel." The elution amount of the drug can be determined by measuring the absorbance corresponding to the drug using high performance liquid chromatography (hereinafter also referred to as "HPLC") or a spectrophotometer.

The shape of the freeze-thaw hydrogel is not particularly limited, and may be, for example, sheet-shaped, lens-shaped, etc. When the freeze-thaw hydrogel is in the form of a sheet, its shape when viewed from above is not particularly limited, and may be, for example, a polygonal shape such as a quadrangle, an annular shape, a semicircular shape, a crescent shape, an arch shape, or the like.

<Method for producing freeze-thaw hydrogel>
As a method for producing the freeze-thaw hydrogel of the first embodiment, for example, a composition containing water, modified PVOH, and a drug is prepared, and the composition is cooled to a temperature of −5° C. or lower and frozen. Examples include a method in which a cycle of heating the composition to a temperature of 5° C. or higher and melting it (hereinafter also referred to as a "freeze-thaw cycle") is repeated two or more times.

The composition can be prepared by mixing water, modified PVOH and drug.
The content of modified PVOH in the composition is preferably 5 to 30% by mass, more preferably 10 to 20% by mass, based on the total mass of the composition. If the modified PVOH is at least the lower limit, the gel strength tends to be better. If the modified PVOH is below the upper limit, oxygen permeability tends to be better.
The content of water in the composition is preferably 60 to 95% by mass, more preferably 70 to 90% by mass, based on the total mass of the composition.

The freezing temperature of the composition is preferably -5°C or lower, more preferably -10°C or lower, from the viewpoint of ease of physical crosslinking.
After freezing and before thawing the frozen composition, it is preferred to maintain the composition at freezing temperatures. The holding time at freezing temperature is preferably 30 minutes or more, more preferably 1 hour or more. The upper limit of the holding time at freezing temperature is not particularly limited, but is, for example, 24 hours.
The melting temperature of the composition is preferably 5°C or higher, more preferably 10°C or higher, from the viewpoint of ease of physical crosslinking. The upper limit of the melting temperature is not particularly limited, but is, for example, 40°C.
After thawing, it is preferred to maintain the composition at the thawing temperature before freezing the composition in the next freeze-thaw cycle. The holding time at the melting temperature is preferably 30 minutes or more, more preferably 1 hour or more. The upper limit of the holding time at the melting temperature is not particularly limited, but is, for example, 24 hours.
Although it is possible to obtain a freeze-thaw hydrogel by one freeze-thaw cycle, it is preferable to repeat the freeze-thaw cycle two or more times, and it is preferable to repeat the freeze-thaw cycle three or more times in order to obtain a freeze-thaw hydrogel with sufficiently high strength. is more preferable. The upper limit of the number of times the freeze-thaw cycle is repeated is not particularly limited, but is, for example, 20 times.

A film-like freeze-thaw hydrogel can be obtained by forming a coating film of the composition on a substrate and performing a freeze-thaw cycle. The freeze-thaw hydrogel peeled from the base material may be further processed, such as cutting.
By casting the composition into a mold of any shape and performing a freeze-thaw cycle, a freeze-thaw hydrogel having a shape corresponding to the mold can be obtained. The freeze-thaw hydrogel removed from the mold may be further processed, such as cutting.

The method for producing the freeze-thaw hydrogel of the present embodiment includes converting an aqueous solution of PVOH into a hydrogel by a first-stage freeze-thaw treatment, and then reducing the water content of the hydrogel to 75% by mass or less, and then performing a second-stage freeze-thaw treatment. A method of freezing and thawing is preferred.

In the first freeze-thaw process, the operation of lowering the temperature of the PVOH aqueous solution, freezing it, and raising the temperature of the frozen aqueous solution to thaw it (hereinafter also referred to as "freeze-thaw cycle") is performed one or more times. Although a hydrogel can be obtained by one freeze-thaw cycle, it is preferable to repeat the freeze-thaw cycle two or more times, more preferably three or more times, in order to obtain a hydrogel with sufficiently high strength. The upper limit of the number of times the freeze-thaw cycle is repeated is not particularly limited, but is, for example, 20 times, or even 10 times.
The freezing temperature of the aqueous solution is preferably -5°C or lower, more preferably -10°C or lower, from the viewpoint of ease of physical crosslinking.
After freezing the aqueous solution, it is preferable to maintain the frozen aqueous solution at a freezing temperature before thawing the frozen aqueous solution. The holding time at freezing temperature is preferably 30 minutes or more, more preferably 1 hour or more. The upper limit of the holding time at freezing temperature is not particularly limited, but is, for example, 24 hours.
The melting temperature of the aqueous solution is preferably 5°C or higher, more preferably 10°C or higher, from the viewpoint of ease of physical crosslinking.
After thawing, it is preferred to maintain the aqueous solution at the melting temperature before freezing it in the next freeze-thaw cycle or adjusting the water content of the hydrogel. The holding time at the melting temperature is preferably 30 minutes or more, more preferably 1 hour or more. The upper limit of the holding time at the melting temperature is not particularly limited, but is, for example, 24 hours.

After performing the first freeze-thaw treatment, the hydrogel is dried to reduce the water content of the hydrogel to 75% by mass or less. The water content may be adjusted by first drying the hydrogel to a large extent (for example, to a water content of 10% by mass or less) and then humidifying it. By setting the water content to 75% by mass or less, the onset temperature on the low temperature side of the absorption peak in differential scanning calorimetry becomes -5° C. or less, as shown in the second embodiment described below. This results in a highly transparent hydrogel with less elution.
The water content of the hydrogel is more preferably 60% by mass or less, and even more preferably 50% by mass or less. The lower limit of the water content is preferably 10% by mass or more, particularly preferably 20% by mass or more, and particularly preferably 30% by mass or more.

Water content is the ratio of the mass of water to the mass of the hydrogel. The water content is calculated by the following formula from the mass of the hydrogel and the mass after drying the hydrogel at 140° C. for 1 hour (mass after drying).
Water content (mass%) = (mass of hydrogel - mass after drying) / mass of hydrogel x 100

After adjusting the moisture content, a second freeze-thaw process is performed. The conditions for the second-stage freeze-thaw treatment may be the same as those for the first-stage freeze-thaw treatment described above.

A film-like freeze-thaw hydrogel is obtained by forming a coating film of an aqueous PVOH solution on a base material, performing the first freeze-thaw treatment, adjusting the water content, and performing the second freeze-thaw treatment. Can be done. The freeze-thaw hydrogel peeled from the base material may be further processed, such as cutting.
By pouring an aqueous solution of PVOH into a mold with an arbitrary shape and performing the above-mentioned first freeze-thaw treatment, adjustment of the water content, and second freeze-thaw treatment, a freeze-thaw hydrogel with a shape corresponding to the mold is created. can be obtained. The freeze-thaw hydrogel removed from the mold may be further processed, such as cutting.

<Effect>
The freeze-thaw hydrogel of the first embodiment has excellent sustained drug release properties.
In the freeze-thaw hydrogel of the first embodiment, PVOH is physically crosslinked, and thus uncrosslinked low molecules are less likely to remain, making it highly safe compared to hydrogels in which PVOH is chemically crosslinked. Furthermore, since PVOH is modified, the content of vinyl alcohol units is lower and the crosslinking density is lower than when PVOH is not modified. Therefore, the drug easily diffuses through the hydrogel, and not only the drug present near the surface of the freeze-thaw hydrogel but also the drug present inside the freeze-thaw hydrogel is eluted, so that the elution of the drug continues for a long time.

The freeze-thaw hydrogel of the first embodiment can be used to treat ophthalmological diseases. When the freeze-thaw hydrogel of the first embodiment is brought into contact with the cornea or conjunctiva, the drug gradually dissolves into the tear fluid from the freeze-thaw hydrogel.
Non-limiting examples of ophthalmological diseases include infections of the eye (including skin, eyelids, conjunctiva or lacrimal drainage system), orbital cellulitis, dacryoadenitis, stye, blepharitis, conjunctivitis, keratitis, corneal infiltrates, Ulcer, endophthalmitis, panophthalmitis, viral keratitis, fungal keratitis ocular herpes zoster, viral conjunctivitis, viral retinitis, uveitis, strabismus, retinal necrosis, scleritis, mucorbacterium infections, dacryotinitis, Acanthamoeba keratitis, toxoplasmosis, giardiasis, leishmaniasis, malaria, helminth infections, and glaucoma.

The freeze-thaw hydrogel of the first embodiment can be used as an ophthalmic medical device, specifically a contact lens, a punctal plug, an intraocular lens, an intraocular ring, and the like.
Since the freeze-thaw hydrogel of the first embodiment has excellent sustained drug release properties, the ophthalmic medical device including the freeze-thaw hydrogel of the first embodiment also has excellent sustained drug release properties.

≪Second embodiment≫
The freeze-thaw hydrogel according to the second embodiment of the present invention contains PVOH.
PVOH is a polymer containing vinyl alcohol units, and is typically a saponified product of a polymer containing vinyl ester monomer units. PVOH may be a polymer containing vinyl ester monomer units.
PVOH may be unmodified PVOH or modified PVOH. Modified PVOH is preferred in terms of sustained drug release.

<Undenatured PVOH>
Unmodified PVOH is PVOH that does not contain any other monomer units other than vinyl alcohol units and vinyl ester monomer units. Unmodified PVOH consists only of vinyl alcohol units, or consists of vinyl alcohol units and vinyl ester monomer units.
Unmodified PVOH can usually be produced by polymerizing a vinyl ester monomer and then saponifying it.

Examples of the vinyl ester monomers include vinyl formate, vinyl acetate, vinyl propionate, vinyl valerate, vinyl butyrate, vinyl isobutyrate, vinyl pivalate, vinyl caprate, vinyl laurate, vinyl stearate, and vinyl versatate. , aliphatic vinyl esters such as vinyl trifluoroacetate, and aromatic vinyl esters such as vinyl benzoate. Among these, aliphatic vinyl esters having 3 to 20 carbon atoms, more preferably 4 to 10 carbon atoms, particularly preferably 4 to 7 carbon atoms are preferred, and vinyl acetate is particularly preferred. These are usually used alone, but multiple types may be used simultaneously if necessary.

The vinyl ester monomer can be polymerized by any known polymerization method, such as solution polymerization, suspension polymerization, emulsion polymerization, etc. Among these, it is preferable to carry out solution polymerization under reflux because it can efficiently remove the heat of reaction. As a solvent for solution polymerization, alcohol is usually used, preferably a lower alcohol having 1 to 3 carbon atoms.

Regarding the saponification of the obtained polymer, conventionally known saponification methods can be employed. That is, it can be carried out using an alkali catalyst or an acid catalyst in a state in which the polymer is dissolved in alcohol or a water/alcohol solvent.
As the alkali catalyst, for example, alkali metal hydroxides or alcoholates such as potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate, potassium methylate, and lithium methylate can be used.

Usually, a transesterification reaction using an alkali catalyst in an anhydrous alcohol solvent is preferably used from the viewpoint of reaction rate and the ability to reduce impurities such as fatty acid salts. The reaction temperature of the saponification reaction is usually 20 to 60°C. If the reaction temperature is too low, the reaction rate tends to be low and the reaction efficiency is reduced; if it is too high, the temperature may exceed the boiling point of the reaction solvent, which tends to reduce safety in production. In addition, when saponifying under high pressure using a column-type continuous saponification tower with high pressure resistance, it is possible to saponify at a higher temperature, for example, 80 to 150°C, and a small amount of saponification catalyst is used. It is also possible to obtain a product with a high degree of saponification in a short period of time.

Furthermore, after saponification, it is preferable to wash the obtained unmodified PVOH with a washing liquid. Examples of such a cleaning liquid include alcohols such as methanol, ethanol, isopropyl alcohol, butanol, and methanol is preferred from the viewpoint of cleaning efficiency and drying efficiency.

The washed unmodified PVOH is dried with hot air or the like in a continuous or batch manner. The drying temperature is usually 50 to 150°C. If the drying temperature is too high, unmodified PVOH tends to be thermally degraded, and if the drying temperature is too low, drying tends to take a long time. Drying time is typically 1 to 48 hours. If the drying time is too long, the unmodified PVOH tends to be thermally degraded, and if the drying time is too short, the drying tends to be insufficient or high temperature drying is required. The content of the solvent contained in the unmodified PVOH after drying is usually 0 to 10% by weight, particularly preferably 0.1 to 5% by weight, and even more preferably 0.1 to 1% by weight.

The average saponification degree of unmodified PVOH is preferably 95 mol% or more, more preferably 96 mol% or more, even more preferably 97 mol% or more, and may be 100 mol%. . If the average degree of saponification is equal to or higher than the lower limit, gelation tends to occur easily and the gel elution rate tends to be reduced.
The average degree of saponification is measured according to 3.5 of JIS K 6726:1994.
Note that the average saponification degree of PVOH does not change before and after forming the freeze-thaw hydrogel. By redissolving the freeze-thawed hydrogel, the average degree of saponification of PVOH can be measured.

The average degree of polymerization of unmodified PVOH can generally be expressed by the viscosity of an aqueous solution.
The viscosity of a 4% by mass aqueous solution of unmodified PVOH at 20° C. is preferably 5 to 100 mPa·s, more preferably 13 to 70 mPa·s, and even more preferably 17 to 40 mPa·s. If the viscosity is above the above lower limit, gelation tends to occur easily and the dissolution rate of the gel can be reduced. On the other hand, if the viscosity is below the above upper limit, the PVOH aqueous solution is easier to handle and the release of the drug is improved. It tends to be better.
The viscosity is measured according to 3.11.2 of JIS K 6726:1994.
Note that the average degree of polymerization of PVOH does not change before and after forming the freeze-thaw hydrogel. By redissolving the freeze-thaw hydrogel, the average degree of polymerization of PVOH can be measured.

<Modified PVOH>
Examples of the modified PVOH include those similar to the modified PVOH mentioned in the first embodiment.

<Drug>
The freeze-thaw hydrogel of the second embodiment preferably contains a drug.
Examples of the drug include the same drugs as those mentioned in the first embodiment.

The freeze-thaw hydrogel may further contain other components other than PVOH and the drug, if necessary, to the extent that the effects of the present invention are not significantly impaired.
For example, when the freeze-thaw hydrogel is used to treat an ophthalmological disease, it may contain known components other than drugs in formulations for ophthalmological diseases (eye drops, etc.).
For example, when a freeze-thaw hydrogel is used for a contact lens, it can contain known ingredients (antioxidants, stabilizers, preservatives, osmotic pressure regulators, etc.) as compounded ingredients other than drugs in the contact lens. .
The other components may be used alone or in combination of two or more.

In the freeze-thaw hydrogel, the content of PVOH is preferably 5 to 60% by mass, more preferably 10 to 50% by mass, based on the total mass of the freeze-thaw hydrogel. If the content of PVOH is at least the lower limit, the strength of the lens tends to be better. If the content of PVOH is below the upper limit, oxygen permeability tends to be better.

In the freeze-thaw hydrogel, the content of the drug is determined by taking into consideration the dosage, release amount, etc. of the drug.
The content of the drug is not particularly limited, but can be set, for example, in the range of 0.1 to 20% by mass based on the total mass of the freeze-thaw hydrogel. Further, it can be set in a range of 0.2 to 80% by mass based on PVOH.

The saturated moisture content of the freeze-thaw hydrogel is preferably 50 to 90% by mass, more preferably 60 to 88% by mass, and even more preferably 60 to 80% by mass. When the saturated moisture content is equal to or higher than the lower limit, oxygen permeability tends to be better. If the saturated moisture content is below the upper limit, the gel strength tends to be better.
The saturated moisture content of the freeze-thaw hydrogel is the water content of the freeze-thaw hydrogel immersed in purified water at 37° C. for 24 hours. The saturated moisture content is measured by the dry weight method and calculated using the following formula. The freeze-thaw hydrogel is dried at 140° C. for 1 hour.
Saturated moisture content = {(mass after immersion) - (mass after drying)}/(mass after immersion) x 100

The compressive modulus of the freeze-thaw hydrogel at 37° C. is preferably 0.1 to 500 kPa, more preferably 1 to 400 kPa, and even more preferably 3 to 300 kPa. If the compressive elastic modulus is equal to or higher than the lower limit value, the wearing feeling tends to be better. If the compressive elastic modulus is below the upper limit, the wearing comfort tends to be better.
Compressive modulus is measured by thermomechanical analysis (TMA method).
The compressive elastic modulus of the freeze-thaw hydrogel can be adjusted by the number of repetitions of the freeze-thaw cycle, the degree of saponification of PVOH, the degree of polymerization, etc., which will be described later. For example, as the number of repeated freeze-thaw cycles increases, the compressive modulus tends to increase.

Sustained release test:
The frozen and thawed hydrogel was placed in a 24-well cell culture plate, 1000 μL of phosphate buffered saline (hereinafter also referred to as "PBS") was added, and after standing at 37°C for 15 minutes, the entire amount of the PBS was collected. Next, 1000 μL of new PBS was added, and after standing at 37°C for 15 minutes (30 minutes in total), the entire amount of the PBS was collected. After standing for a minute (1 hour in total), the entire amount of the PBS is collected. Repeat this, and use the PBS collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after the first addition of PBS as a measurement sample to determine the elution amount of the drug, Calculate the cumulative elution percentage at each time.
Here, the "cumulative elution ratio" is the mass percentage of the "total amount of drugs eluted by each time" relative to the "drug content of the freeze-thaw hydrogel." The elution amount of the drug can be determined by measuring the absorbance corresponding to the drug using HPLC or a spectrophotometer.

<Method for producing freeze-thaw hydrogel>
The method for producing the freeze-thaw hydrogel of the second embodiment includes, for example, converting an aqueous solution of PVOH into a hydrogel by a first-stage freeze-thaw treatment, and then reducing the water content of the hydrogel to 75% or less, and then performing a second-stage freeze-thaw treatment. Examples include a method of performing freeze-thaw treatment.

The aqueous solution of PVOH contains PVOH and water. The aqueous solution of PVOH may contain a drug. The aqueous solution of PVOH may further contain other components other than PVOH, water and the drug.
Aqueous solutions of PVOH can be prepared by mixing water and PVOH, optionally drugs and other ingredients.
The content of PVOH in the aqueous solution is preferably 5 to 30% by mass, more preferably 10 to 20% by mass, based on the total mass of the aqueous solution. If the content of PVOH is at least the lower limit, the resulting gel tends to have better gel strength. If the content of PVOH is below the upper limit, the resulting gel tends to have better oxygen permeability.
The content of water in the aqueous solution is preferably 60 to 95% by mass, more preferably 70 to 90% by mass, based on the total mass of the aqueous solution.

After performing the first freeze-thaw treatment, the hydrogel is dried to reduce the water content of the hydrogel to 75% by mass or less. The water content may be adjusted by first drying the hydrogel to a large extent (for example, to a water content of 10% by mass or less) and then humidifying it. When the water content exceeds 75% by mass, the onset temperature on the low-temperature side of the absorption peak of the melting point of water in the hydrogel in differential scanning calorimetry does not fall below -5°C, resulting in a large amount of elution and decreased transparency. It becomes a hydrogel.
The water content of the hydrogel is more preferably 60% by mass or less, and even more preferably 50% by mass or less. The lower limit of the water content is preferably 10% by mass or more, particularly preferably 20% by mass or more, and particularly preferably 30% by mass or more.
Water content is the ratio of the mass of water to the mass of the hydrogel. The water content is calculated by the following formula from the mass of the hydrogel and the mass after drying the hydrogel at 140° C. for 1 hour (mass after drying).
Water content (mass%) = (mass of hydrogel - mass after drying) / mass of hydrogel x 100

After adjusting the water content, a second freeze-thaw treatment is performed to obtain the freeze-thaw hydrogel of the second embodiment. The conditions for the second-stage freeze-thaw treatment may be the same as those for the first-stage freeze-thaw treatment described above.

A film-like freeze-thaw hydrogel is obtained by forming a coating film of an aqueous solution of PVOH on a base material, performing the first freeze-thaw treatment, adjusting the water content, and performing the second freeze-thaw treatment. Can be done. The freeze-thaw hydrogel peeled from the base material may be further processed, such as cutting.
By pouring an aqueous solution of PVOH into a mold with an arbitrary shape, and performing the first freeze-thaw treatment, adjustment of water content, and second freeze-thaw treatment, a freeze-thaw hydrogel with a shape corresponding to the mold is created. can be obtained. The freeze-thaw hydrogel removed from the mold may be further processed, such as cutting.

<DSC onset temperature>
The freeze-thaw hydrogel of the second embodiment has a temperature range of 0°C or less in differential scanning calorimetry (hereinafter also referred to as "DSC") under the conditions of -50°C to 150°C and a heating rate of 10°C/min. The onset temperature of the observed endothermic peak (hereinafter also referred to as "DSC onset temperature") is -5°C or lower.
The DSC onset temperature is the temperature at which ice melts, and can also be called the melting point of water in the freeze-thaw hydrogel.
When the DSC onset temperature is −5° C. or lower, a freeze-thaw hydrogel with little elution and excellent transparency can be obtained. The DSC onset temperature is more preferably -7°C or lower, particularly preferably -8°C or lower. The lower limit of the DSC onset temperature is usually -20°C or higher.

Details of the method for measuring DSC onset temperature are shown below.
After immersing the hydrogel in water at 30° C. for 1 hour, about 5 mg of the hydrogel is cut out and used as a measurement sample, and the sample is sealed in a high-pressure pan for measurement. Endothermic peak when the measurement sample was held at -50°C in a holder for 1 minute and then heated from -50°C to 150°C at 10°C/min using a METTLER TOLEDO differential scanning calorimeter. Measure. There is an endothermic peak of water in the hydrogel below 0°C, and the temperature at the intersection of the tangent at the inflection point on the low temperature side (melting start side) of that endothermic peak and the extension of the baseline is the DSC onset temperature. .

Although it is not clear why a DSC onset temperature of -5°C or lower results in a hydrogel with less elution and excellent transparency, it is clear that when the crystallization of polyvinyl alcohol progresses through freezing and thawing, the crystals form more densely and uniformly. It is assumed that this is because it is generated.
As the area occupied by water clusters in the hydrogel becomes smaller, the surface free energy decreases and the melting temperature decreases, causing the onset temperature to shift toward lower temperatures. While some polyvinyl alcohol crystals have formed due to the freeze-thaw treatment, by adjusting the water content and performing the freeze-thaw treatment again, the polyvinyl alcohol crystals are formed while the water in the hydrogel is neatly dispersed. Uniform and dense formation results in a lower onset temperature, less elution, and a highly transparent hydrogel.

If the hydrogel contains modified PVOH, crystallization of PVOH will be more uniformly produced, so it is preferable that the hydrogel contains modified PVOH.
The amount of modification of the modified PVOH in the second embodiment is preferably 10 mol% or less, more preferably 5 mol% or less, further preferably 3 mol% or less, and even more preferably 1.5 mol% or less, in terms of reducing the amount of elution. Particularly preferred. The preferable lower limit of the amount of modification is the same as above. These upper limit values and lower limit values can be combined as appropriate.
The freeze-thaw hydrogel of the second embodiment preferably has a light transmittance of 80% or more at a wavelength of 600 nm, more preferably 90% or more, and most preferably 95% or more. The upper limit of the light transmittance at a wavelength of 600 nm is usually 100% or less.
Further, the freeze-thaw hydrogel of the second embodiment preferably has a haze value of 30% or less, more preferably 20% or less, and most preferably 15% or less. The lower limit of the haze value is usually 1% or more.

<Effect>
The freeze-thaw hydrogel of the second embodiment has little elution and excellent transparency.
In the freeze-thaw hydrogel of the second embodiment, the crystallization of polyvinyl alcohol progresses densely and uniformly through the freeze-thaw process, so there is little elution and it has excellent transparency, so when used as a medical contact lens, it can be Visibility is secured without any problems, making it an excellent hydrogel for use in contact lenses.

When the freeze-thaw hydrogel of the second embodiment contains a drug, the freeze-thaw hydrogel can be used, for example, to treat ophthalmological diseases. When the freeze-thaw hydrogel of the second embodiment is brought into contact with the cornea or conjunctiva, the drug gradually dissolves into the tear fluid from the freeze-thaw hydrogel.
Non-limiting examples of ophthalmological diseases include infections of the eye (including skin, eyelids, conjunctiva or lacrimal drainage system), orbital cellulitis, dacryoadenitis, stye, blepharitis, conjunctivitis, keratitis, corneal infiltrates, Ulcer, endophthalmitis, panophthalmitis, viral keratitis, fungal keratitis ocular herpes zoster, viral conjunctivitis, viral retinitis, uveitis, strabismus, retinal necrosis, scleritis, mucorbacterium infections, dacryotinitis, Acanthamoeba keratitis, toxoplasmosis, giardiasis, leishmaniasis, malaria, helminth infections, and glaucoma.

The freeze-thaw hydrogel of the second embodiment can be used as an ophthalmic medical device, specifically a contact lens, a punctal plug, an intraocular lens, an intraocular ring, and the like.
Since the freeze-thaw hydrogel of the second embodiment has less elution and excellent transparency, the ophthalmological medical device containing the freeze-thaw hydrogel of the second embodiment also has less elution and excellent transparency.

〔contact lens〕
The contact lens of the present invention includes the freeze-thaw hydrogel of the first embodiment or the second embodiment.
The contact lens of the present invention may consist only of the freeze-thaw hydrogel of the first embodiment or the second embodiment, or may consist of the freeze-thaw hydrogel of the first embodiment or the second embodiment and other lens materials. It may consist of.
When the freeze-thaw hydrogel is opaque or translucent, it is preferable that the region through which the optical axis of the contact lens passes is made of another lens material.

As other lens materials, for example, lens materials known in the field of contact lenses can be used. Other lens materials may be hydrogels.
Non-limiting examples of other lens materials include Polymacon, Ocufilcon D, Etafilcom, Omafilcon A, Nelfilcon, Hilafilcom B, Lotrafilcon B, Senofilcon A, Galyfilcon A, Net rafilcon A, Lidofilcon B, Bufilcon A, Deltafilcon A, Phemfilcon , Hioxifilcon A, Perfilcon A, Methafilcon A, and the like.

Examples of forms of contact lenses made of freeze-thaw hydrogel and other lens materials include (1) a form in which freeze-thaw hydrogel is embedded in a lens-shaped other lens material, and (2) a lens-shaped other lens material. and (3) a form in which freeze-thaw hydrogel is layered on another lens-shaped lens material.

In the form (1) above, the number of freeze-thaw hydrogels embedded in the other lens material may be one or more. A portion of the freeze-thaw hydrogel may be exposed on the surface of the contact lens (for example, the surface that contacts the cornea or conjunctiva).
The freeze-thaw hydrogel is preferably placed in a region other than the region through which the optical axis of the contact lens passes. In this case, the shape of the freeze-thaw hydrogel may be annular, semicircular, crescent, arch, etc.
Since the freeze-thaw hydrogel of the second embodiment has excellent transparency, it may be placed in a region through which the optical axis of a contact lens passes.

Contact lenses made of freeze-thaw hydrogel and other lens materials can be manufactured with reference to known methods (for example, the method described in Japanese Patent Publication No. 2012-511395). For example, by placing the freeze-thaw hydrogel of the present invention in a contact lens mold, injecting a liquid lens material precursor, and curing the injected lens material precursor, a contact lens of the form (1) above can be formed. We can manufacture lenses.

The contact lens of the present invention can be housed in a container to form a contact lens product. As the container, containers similar to known contact lens containers can be used.
The container may contain an aqueous solution of the drug along with the contact lens. The aqueous solution of the drug may contain an antioxidant, a stabilizer, a preservative, an osmotic pressure regulator, and the like, if necessary.

The contact lens of the present invention can be used, for example, to treat ophthalmological diseases. The ophthalmological diseases include those mentioned above.

Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited by the Examples in any way. "Part" indicates "part by mass."

[Manufacture of PVOH]
<Manufacture example 1>
Modified PVOH (hereinafter also referred to as "PVOH1") having a quaternary ammonium base as a cationic group was produced by the following procedure.
A reaction vessel equipped with a reflux condenser, a dropping funnel, and a stirrer was charged with 20 parts of methanol, 100 parts of vinyl acetate, and 0.7 parts of a 65% by mass aqueous solution of diallyldimethylammonium chloride. Using acetyl peroxide as an initiator, nitrogen was added. The mixture was heated to reflux under a stream of air to initiate polymerization. Immediately after the start of polymerization, 2.7 parts of a 65% by mass aqueous solution of diallyldimethylammonium chloride was added dropwise over 5 hours, and when the polymerization rate reached 71%, m-dinitrobenzene was added as a polymerization inhibitor to terminate the polymerization. . Subsequently, unreacted monomers were removed from the system by blowing methanol vapor to obtain a methanol solution of the copolymer.
Next, the obtained methanol solution was diluted with methanol to adjust the solid content concentration to 32% by mass, and the mixture was charged into a kneader, and while maintaining the solution temperature at 35°C, the methanol solution of sodium hydroxide was added to the copolymer. Saponification was carried out by adding sodium hydroxide at a ratio of 20 mmol to 1 mole of vinyl acetate units. The generated solid was filtered, thoroughly washed with methanol, and dried in a hot air drier to obtain the target product, PVOH1. The average degree of saponification of the obtained PVOH1 was 99.4 mol%, the viscosity of a 4% by mass aqueous solution was 25.9 mPa·s, and the amount of quaternary ammonium modification was 1 mol%.

<Manufacture example 2>
Modified PVOH (hereinafter also referred to as "PVOH2") having a maleic acid group, which is an anionic group, was produced by the following procedure.
A reaction vessel equipped with a reflux condenser, a dropping funnel, and a stirrer was charged with 26 parts of methanol, 100 parts of vinyl acetate, and 0.1 part of monomethyl maleate, and the temperature was raised to 60°C under a nitrogen stream while stirring. As a polymerization catalyst, 0.001 mol% (based on the total amount of vinyl acetate) of t-butyl peroxyneodecanoate (temperature at which the half-life is 1 hour is 65°C) was added to initiate polymerization. Immediately after the start of polymerization, 2.2 parts of monomethyl maleate (2 mol % based on the total amount of vinyl acetate) and 0.008 mol % (based on the total amount of vinyl acetate) of t-butyl peroxyneodecanoate were adjusted to the polymerization rate. When the polymerization rate of vinyl acetate reached 73%, 0.01 part of 4-methoxyphenol and 58 parts of methanol for dilution and cooling were added to terminate the polymerization. The amount of active catalyst remaining at the end of the polymerization was 2 ppm based on the total amount of the reaction solution. Subsequently, unreacted vinyl acetate monomer was removed from the system by blowing methanol vapor to obtain a methanol solution of the copolymer.
Next, the obtained methanol solution was diluted with methanol to adjust the solid content concentration to 40% by mass, and a 4% by mass methanol solution of sodium hydroxide was added to 1 mole of vinyl acetate units in the copolymer with sodium hydroxide. were mixed at a ratio of 30 mmol, and a saponification reaction was carried out at a temperature of 40 to 50° C. for 25 minutes. The resin solidified by the saponification reaction was cut to obtain the target product, PVOH2. The average degree of saponification of the obtained PVOH2 was 99 mol%, the viscosity of a 4% by mass aqueous solution was 29 mPa·s, and the amount of modification with maleic acid was 2.1 mol%.

<Manufacture example 3>
Modified PVOH (hereinafter also referred to as "PVOH3") having an acetoacetyl group, which is a nonionic group, was produced by the following procedure.
100 parts of vinyl acetate and 33 parts of methanol were placed in a reaction vessel equipped with a reflux condenser, a dropping device, and a stirrer, and the temperature was raised under a nitrogen stream while stirring. After reaching the boiling point, 1 part of acetyl peroxide was added. .3 parts were added to start polymerization. When the polymerization rate of vinyl acetate reaches 81%, a predetermined amount of hydroquinone monomethyl ether is added to terminate the polymerization, and unreacted vinyl acetate monomer is removed from the system by distillation while blowing methanol vapor. This was removed to obtain a methanol solution of vinyl acetate polymer.
Next, the obtained methanol solution was diluted with methanol to adjust the solid content concentration to 47% by mass, and the mixture was charged into a kneader, and while maintaining the solution temperature at 35°C, the methanol solution of sodium hydroxide was added to the copolymer. Saponification was carried out by adding sodium hydroxide at a ratio of 7 mmol to 1 mol of vinyl acetate units. As saponification progresses, the saponified product precipitates, and when it becomes particulate, it is filtered, washed thoroughly with methanol, and dried in a hot air dryer to obtain a 4% by mass aqueous solution with an average saponification degree of 98.0 mol%. Unmodified PVOH with a viscosity of 28 mPa·s was obtained.
100 parts of the obtained unmodified PVOH was placed in a kneader, 30 parts of acetic acid was added thereto to swell it, the temperature was raised to 60°C while stirring at a rotational speed of 20 rpm, and 5 parts of diketene was added dropwise over 5 hours. The reaction was further continued for 1 hour. After the reaction was completed, the product was washed with methanol and then dried at 70°C for 12 hours to obtain the target product, PVOH3. The average degree of saponification of the obtained PVOH3 was 98.6 mol%, the viscosity of a 4% by mass aqueous solution was 27.5 mPa·s, and the amount of acetoacetyl group modification was 2.1 mol%.

<Manufacture example 4>
Unmodified PVOH (hereinafter also referred to as "PVOH4") was produced according to the following procedure.
100 parts of vinyl acetate and 33 parts of methanol were placed in a reaction vessel equipped with a reflux condenser, a dropping device, and a stirrer, and the temperature was raised under a nitrogen stream while stirring. After reaching the boiling point, 1 part of acetyl peroxide was added. .3 parts were added to start polymerization. When the polymerization rate of vinyl acetate reaches 81%, a predetermined amount of hydroquinone monomethyl ether is added to terminate the polymerization, and unreacted vinyl acetate monomer is removed from the system by distillation while blowing methanol vapor. This was removed to obtain a methanol solution of vinyl acetate polymer.
Next, the obtained methanol solution was diluted with methanol, the solid content concentration was adjusted to 47% by mass, and the mixture was charged into a kneader.While maintaining the solution temperature at 35°C, the methanol solution of sodium hydroxide was added to the copolymer. Saponification was carried out by adding sodium hydroxide at a ratio of 7 mmol to 1 mol of vinyl acetate units. As the saponification progressed, the saponified product precipitated, and when it became particulate, it was filtered out, thoroughly washed with methanol, and dried in a hot air drier to obtain the target product, PVOH4. The average degree of saponification of the obtained PVOH4 was 98.5 mol%, and the viscosity of the 4% by mass aqueous solution was 27 mPa·s.

[Examples A1 to A3, Example A5]
<Manufacture of drug-containing hydrogel contact lenses>
The PVOH shown in Table 1 was added to purified water with stirring, heated to 90° C., and stirred for 1 hour to completely dissolve. After slowly cooling to room temperature while stirring, purified water was added to adjust the PVOH concentration to 15% by mass, and the mixture was sterilized in an autoclave at 120° C. for 30 minutes. After cooling to room temperature, 0.8% by mass of nucleic acid as a model drug was mixed with the PVOH aqueous solution based on PVOH to obtain a drug-containing PVOH solution. The nucleic acid is a Malat1 antisense oligonucleotide represented by CdsTdsAdsGdsTdsTdsCdsAdsCdsTdsGdsAdsAdsAdsTdsGdsCd (in the formula, each nucleobase is represented by A=adenine, T=thymine, G=guanine, C=cytosine, and each sugar moiety is d=2 '-deoxyribose, and each internucleoside bond is represented by s=phosphorothioate).
The obtained drug-containing PVOH solution was transferred to DIA 11 mm, B. C. (Base Curve) 6.5 Injected into a contact lens mold, sandwiched between male and female molds, frozen at -20℃ for 4 hours, and melted at 20℃ for 2 hours, repeated 5 times to form a contact lens-shaped drug. A containing hydrogel was created. After removing the female contact lens mold and drying the hydrogel on the male mold in an oven at 40°C for 1 hour, it was allowed to absorb moisture in a constant temperature and humidity oven at 60°C and 100% RH, until the water content of the hydrogel was 75% by mass. After making the following adjustments, the hydrogel was placed between contact lens molds again, and the process of freezing at -20°C for 4 hours and melting at 20°C for 2 hours was repeated 5 times to form a drug-containing hydrogel contact lens. Obtained.
The obtained drug-containing hydrogel contact lens was placed in a container with 1 mL of phosphate buffered saline (PBS) (approximately 150 times the dry mass of the contact lens) as a storage solution, and the container was heated to prevent PBS from leaking. The container was sealed, immediately cooled to -20°C at a cooling rate of -1°C/min or higher, and stored in a freezer at -20°C for 72 hours. After storage, the container was taken out of the freezer and warmed to room temperature for 10 minutes to obtain a saturated, water-containing, drug-containing hydrogel contact lens for evaluation.

<Measurement method of saturated moisture content>
The mass (mass after immersion) of the drug-containing hydrogel contact lens with saturated water content was measured. Next, the drug-containing hydrogel contact lens was dried at 140° C. for 1 hour, and then its mass (mass after drying) was measured. From the measurement results, the saturated moisture content was calculated using the following formula. The results are shown in Table 1.
Saturated moisture content = {(mass after immersion) - (mass after drying)}/(mass after immersion) x 100

<Method of measuring compressive elastic modulus>
The compressive elastic modulus of the drug-containing hydrogel contact lens containing saturated water was measured by penetration measurement using a thermomechanical analyzer (TMA method). Specifically, after a drug-containing hydrogel contact lens was immersed in water to bring it to a saturated hydrated state, a probe with a diameter of 1 mm and ^a cross-sectional area of 0.785 mm was inserted into an aluminum pan containing water and a sample. A load of 10 mN was held for 30 minutes until the sample temperature stabilized at 37°C, and then a load of 5 mN/min was applied to 300 mN at 37°C to calculate a stress-strain curve and measure the compressive elastic modulus. The results are shown in Table 1.

<Sustained release test>
A drug-containing hydrogel contact lens saturated with water was placed in a 24-well cell culture plate, 1000 μL of phosphate buffered saline (PBS) was added, and after standing at 37° C. for 15 minutes, the entire amount of PBS was collected. Next, 1000 μL of PBS was newly added, and after standing at 37° C. for 15 minutes (30 minutes in total), the entire amount of PBS was collected. Next, 1000 μL of PBS was newly added, and after standing at 37° C. for 30 minutes (1 hour in total), the entire amount of PBS was collected. After that, addition of new PBS, standing at 37° C. for 30 minutes, and collection of the entire amount of PBS were repeated. PBS collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after the initial addition of PBS was used as a measurement sample, and was analyzed by HPLC [manufactured by Agilent Technologies] with 0. Apply a gradient with a 1M triethyleneamine aqueous solution and a 50% acetonitrile/aqueous solution of 0.1M triethylamine, measure the absorbance at a wavelength of 260 nm, determine the nucleic acid concentration using a calibration curve prepared in advance, and calculate the cumulative elution rate at each time. was calculated. The results are shown in Table 1 and Figure 1.

[Example A4]
In Example A2, the low molecular weight cationic drug ripasudil hydrochloride dihydrate (4-Fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline monohydrochloride dihydrate) was used as a model drug. ) was used in the same manner as in Example A2 to obtain a saturated hydrated drug-containing hydrogel contact lens for evaluation, and the saturated moisture content and compressive elastic modulus were evaluated. In addition, sustained release test 2 below was conducted. The results are shown in Table 1 and Figure 1.

<Sustained release test 2>
A drug-containing hydrogel contact lens saturated with water was placed in a 24-well cell culture plate, 1000 μL of phosphate buffered saline (PBS) was added, and after standing at 37° C. for 15 minutes, the entire amount of PBS was collected. Next, 1000 μL of PBS was newly added, and after standing at 37° C. for 15 minutes (30 minutes in total), the entire amount of PBS was collected. Next, 1000 μL of PBS was newly added, and after standing at 37° C. for 30 minutes (1 hour in total), the entire amount of PBS was collected. After that, addition of new PBS, standing at 37° C. for 30 minutes, and collection of the entire amount of PBS were repeated. PBS collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after the initial addition of PBS was used as the measurement sample, and a spectrophotometer [Spectrophotometer manufactured by Jusco Engineering Co., Ltd.] was used. Absorbance at a wavelength of 279 nm was measured using a JASCO V-750], the drug concentration was determined using a calibration curve prepared in advance, and the cumulative elution rate at each time was calculated.

In the drug-containing hydrogel contact lens of Example A5 using unmodified PVOH, the elution of the drug stopped after about 30 minutes, and the elution rate was also low, resulting in poor sustained release properties. This is thought to be because the crosslinking density of the hydrogel is high, and the drug present near the surface of the hydrogel is eluted at once, but the drug inside the hydrogel is not eluted.
On the other hand, the drug-containing hydrogel contact lenses of Examples A1 to A4 using modified PVOH tended to have a high elution rate, and the drug was gradually eluted even after 1 hour, showing excellent sustained release properties. It was confirmed that there is. This is thought to be because the crosslinking density of the hydrogel was controlled by the denaturation, and the drug was eluted not only from near the surface of the hydrogel but also from within.
In particular, the drug-containing hydrogel contact lenses of Example A1, which is a combination of PVOH1 having a cationic group and a nucleic acid, and Example A4, which is a combination of PVOH2 having an anionic group and ripasudil, have slower elution and excellent sustained release properties. was. Specifically, although the absolute amount of initial elution was small, the drug continued to elute after 4 hours. Furthermore, from FIG. 1, it was predicted that elution would continue even after 24 hours. This is thought to be because the hydrogel using PVOH1, which has a cationic group, has a high affinity with anionic drugs, and the hydrogel using PVOH2, which has an anionic group, has a high affinity with cationic drugs. .

[Example B1, B2]
<Manufacture of drug-containing hydrogel contact lenses>
The PVOH shown in Table 2 was added to purified water with stirring, heated to 90° C., and stirred for 1 hour to completely dissolve. After slowly cooling to room temperature while stirring, purified water was added to adjust the PVOH concentration to 15% by mass, and the mixture was sterilized in an autoclave at 120° C. for 30 minutes. After cooling to room temperature, 0.8% by mass of nucleic acid as a model drug was mixed with the PVOH aqueous solution based on PVOH to obtain a drug-containing PVOH solution. The nucleic acid is a Malat1 antisense oligonucleotide represented by CdsTdsAdsGdsTdsTdsCdsAdsCdsTdsGdsAdsAdsAdsTdsGdsCd (in the formula, each nucleobase is represented by A=adenine, T=thymine, G=guanine, C=cytosine, and each sugar moiety is d=2 '-deoxyribose, and each internucleoside bond is represented by s=phosphorothioate).
The obtained drug-containing PVOH solution was transferred to DIA 11 mm, B. C. (Base Curve) 6.5 Injected into a contact lens mold, sandwiched between male and female molds, frozen at -20℃ for 2 hours, and melted at 20℃ for 1 hour, repeated 5 times to form a contact lens-shaped drug. A containing hydrogel was prepared. After removing the female contact lens mold and drying the hydrogel on the male mold in an oven at 40°C for 1 hour, it was allowed to absorb moisture in a constant temperature and humidity oven at 60°C and 100% RH, and the water content of the hydrogel is shown in Table 2. The water content was adjusted to the specified moisture content. The hydrogel was placed between contact lens molds again, and freezing at -20°C for 2 hours and thawing at 20°C for 1 hour was repeated five times to obtain a contact lens-shaped drug-containing PVOH freeze-thaw hydrogel.
The obtained drug-containing PVOH freeze-thaw hydrogel is placed in a container with 1 mL of phosphate buffered saline (PBS) (approximately 150 times the dry mass of the drug-containing PVOH freeze-thaw hydrogel) as a storage solution, The container was sealed to prevent PBS from leaking, immediately cooled to -20°C at a cooling rate of -1°C/min or higher, and stored at -20°C in a freezer for 72 hours. After storage, the container was taken out of the freezer and warmed to room temperature for 10 minutes to obtain a saturated hydrated drug-containing PVOH freeze-thaw hydrogel for evaluation.

[Example B3, B4]
The same drug-containing PVOH solution as in Examples B1 and B2 was added to DIA 11 mm, B. C. (Base curve) Inject into a contact lens mold of 6.5, sandwich between male and female molds, freeze at -20℃ for 2 hours, and thaw at 20℃ for 1 hour. Repeat the process 10 times to freeze the drug-containing PVOH in the shape of a contact lens. A melted hydrogel was obtained.
The obtained drug-containing PVOH freeze-thaw hydrogel was placed in a container with 1 mL of PBS (approximately 150 times the dry mass of the drug-containing PVOH freeze-thaw hydrogel), the container was sealed to prevent PBS from leaking, and the container was immediately poured. It was cooled to -20°C at a cooling rate of -1°C/min or higher and stored at -20°C in a freezer for 72 hours. After storage, the container was taken out of the freezer and warmed to room temperature for 10 minutes to obtain a saturated hydrated drug-containing PVOH freeze-thaw hydrogel for evaluation.

The following characteristics were evaluated using the saturated hydrated drug-containing PVOH freeze-thaw hydrogel obtained in each example as an evaluation sample.

<Saturated moisture content>
The mass of the evaluation sample (mass after immersion) was measured. Next, the evaluation sample was dried at 140° C. for 1 hour, and then its mass (mass after drying) was measured. From the measurement results, the saturated moisture content was calculated using the following formula. The results are shown in Table 2.
Saturated moisture content = {(mass after immersion) - (mass after drying)}/(mass after immersion) x 100

<DSC onset temperature>
After the evaluation sample was immersed in water at 30° C. for 1 hour, about 5 mg of the evaluation sample was cut out and used as a measurement sample, and the sample was sealed in a high-pressure pan for measurement. Endothermic peak when the measurement sample was held at -50°C in a holder for 1 minute and then heated from -50°C to 150°C at 10°C/min using a METTLER TOLEDO differential scanning calorimeter. was measured. Since there is an endothermic peak of water in the evaluation sample below 0° C., the temperature at the intersection of the baseline on the low temperature side (melting start side) of the endothermic peak and the tangent of the inflection point was defined as the DSC onset temperature. The results are shown in Table 2. Moreover, FIG. 2 shows a graph of the endothermic peak of water obtained by differential scanning calorimetry of the PVOH freeze-thaw hydrogel of Example B1.

<Elution rate>
The evaluation sample was immersed in purified water at 37° C. for 24 hours, and the elution rate was calculated from the change in mass before and after immersion using the following formula. The results are shown in Table 2.
Elution rate (%) = (mass of evaluation sample before immersion) - (mass of evaluation sample after immersion) / (mass of evaluation sample before immersion) x 100

<Light transmittance>
The evaluation sample was sandwiched between glass plates to a thickness of 1 mm, and the light transmittance at 600 nm was measured using an ultraviolet-visible near-infrared spectrophotometer (model: V-7200) manufactured by JASCO Corporation. Note that the light transmittance was corrected using the light transmittance of the glass plate as a reference. The results are shown in Table 2.

<Haze measurement>
The evaluation sample was sandwiched between glass plates to a thickness of 1 mm, and the haze value was measured using Haza Meter NDH4000 manufactured by Nippon Denshoku Industries Co., Ltd. Note that the haze value was corrected using the haze value of the glass plate as a reference. The results are shown in Table 2.

The PVOH freeze-thaw hydrogels of Examples B1 and B2, in which the water content of the hydrogel was adjusted between the first freeze-thaw treatment and the second freeze-thaw treatment, had a low dissolution rate in warm water, and The light transmittance at 600 nm was high and the haze value was low, indicating that it had excellent stability and transparency in hot water.
It can be seen that Examples B3 and B4 in which the water content was not adjusted had high elution rates and insufficient transparency.
The PVOH freeze-thaw hydrogels of Examples B1 and B2 had lower DSC onset temperatures than the PVOH freeze-thaw hydrogels of Examples B3 and B4, respectively. This shows that the DSC onset temperature affects the dissolution rate and transparency.

The freeze-thaw hydrogel of the present invention can be used as ophthalmic medical devices such as contact lenses, punctal plugs, intraocular lenses, and intraocular rings.

Claims

Freeze-thaw hydrogel containing modified polyvinyl alcohol and drugs.
The freeze-thaw hydrogel according to claim 1, wherein the average degree of saponification of the modified polyvinyl alcohol is 95 mol% or more.
The freeze-thaw hydrogel according to claim 1 or 2, wherein the 4% by mass aqueous solution of the modified polyvinyl alcohol has a viscosity of 5 to 100 mPa·s at 20°C.
The freeze-thaw hydrogel according to claim 1 or 2, wherein the modified polyvinyl alcohol has at least one selected from the group consisting of cationic groups, anionic groups, and nonionic groups.
The freeze-thaw hydrogel according to claim 4, wherein the amount of modification of the modified polyvinyl alcohol is 0.1 to 30 mol%.
The freeze-thaw hydrogel according to claim 1, which has a saturated moisture content of 50 to 90% by mass.
The freeze-thaw hydrogel according to claim 1 or 6, which has a compressive modulus of elasticity at 37°C of 0.001 to 0.5 MPa.
the modified polyvinyl alcohol has a cationic group,
The freeze-thaw hydrogel according to claim 1 or 2, wherein the drug includes an anionic drug.
the modified polyvinyl alcohol has an anionic group,
The freeze-thaw hydrogel according to claim 1 or 2, wherein the drug includes a cationic drug.
The freeze-thaw hydrogel according to claim 1 or 2, wherein in the sustained release test below, the cumulative dissolution rate of the drug after 1 hour is 80% by mass or less of the cumulative dissolution rate after 24 hours.
Sustained release test:
The frozen and thawed hydrogel was placed in a 24-well cell culture plate, 1000 μL of phosphate buffered saline was added, and after standing at 37°C for 15 minutes, the entire amount of the phosphate buffered saline was collected, and then freshly After adding 1000 μL of phosphate buffered saline and allowing it to stand at 37°C for 15 minutes (30 minutes in total), the entire amount of the phosphate buffered saline was collected, and then 1000 μL of fresh phosphate buffered saline was added. After adding physiological saline and allowing it to stand at 37° C. for 30 minutes (1 hour in total), the entire amount of the phosphate buffered saline is collected. Repeat this and measure the phosphate buffered saline collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after adding the phosphate buffered saline for the first time. The elution amount of the drug is determined as a sample, and the cumulative elution rate at each time is calculated.
preparing a composition comprising water, modified polyvinyl alcohol and a drug;
A method for producing a freeze-thaw hydrogel, comprising repeating a cycle of lowering the temperature of the composition to a temperature of -5°C or lower, freezing it, and raising the temperature of the frozen composition to a temperature of 5°C or higher to melt it, twice or more.
An ophthalmological medical device comprising the freeze-thaw hydrogel according to claim 1 or 2.
A contact lens comprising the freeze-thaw hydrogel according to claim 1 or 2.
A freeze-thaw hydrogel of polyvinyl alcohol,
Freezing and thawing of polyvinyl alcohol whose onset temperature of the endothermic peak observed in the range of 0°C or lower is -5°C or lower in differential scanning calorimetry under the conditions of -50°C to 150°C and a heating rate of 10°C/min. Hydrogel.
The freeze-thaw hydrogel according to claim 14, wherein the polyvinyl alcohol is modified polyvinyl alcohol.
The freeze-thaw hydrogel according to claim 14, which contains a drug.
An ophthalmic medical device comprising the freeze-thaw hydrogel according to any one of claims 14 to 16.
A contact lens comprising the freeze-thaw hydrogel according to any one of claims 14 to 16.
After turning an aqueous solution of polyvinyl alcohol into a hydrogel through a first-stage freeze-thaw treatment, the water content of the hydrogel is reduced to 75% by mass or less, and then a second-stage freeze-thaw treatment is performed to produce a freeze-thaw hydrogel of polyvinyl alcohol. Production method.