Ophthalmic medical device and method of manufacturing the same

Abstract

To provide an ophthalmic medical device which has superior hydrophilicity, is comfortable to wear, and exhibits superior sustained releasability when loaded with a drug.SOLUTION: An ophthalmic medical device is provided, containing a cross-linked polyvinyl alcohol resin formed by crosslinking with a crosslinking group-containing polyvinyl alcohol resin having a monomer unit with an ionic group and a crosslinking group-containing structure represented by a formula (1) below.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an ophthalmic medical device and a method for manufacturing the same. [Background technology]

[0002] Contact lenses using polyvinyl alcohol having a crosslinked structure as a base material have been investigated as hydrophilic ophthalmic medical devices (Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Special Publication No. 10-513408 Summary of the Invention [Problem to be solved by the invention]

[0004] However, the contact lenses in Patent Document 1 were unable to provide sustained drug release properties, such as the ability to deliver drugs to the affected area in the eye over a long period of time by impregnating the lenses with drugs for therapeutic purposes and wearing them on the eye.

[0005] An object of the present invention is to provide an ophthalmic medical device which has excellent hydrophilicity, is comfortable to wear, and exhibits excellent sustained release of a drug when it is contained therein, and a method for producing the same. [Means for solving the problem]

[0006] The present invention has the following aspects. [1] An ophthalmic medical device containing a crosslinked polyvinyl alcohol-based resin obtained by crosslinking a crosslinking group-containing polyvinyl alcohol-based resin having a monomer unit having an ionic group and a crosslinking group-containing structure represented by the following formula (1): [ka] where R is an alkylene group, R 1is a hydrogen atom, an alkyl group, or a cycloalkyl group, R 2 is a hydrogen atom or an alkyl group, R 3 is a single bond or -C(R 5 )(R 6 )-NH-C(=O)-, R 4 is a hydrogen atom or an alkyl group, R 5 and R 6 are each independently a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group. The wavy lines indicate the bonding sites with the polyvinyl alcohol resin. [2] The ophthalmic medical device according to [1], wherein the ionic group is a cationic group. [3] The ophthalmic medical device according to [2], wherein the cationic group is a quaternary ammonium salt group. [4] The ophthalmic medical device according to any one of [1] to [3] above, wherein the degree of polymerization of the crosslinking group-containing polyvinyl alcohol resin is 1,000 or more. [5] An ophthalmic medical device according to any one of [1] to [4] above, which contains a drug. [6] The ophthalmic medical device according to [5], wherein in the sustained release test described below, the cumulative amount of the drug dissolved after 1 hour is 80% by mass or less of the cumulative amount dissolved after 24 hours. Sustained release test: The ophthalmic medical device is placed in a 24-well cell culture plate, 1000 μL of phosphate buffered saline is added, and after standing at 37° C. for 15 minutes, the entire amount of the phosphate buffered saline is collected. Next, another 1000 μL of phosphate buffered saline is added, and after standing at 37° C. for 15 minutes (a total of 30 minutes), the entire amount of the phosphate buffered saline is collected. Next, another 1000 μL of phosphate buffered saline is added, and after standing at 37° C. for 30 minutes (a total of 1 hour), the entire amount of the phosphate buffered saline is collected. This process is repeated, and the phosphate buffered saline samples collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after the initial addition of the phosphate buffered saline are used as measurement samples to determine the concentration of the drug, and the cumulative amount of elution at each time is calculated. [7] The ophthalmic medical device according to any one of [1] to [6] above, which is a contact lens. [8] A polyvinyl alcohol-based resin having a monomer unit having an ionic group is reacted with a crosslinking group-containing compound represented by the following formula (2) to obtain a crosslinking group-containing polyvinyl alcohol-based resin, preparing a composition containing the crosslinking group-containing polyvinyl alcohol-based resin, a drug, and water; The method for producing an ophthalmic medical device includes irradiating the composition with active energy rays to crosslink the crosslinking group-containing polyvinyl alcohol-based resin. [ka] wherein R' and R" are each independently a hydrogen atom, an alkyl group, or an alkanoyl group; R is an alkylene group, R 1 is a hydrogen atom, an alkyl group, or a cycloalkyl group, R 2 is a hydrogen atom or an alkyl group, R 3 is a single bond or -C(R 5 )(R 6 )-NH-C(=O)-, R 4 is a hydrogen atom or an alkyl group, R 5 and R 6 are each independently a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide an ophthalmic medical device that has excellent hydrophilicity, is comfortable to wear, and exhibits excellent sustained release properties when a drug is contained therein, and a method for producing the same. [Brief explanation of the drawings]

[0008] [Figure 1] 1 is a graph showing the results of sustained release tests for the contact lenses of Example 1 and Comparative Examples 1 and 2. DETAILED DESCRIPTION OF THE INVENTION

[0009] In this specification, polyvinyl alcohol resin is also referred to as "PVOH." In this specification, the use of "to" to indicate a range of values ​​means that the values ​​before and after it are included as the lower and upper limits.

[0010] [Ophthalmic medical devices] An ophthalmic medical device according to one embodiment of the present invention contains crosslinked PVOH obtained by crosslinking a specific crosslinking group-containing PVOH. The ophthalmic medical device may contain water. The ophthalmic medical device may contain a drug. The ophthalmic device may contain other ingredients in addition to the crosslinked PVOH, water, and drug. The crosslinking group-containing PVOH, the drug, and other ingredients are described in more detail below.

[0011] Ophthalmic medical devices typically contain a hydrogel containing crosslinked PVOH. A "hydrogel" is a structure that has a network structure formed by physically or chemically crosslinking polymer molecular chains and that swells by absorbing water into the network structure.

[0012] In the ophthalmic medical device, the content of crosslinked PVOH is preferably 5 to 70 mass %, more preferably 10 to 50 mass %, relative to the total mass of the ophthalmic medical device. When the content of crosslinked PVOH is equal to or greater than the lower limit, the strength of the ophthalmic medical device tends to be superior. When the content of crosslinked PVOH is equal to or less than the upper limit, the oxygen permeability tends to be superior.

[0013] In an ophthalmic medical device, the amount of drug contained is set in consideration of the amount of drug administered, the amount released, and the like. The content of the drug is not particularly limited, but can be set, for example, in the range of 0.01 to 5% by mass relative to the total mass of the ophthalmic medical device, or in the range of 0.1 to 10% by mass relative to the mass of the crosslinked PVOH.

[0014] When an ophthalmic medical device contains a drug, the ophthalmic medical device preferably has a cumulative elution amount of the drug after 1 hour of 90% by mass or less, more preferably 80% by mass or less, and even more preferably 70% by mass or less of the cumulative elution amount after 24 hours in the sustained release test described below. If the ratio of the cumulative elution amount after 1 hour to the cumulative elution amount after 24 hours is equal to or less than the upper limit mentioned above, the sustained release property is excellent. The ratio of the cumulative amount of elution after 1 hour to the cumulative amount of elution after 24 hours can be adjusted by adjusting the content of ionic groups in PVOH, etc.

[0015] Sustained release test: The ophthalmic medical device is placed in a 24-well cell culture plate, 1000 μL of phosphate-buffered saline (hereinafter also referred to as "PBS") is added, and after standing at 37°C for 15 minutes, the entire PBS is collected. Next, 1000 μL of new PBS is added, and after standing at 37°C for 15 minutes (30 minutes in total), the entire PBS is collected. Next, 1000 μL of new PBS is added, and after standing at 37°C for 30 minutes (1 hour in total), the entire PBS is collected. This process is repeated, and the PBS collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after the initial addition of PBS is used as a measurement sample to determine the amount of elution of the drug, and the cumulative amount of elution at each time is calculated. Here, the "cumulative elution amount" is the mass percentage of the "total amount of drug eluted up to each time point" relative to the "drug content of the ophthalmic medical device." The elution amount of 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.

[0016] The shape of the ophthalmic medical device is not particularly limited, and may be, for example, a sheet shape, a lens shape, etc. When the ophthalmic medical device is in the form of a sheet, the shape thereof in top view is also not particularly limited, and may be, for example, a polygonal shape such as a square, a ring shape, a semicircular shape, a crescent shape, an arch shape, etc.

[0017] Specific examples of ophthalmic medical devices include contact lenses, punctal plugs, intraocular lenses, intraocular rings, etc. Of these, contact lenses are preferred.

[0018] When an ophthalmic medical device contains a hydrogel containing cross-linked PVOH, the ophthalmic medical device may consist solely of a hydrogel containing cross-linked PVOH, or may consist of a hydrogel containing cross-linked PVOH and other materials. For example, a contact lens containing a hydrogel containing cross-linked PVOH may consist solely of a hydrogel containing cross-linked PVOH, or may consist of a hydrogel containing cross-linked PVOH and other lens materials. When the hydrogel containing crosslinked PVOH is opaque or translucent, it is preferable that the region of the contact lens through which the optical axis passes is made of another lens material.

[0019] Other lens materials may be used, for example, lens materials known in the field of contact lenses, and may be hydrogels. Non-limiting examples of other lens materials include Polymacon, Ocufilcon D, Etafilcon, Omafilcon A, Nelfilcon, Hilafilcon B, Lotrafilcon B, Senofilcon A, Galyfilcon A, Netrafilcon A, Lidofilcon B, Bufilcon A, Deltafilcon A, Phemfilcon, Hioxifilcon A, Perfilcon A, Methafilcon A, and the like.

[0020] Examples of contact lenses made of a hydrogel containing cross-linked PVOH and another lens material include: (1) a contact lens in which a hydrogel containing cross-linked PVOH is embedded in another lens material; (2) a contact lens in which another lens material and a hydrogel containing cross-linked PVOH are laminated; and (3) a contact lens in which a hydrogel containing cross-linked PVOH is interspersed in another lens material.

[0021] In the above embodiment (1), one or more hydrogels may be embedded in the other lens material, and a portion of the hydrogel may be exposed on the surface of the contact lens (for example, the surface that comes into contact with the cornea or conjunctiva). When the hydrogel containing crosslinked PVOH is placed in an area other than the area through which the optical axis of the contact lens passes, the shape of the hydrogel may be ring-shaped, semicircular, crescent-shaped, arch-shaped, or the like.

[0022] The contact lens can be contained in a container to form a contact lens product. The container can be the same as known contact lens containers. The container may contain an aqueous solution of the drug together with the contact lens. The aqueous solution of the drug may contain antioxidants, stabilizers, preservatives, osmotic pressure adjusters, etc., as needed.

[0023] <PVOH containing crosslinking group> In this embodiment, the crosslinking group-containing PVOH is a PVOH having a monomer unit having an ionic group and a crosslinking group-containing structure represented by a specific formula (1). PVOH is a polymer having vinyl alcohol units, and is typically a saponified polymer having vinyl ester-based monomer units. PVOH may also have vinyl ester-based monomer units. The crosslinking group-containing PVOH typically has a vinyl alcohol unit, a monomer unit having an ionic group, and a crosslinking group-containing structure represented by formula (1).

[0024] Examples of the ionic group in the monomer unit having an ionic group include cationic groups and anionic groups. Examples of the cationic group include quaternary ammonium bases such as diallyldimethylammonium base, (3-methacrylamidopropyl)trimethylammonium base, and [2-(methacryloyloxy)ethyl]trimethylammonium base, as well as sulfonium groups, oxonium groups, and phosphonium groups. Examples of counter ions that form salts with the quaternary ammonium ion in the quaternary ammonium base include chloride ions, fluoride ions, bromide ions, and iodide ions. Examples of the anionic group include carboxy groups and salts thereof, sulfo groups and salts thereof, and phosphate groups and salts thereof. When an anionic drug is used as the drug, the ionic group is preferably a cationic group because it has a high affinity with the anionic drug and provides good sustained release of the anionic drug.When a cationic drug is used as the drug, the ionic group is preferably an anionic group because it has a high affinity with the cationic drug and provides good sustained release of the cationic drug. Two or more types of ionic groups may be used in combination.

[0025] The monomer unit having an ionic group may be a unit formed by polymerization of a monomer having an ionic group, or may be a unit formed by post-modification of PVOH, in which an ionic group is typically introduced into the OH group of the vinyl alcohol unit of PVOH. The unit having an ionic group is preferably a unit formed by polymerization of a monomer having an ionic group, from the viewpoints of easier adjustment of the ionic group content compared to post-modification and prevention of elimination due to hydrolysis reaction or the like.

[0026] The monomer having an ionic group may be any monomer copolymerizable with the vinyl ester monomer, such as an unsaturated monomer having an ionic group. The unsaturated monomer is a monomer having one or more polymerizable unsaturated bonds, such as an ethylenically unsaturated bond. The upper limit of the number of polymerizable unsaturated bonds is, for example, 2. Examples of the unsaturated monomer having an ionic group include an unsaturated monomer having a cationic group and an unsaturated monomer having an anionic group. Examples of the unsaturated monomer having a cationic group include N-acrylamidomethyltrimethylammonium chloride, allyltrimethylammonium chloride, and diallyldimethylammonium 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; esters in which a portion of the carboxyl groups of polycarboxylic acids, such as maleic acid, itaconic acid, and fumaric acid, are esterified (e.g., monoalkyl esters of unsaturated dicarboxylic acids); and olefin sulfonic acids, such as ethylene sulfonic acid, allyl sulfonic acid, and methallylsulfonic acid, or salts thereof. As a monomer having an ionic group, one having two or more polymerizable unsaturated bonds is preferred in terms of ease of monomer availability, etc. Examples of a monomer having an ionic group and two or more polymerizable unsaturated bonds include diallyldialkylammonium salts such as diallyldimethylammonium chloride. The number of carbon atoms in the alkyl group in the diallyldialkylammonium salt is, for example, 1 to 3.

[0027] The crosslinking group-containing structure is represented by the following formula (1). -C(R 4 )=CH2 corresponds to the bridging group.

[0028] [ka] where R is an alkylene group, R 1 is a hydrogen atom, an alkyl group, or a cycloalkyl group, R 2 is a hydrogen atom or an alkyl group, R 3 is a single bond or -C(R 5 )(R 6 )-NH-C(=O)-, R 4 is a hydrogen atom or an alkyl group, R 5 and R 6 are each independently a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group. The wavy line indicates the binding site with PVOH.

[0029] In formula (1), the alkylene group of R may be linear or branched. The alkylene group has, for example, 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms, and further preferably 1 carbon atom.

[0030] R 1 The alkyl group may be linear or branched. The alkyl group has, for example, 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and further preferably 1 carbon atom. R 1 The cycloalkyl group may be monocyclic or polycyclic. The number of carbon atoms in the cycloalkyl group is, for example, 4 to 8. The cycloalkyl group is preferably a cyclohexyl group. R 1 is preferably a hydrogen atom.

[0031] R 2 The alkyl group may be linear or branched. The alkyl group has, for example, 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and further preferably 1 carbon atom. R 2 is preferably a hydrogen atom.

[0032] R 3 is preferably a single bond. R 3 is a single bond, the carbon atom of the carbonyl group in formula (1) and R 4 is directly bonded to the carbon atom to which it is bonded.

[0033] R 4 The alkyl group may be linear or branched. The alkyl group may have 1 to 4 carbon atoms, for example, or may have 1 carbon atom. R 4 is preferably a hydrogen atom or a methyl group.

[0034] R5 and R 6 The alkyl group in may be linear or branched. The number of carbon atoms in the alkyl group is, for example, 1 to 8, and preferably 1 to 4. R 5 and R 6 The cycloalkyl group in the formula (I) may be monocyclic or polycyclic. The number of carbon atoms in the cycloalkyl group is, for example, 4 to 8. The cycloalkyl group is preferably a cyclohexyl group. R 5 and R 6 The aryl group in the formula (I) may be monocyclic or polycyclic. The number of carbon atoms in the aryl group is, for example, 6 to 8. The aryl group is preferably a phenyl group.

[0035] The crosslinking group-containing structure is typically a structure formed by post-modification (acetal modification) of PVOH with a crosslinking group-containing compound represented by the following formula (2). PVOH has a structure in which two vinyl alcohol units are adjacent to each other (1,3-diol structure). The crosslinking group-containing structure is formed by an acetalization reaction between the 1,3-diol structure of PVOH and the crosslinking group-containing compound. The acetal modification method will be described in detail later.

[0036] [ka] wherein R' and R" are each independently a hydrogen atom, an alkyl group, or an alkanoyl group; R is an alkylene group, R 1 is a hydrogen atom, an alkyl group, or a cycloalkyl group, R 2 is a hydrogen atom or an alkyl group, R 3 is a single bond or -C(R 5 )(R 6 )-NH-C(=O)-, R 4 is a hydrogen atom or an alkyl group, R 5 and R 6are each independently a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group.

[0037] In formula (2), R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described above. The alkyl groups of R' and R'' may be linear or branched. The alkyl group has, for example, 1 to 4 carbon atoms, and preferably 1 to 2 carbon atoms. An alkanoyl group is -C(=O)-R 7 It is expressed as R 7 is an alkyl group. 7 The alkyl group may be linear or branched. The number of carbon atoms in the alkyl group is, for example, 1 to 4, and preferably 1 to 2. The crosslinking group-containing compound represented by formula (2) can be produced by, for example, the method described in JP-A-10-513408.

[0038] The crosslinking group-containing PVOH may have a vinyl ester monomer unit. Examples of vinyl ester monomers include aliphatic vinyl esters such as vinyl formate, vinyl acetate, vinyl propionate, vinyl valerate, vinyl butyrate, vinyl isobutyrate, vinyl pivalate, vinyl caprate, vinyl laurate, vinyl stearate, vinyl versatate, and vinyl trifluoroacetate, and aromatic vinyl esters such as vinyl benzoate. Among these, aliphatic vinyl esters having 3 to 20 carbon atoms are preferred, those having 4 to 10 carbon atoms are more preferred, and those having 4 to 7 carbon atoms are particularly preferred, with vinyl acetate being particularly preferred. These are usually used alone, but multiple types may be used simultaneously as necessary.

[0039] The crosslinking group-containing PVOH may have a vinyl alcohol unit, a vinyl ester-based monomer unit, a unit having an ionic group, and a monomer unit other than the crosslinking group-containing structure. Examples of other monomer units include monomer units that do not have an ionic group but have a nonionic group (excluding vinyl alcohol units, vinyl ester-based monomer units and crosslinking group-containing structures). 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.

[0040] The monomer unit having a nonionic group may be a unit formed by polymerization of a monomer having a nonionic group, or may be a unit formed by post-modification of PVOH. Examples of unsaturated monomers having a nonionic group include olefins such as ethylene, propylene, isobutylene, α-octene, α-dodecene, and α-octadecene; esters in which all of the carboxy groups of unsaturated carboxylic acids such as acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itaconic acid, and undecylenic acid are esterified (dialkyl esters of unsaturated dicarboxylic acids, etc.); nitriles such as acrylonitrile and methacrylonitrile; amides such as diacetone acrylamide, acrylamide, and methacrylamide; alkyl vinyl ethers; dimethyl allyl vinyl ketone; N-vinylpyrrolidone; vinyl chloride; vinylidene chloride; polyoxyalkylene (meth) allyl ethers such as polyoxyethylene (meth) allyl ether and polyoxypropylene (meth) allyl ether; polyoxyalkylene (meth) acrylates such as polyoxyethylene (meth) acrylate and polyoxypropylene (meth) acrylate; polyoxyethylene (meth) acrylamide; polyoxypropylene (meth) allyl ether; Examples of the vinyl ester include polyoxyalkylene (meth)acrylamides such as acrylamide; polyoxyethylene (1-(meth)acrylamide-1,1-dimethylpropyl) esters; polyoxyalkylene vinyl ethers such as polyoxyethylene vinyl ether and polyoxypropylene vinyl ether; polyoxyalkylene allylamines such as polyoxyethylene allylamine and polyoxypropylene allylamine; polyoxyalkylene vinylamines such as polyoxyethylene vinylamine and polyoxypropylene vinylamine; hydroxy group-containing α-olefins such as 3-buten-1-ol, 4-penten-1-ol, and 5-hexen-1-ol or acylated products thereof, vinyl ethylene carbonate; 2,2-dialkyl-4-vinyl-1,3-dioxolane; glycerin monoallyl ether; vinyl compounds such as 3,4-diacetoxy-1-butene; isopropenyl acetate; substituted vinyl acetates such as 1-methoxyvinyl acetate, 1,4-diacetoxy-2-butene, vinylene carbonate, and vinyl acetoacetate.

[0041] In the crosslinking group-containing PVOH, the content of the monomer unit having the ionic group is preferably 0.1 to 30 mol %, more preferably 0.3 to 20 mol %, and even more preferably 0.5 to 10 mol %, calculated as the ion-modified amount described below. When the ion-modified amount is equal to or greater than the lower limit, the sustained release of the drug and the wearing comfort due to moisture absorption tend to be better. When the ion-modified amount is equal to or less than the upper limit, the strength and shape stability due to crosslinking tend to be better. Amount of ion modification: number of moles of units having an ionic group / (total number of moles of vinyl alcohol units, number of moles of vinyl ester monomer units, number of moles of units having an ionic group, number of moles of crosslinking group-containing structure × 2, and number of moles of other monomer units) × 100 The reason why the number of moles of the crosslinking group-containing structure in the denominator is multiplied by 2 is that 1 mole of the crosslinking group-containing structure is formed by modifying 2 moles of vinyl alcohol units (1,3-diol structures). The amount of ionic modification is measured by NMR or titration.

[0042] The content of the crosslinking group-containing structure is preferably 0.1 to 50 mol %, more preferably 1 to 20 mol %, and even more preferably 2 to 10 mol %, converted into the crosslinking group modification amount described below. If the crosslinking group modification amount is equal to or greater than the lower limit, the strength and shape stability of the PVOH after crosslinking tend to be better. If the crosslinking group modification amount is equal to or less than the upper limit, the ophthalmic medical device tends to have a better wearing comfort when it is hydrated. Amount of crosslinking group modification: number of moles of crosslinking group-containing structure / (total number of moles of vinyl alcohol units, number of moles of vinyl ester monomer units, number of moles of units having ionic groups, number of moles of crosslinking group-containing structure × 2, and number of moles of other monomer units) × 100 The content of the crosslinking group-containing structure is measured by NMR or the like.

[0043] The degree of saponification of the crosslinking group-containing PVOH is preferably 50 to 100 mol %, and more preferably 70 If the degree of saponification is equal to or greater than the lower limit, the number of hydroxy groups that can be acetalized increases, and the strength of the PVOH after crosslinking tends to be superior. The degree of saponification is measured in accordance with JIS K 6726:1994, 3.5.

[0044] The degree of polymerization of the crosslinking group-containing PVOH is preferably 1000 or more, more preferably 1300 or more, and preferably 2500 or less, more preferably 2000 or less. If the degree of polymerization is equal to or greater than the lower limit, the strength of the PVOH after crosslinking tends to be superior. If the degree of polymerization is equal to or less than the upper limit, the solubility in water during crosslinking tends to be superior. The lower limit and the upper limit can be combined as appropriate. The degree of polymerization is measured in accordance with JIS K 6726. Generally, the degree of polymerization does not change before and after crosslinking, so the degree of polymerization of the crosslinking group-containing PVOH can be considered as the degree of polymerization of the crosslinked PVOH.

[0045] The crosslinking group-containing PVOH can be crosslinked by having the crosslinking group-containing structure. For example, when the crosslinking group-containing PVOH is irradiated with active energy rays or heated, the crosslinking groups in the crosslinking group-containing structure react with each other to cause crosslinking.

[0046] <Drugs> The drug is not particularly limited and can be appropriately selected from known drugs depending on the disease to be treated. The drug 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 of these.

[0047] Examples of drugs applicable to ophthalmic diseases include, but are not limited to, anti-infective agents (antibacterial agents, antiviral agents, antifungal agents, antiprotozoal agents, etc.), angiogenesis inhibitors (anti-vascular endothelial growth factor (VEGF) agents, etc.), anti-inflammatory agents, ocular hypotensive agents, anti-cancer agents, anesthetics, autonomic nervous system agents, steroids (corticosteroids, etc.), antihistamines, mast cell stabilizers, immunosuppressants, and mitotic inhibitors.

[0048] Non-limiting examples of antibacterial agents include bacitracin, chloramphenicol, ciprofloxacin, erythromycin, moxifloxacin, gatifloxacin, gentamicin, levofloxacin, sulfacetamide, polymyxin B, vancomycin, tobramycin, or combinations thereof. 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.

[0049] Non-limiting examples of anti-inflammatory agents include any known steroidal anti-inflammatory drug (SAID), any known non-steroidal anti-inflammatory drug (NSAID), or a combination thereof. Non-limiting examples of SAIDs include glucocorticoids such as dexamethasone, prednisolone, fluorometholone, loteprednol, medrysone, and rimexolone. Non-limiting examples of NSAIDs include diclofenac, flurbiprofen, ketorolac, bromofenac, nepafenac, or a combination thereof.

[0050] Non-limiting examples of anti-neoplastic agents include chemotherapeutic agents well known in the art. Non-limiting examples of anesthetic agents include aminoamides, aminoesters, or combinations thereof. Non-limiting examples of aminoamides include lidocaine, prilocaine, mepivacaine, ropivacaine, or combinations thereof. Non-limiting examples of possible aminoesters include benzocaine, procaine, proparacaine, tetracaine, or combinations thereof.

[0051] Non-limiting examples of autonomic agents include acetylcholine, carbachol, pilocarpine, physostigmine, echothiophate, atropine, scopolamine, homotrapine, cyclopentolate, tropicamide, dipivefrin, epinephrine, phenylephrine, apraclonidine, brimonidine, cocaine, hydroxyamphetamine, naphazoline, tetrahydrozoline, dapiprazole, betaxolol, carteolol, levobunolol, metipranolol, timolol, bepotastine besilate, or combinations thereof.

[0052] 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.

[0053] The drug is preferably an anionic drug, an amphoteric drug, or a cationic drug, since it is easily adsorbed to crosslinked PVOH having an ionic group and the release of the drug is easily controlled. Anionic drugs are drugs that have anionic groups 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. An example of a nucleic acid as a drug is an antisense oligonucleotide.Antisense oligonucleotide, also called antisense nucleic acid, refers to a single-stranded oligonucleotide that contains a base sequence that can hybridize to (i.e., complementary to) at least a part of a transcription product of a target gene or a target transcription product, and can suppress the expression of the transcription product of the target gene or the level of the target transcription product mainly through the antisense effect. The target gene or target transcript whose expression is suppressed, altered, or modified by the antisense effect is not particularly limited, but may include, for example, genes derived from the organism into which the nucleic acid complex is introduced, such as genes whose expression is increased in various diseases. Furthermore, the target gene transcript is mRNA transcribed from genomic DNA encoding the target gene, and also includes mRNA without base modifications and unprocessed mRNA precursors. The target transcript may include not only mRNA but also non-coding RNA (ncRNA) such as miRNA. More generally, the transcript may be any RNA synthesized by a DNA-dependent RNA polymerase. In one embodiment, the target transcript may be, 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. The nucleotide sequences of genes and transcripts can be obtained from publicly known databases, such as the NCBI (National Center for Biotechnology Information) database. Anionic drugs may be used in combination with other drugs.

[0054] An amphoteric drug is one that has an anionic group and a cationic group and has a 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.

[0055] Cationic drugs are drugs that have a cationic group and exhibit a positive charge in water. In one example, the cationic agent 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, the cationic drug comprises a guanidinium group, which is a positively charged group containing a central carbon atom covalently bonded to three nitrogen atoms and having a double bond between one of the nitrogen atoms and the central carbon. Typical beneficial agents for ophthalmic use that contain at least one guanidinium group include antihistamines such as epinastine and emedastine; glaucoma medications such as apraclonidine and brimonidine; guanine derivative antivirals such as ganciclovir and valganciclovir; arginine-containing antibacterial peptides such as defensins and indolicidin; and biguanide antibacterial agents such as chlorhexidine, alexidine, and polyhexamethylene biguanide (PHMB). Other cationic drugs for ophthalmic use include ketotifen, cationic steroids, neostigmine methylsulfate, oxybuprocaine hydrochloride, naphazoline nitrate, naphazoline hydrochloride, sodium chondroitin sulfate, pilocarpine hydrochloride, distigmine bromide, echothiopate iodide, epinepherine, epinepherine bitartrate, carteolol hydrochloride, befunolol hydrochloride, and ripasudil. The cationic drug may be used in combination with other drugs. The amount of drug contained can be appropriately determined taking into consideration the dosage, release amount, etc. of the drug.

[0056] <Other ingredients> For example, when crosslinking group-containing PVOH is to be crosslinked by irradiation with active energy rays, a photopolymerization initiator such as an alkylphenone initiator or an acylphosphine oxide initiator may be contained. For example, when the ophthalmic medical device is used to treat an ophthalmic disease, it may contain known ingredients other than the drug in a preparation (eye drops, etc.) for an ophthalmic disease. For example, when the ophthalmic medical device is a contact lens, known ingredients (antioxidants, stabilizers, preservatives, osmotic pressure adjusters, etc.) other than the drug may be contained in the contact lens. The other components may be used singly or in combination of two or more.

[0057] <Method for manufacturing ophthalmic medical devices> Examples of methods for producing the ophthalmic medical device of this embodiment include a method comprising the steps of: reacting PVOH having a monomer unit having an ionic group (hereinafter also referred to as "ionic group-containing PVOH") with a crosslinking group-containing compound represented by the above formula (2) to obtain crosslinking group-containing PVOH (acetal modification step); preparing a composition containing the crosslinking group-containing PVOH, a drug, and water (composition preparation step); and irradiating the composition with active energy rays to crosslink the crosslinking group-containing PVOH (crosslinking step). The crosslinking group-containing PVOH in the composition is crosslinked to form a hydrogel containing crosslinked PVOH.

[0058] (PVOH containing ionic groups) The ionic group-containing PVOH is similar to the crosslinkable group-containing PVOH except that the crosslinkable group-containing structure in the crosslinkable group-containing PVOH is replaced with a 1,3-diol structure.

[0059] The preferred degree of polymerization of the ionic group-containing PVOH is the same as that of the crosslinkable group-containing PVOH. Note that the degree of polymerization of the ionic group-containing PVOH can be considered as the degree of polymerization of the crosslinkable group-containing PVOH obtained from that ionic group-containing PVOH.

[0060] The ionic group-containing PVOH can be produced by a known method. An example of a method for producing ionic group-containing PVOH is a method in which a monomer mixture containing a vinyl ester monomer and a monomer having an ionic group is polymerized, and the resulting copolymer is saponified. The monomer mixture may further contain other monomers in addition to the vinyl ester monomer and the monomer having an ionic group.

[0061] The content of the monomer having an ionic group in the monomer mixture is preferably 0.1 to 30 mol %, more preferably 0.5 to 10 mol %, relative to 100 mol % of the monomer mixture. When the content of the monomer having an ionic group is within the above range, the degree of ion-modification of the crosslinking group-containing PVOH tends to fall within the preferred range. The total content of the vinyl ester monomer and the monomer having an ionic group is preferably 60 mol % or more, more preferably 80 mol % or more, and may be 100 mol % based on 100 mol % of the monomer mixture.

[0062] The polymerization of the monomer mixture can be carried out by any known polymerization method, such as solution polymerization, suspension polymerization, emulsion polymerization, etc. Among them, solution polymerization, which can efficiently remove the heat of reaction, is preferably carried out under reflux. As a solvent for solution polymerization, an alcohol is usually used, and preferably a lower alcohol having 1 to 3 carbon atoms is used. The resulting copolymer can also be saponified by a known method, i.e., the copolymer can be dissolved in an alcohol or water / alcohol solvent and saponified using an alkali catalyst or an acid catalyst. As the alkali catalyst, for example, hydroxides or alcoholates of alkali metals such as potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate, potassium methylate, and lithium methylate can be used. Generally, transesterification using an alkali catalyst in an absolute alcohol solvent is preferably used in terms of reaction rate and ability to reduce impurities such as fatty acid salts. The reaction temperature for the saponification reaction is usually 20 to 60°C. If the reaction temperature is too low, the reaction rate tends to be slow and the reaction efficiency tends to decrease, while if the reaction temperature is too high, the temperature may exceed the boiling point of the reaction solvent, which tends to reduce safety in terms of production. When saponification is performed under high pressure using a highly pressure-resistant tower-type continuous saponification tower or the like, saponification can be performed at a higher temperature, for example, 80 to 150°C, and a product with a high degree of saponification can be obtained in a short time even with a small amount of saponification catalyst.

[0063] After saponification, the resulting ionic group-containing PVOH is preferably washed with a washing liquid. Examples of the cleaning liquid include alcohols such as methanol, ethanol, isopropyl alcohol, and butanol, with methanol being preferred from the viewpoint of cleaning efficiency and drying efficiency. The washing method may be a continuous method, but a batch method is usually adopted. The bath ratio (mass of washing solution / mass of ionic group-containing PVOH) is usually 1 to 30, preferably 2 to 20. If the bath ratio is too large, a large washing device will be required, which tends to increase costs, while if the bath ratio is too small, the washing effect will decrease and the number of washings 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 evaporation of the washing liquid increases, and reflux equipment tends to be required. If the temperature is too low, the washing efficiency tends to decrease. The washing time is usually 5 minutes to 12 hours. If the washing time is too long, production efficiency tends to decrease, and if the washing time is too short, washing tends to be insufficient. The number of washings is usually 1 to 10 times, and preferably 1 to 5 times. If the number of washings is too many, productivity tends to decrease and costs tend to increase.

[0064] The washed ionic group-containing 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 ionic group-containing PVOH tends to be thermally deteriorated, and if the drying temperature is too low, the drying tends to take a long time. The drying time is usually 1 to 48 hours. If the drying time is too long, the ionic group-containing PVOH tends to be thermally deteriorated, whereas if the drying time is too short, drying tends to be insufficient or high-temperature drying may be required. The content of the solvent in the ionic group-containing 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.

[0065] The resulting ionic group-containing PVOH usually contains an alkali metal salt of acetic acid derived from the alkali catalyst used in the saponification. The content of the alkali metal salt is usually 0.001 to 2 mass%, preferably 0.005 to 1 mass%, more preferably 0.01 to 0.1 mass%, based on the total mass of the ionic group-containing PVOH. The content of the alkali metal salt can be adjusted by adjusting the amount of the alkali catalyst used during saponification, or by washing the ionic group-containing PVOH with an alcohol such as ethanol or methanol. The alkali metal salt content can be determined, for example, by dissolving ionic group-containing PVOH powder in water and neutralizing titrating with hydrochloric acid using methyl orange as an indicator.

[0066] Another example of a method for producing ionic group-containing PVOH is a method in which PVOH is post-modified. For example, PVOH containing an ionic group can be obtained by reacting a compound having a functional group capable of reacting with a hydroxyl group and an ionic group with PVOH. Modified groups other than ionic groups (for example, nonionic groups) may be introduced by post-modification.

[0067] Examples of post-modification methods include acetoacetic acid esterification, acetalization, urethanization, etherification, phosphate esterification, oxyalkylenation, or dehydration condensation with an acid. Examples of acetoacetic acid esterification methods include transesterification of the hydroxyl groups of PVOH with acetoacetic acid esters, and reaction of unmodified PVOH with diketene.

[0068] (Acetal modification process) The reaction (acetalization reaction) between the ionic group-containing PVOH and the crosslinking group-containing compound can be carried out by a known method. For example, a method is exemplified in which a crosslinking group-containing compound is added to an aqueous solution of ionic group-containing PVOH in the presence of an acid catalyst and stirred. In this method, particles of the reactant (crosslinking group-containing PVOH) are generally precipitated as the acetalization reaction proceeds, and the reaction then proceeds in a heterogeneous system.

[0069] The acetalization reaction is preferably initiated at a low temperature. Examples of methods for initiating the acetalization reaction at a low temperature include I) a method in which an aqueous solution of ionic group-containing PVOH is cooled, and an acid catalyst and a crosslinking group-containing compound are added to initiate the reaction, II) a method in which a crosslinking group-containing compound is added to an aqueous solution of ionic group-containing PVOH, the mixture is cooled, and then an acid catalyst is added to initiate the reaction, and III) a method in which an acid catalyst is added to an aqueous solution of ionic group-containing PVOH, the mixture is cooled, and then a crosslinking group-containing compound is added to initiate the reaction. In general, when preparing an aqueous solution of ionic group-containing PVOH, it is preferable to heat the liquid to dissolve it, but in the above I) to III), unless otherwise specified, the aqueous solution refers to the aqueous solution that has been heated and dissolved and then cooled to room temperature. The crosslinking group-containing compound may be added to the aqueous solution of ionic group-containing PVOH all at once or in portions. For example, a portion may be added before cooling and the remainder may be added after cooling. Preferably, an ionic group-containing PVOH is dissolved in water to prepare an aqueous solution, which is cooled to 5 to 50°C, to which a crosslinking group-containing compound is added, and then an acid catalyst is added to initiate the reaction.

[0070] Examples of the acid catalyst used in the acetalization reaction include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as p-toluenesulfonic acid, etc. One type of acid catalyst may be used alone, or two or more types may be used in combination. The acetalization reaction is preferably carried out under stirring. To ensure complete acetalization, the reaction is preferably continued at 50 to 80° C. The acetalization reaction is usually carried out for 1 to 10 hours.

[0071] After the reaction is complete, the acid catalyst is neutralized. Neutralization of the acid catalyst is usually carried out by adding a neutralizing agent, such as an alkali compound, including alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, ammonia, and amine compounds such as triethylamine and pyridine.

[0072] After neutralizing the acid catalyst, it is preferable to add an alcohol to the reaction solution and perform solid-liquid separation. When the alcohol is added, the crosslinked group-containing PVOH in the reaction solution precipitates and can be recovered by solid-liquid separation. Water may also be added together with the alcohol. The alcohol may be, for example, an alcohol having 1 to 4 carbon atoms. Examples include methanol, ethanol, 1-propanol, 2-propanol, n-butyl alcohol, isobutyl alcohol, and tert-butyl alcohol, with methanol being preferred. One type of alcohol may be used alone, or two or more types may be used in combination. The amount of alcohol added is preferably such that the content of alcohol in the reaction liquid after the addition of the alcohol is 50 to 150 parts by mass, more preferably 75 to 125 parts by mass, per 100 parts by mass of water. If necessary, the crosslinking group-containing PVOH recovered by solid-liquid separation is washed and dried. In this way, a crosslinking group-containing PVOH is obtained.

[0073] (Composition preparation process) The composition can be prepared by mixing the crosslinking group-containing PVOH, the agent, water, and, if necessary, other components, which preferably contain a photopolymerization initiator.

[0074] The content of the crosslinking group-containing PVOH in the composition is preferably 1 to 30% by mass, more preferably 10 to 20% by mass, based on the total mass of the composition. When the content of the crosslinking group-containing PVOH is equal to or greater than the lower limit, the strength of the hydrogel tends to be superior. When the content of the crosslinking group-containing PVOH is equal to or less than the upper limit, the oxygen permeability of the hydrogel tends to be superior. The content of water in the composition is preferably from 65 to 95 mass %, more preferably from 80 to 90 mass %, based on the total mass of the composition.

[0075] (Crosslinking process) The crosslinking group-containing PVOH can be crosslinked by either irradiation with active energy rays (photocrosslinking) or heating (thermal crosslinking), but irradiation with active energy rays is preferred. When crosslinking group-containing PVOH is irradiated with active energy rays, the unsaturated bond (-C(R 4 )=CH2) reacts to form a crosslink. Examples of the active energy rays include ultraviolet rays and electron beams.

[0076] The composition is poured into a mold and irradiated with active energy rays to obtain an ophthalmic medical device made of a hydrogel having the desired shape. For example, when the ophthalmic medical device is a contact lens, the composition is injected between the male and female contact lens molds, and then irradiated with active energy rays to obtain a contact lens made of a hydrogel. An ophthalmic medical device made of a film-like hydrogel can be obtained by forming a coating film of the composition on a substrate and irradiating it with active energy rays. The hydrogel peeled from the substrate may be further processed, such as by cutting. The hydrogel containing crosslinked PVOH may be combined with other materials to form an ophthalmic medical device. For example, the contact lens of the above-mentioned form (1) can be produced by placing the hydrogel containing crosslinked PVOH in a contact lens mold, injecting a liquid lens material precursor into the mold, and then curing the injected lens material precursor.

[0077] <Action and effect> The ophthalmic medical device of the present embodiment contains crosslinked PVOH and therefore has excellent hydrophilicity. Because of its excellent hydrophilicity, it easily conforms to the eyeball surface when brought into contact with the eyeball, providing a comfortable fit. Furthermore, the ophthalmic medical device of this embodiment exhibits excellent sustained release properties when a drug is contained therein due to the presence of ionic groups in the crosslinked PVOH having a specific crosslinked structure. This is thought to be because the electrostatic interaction between the ionic groups and the drug makes it easier for the drug to be retained within the ophthalmic medical device, thereby preventing the drug from being rapidly eluted after wearing.

[0078] The ophthalmic medical device of this embodiment can be used, for example, to treat ophthalmic diseases. When an ophthalmic medical device contains a drug, the drug gradually elutes from the ophthalmic medical device into tears when the ophthalmic medical device is brought into contact with the cornea or conjunctiva. Non-limiting examples of ophthalmic diseases include infections of the eye (including the skin, eyelid, conjunctiva, or lacrimal drainage system), orbital cellulitis, dacryoadenitis, hordeolum, blepharitis, conjunctivitis, keratitis, corneal infiltrates, ulcers, endophthalmitis, panophthalmitis, viral keratitis, fungal keratitis, herpes zoster ophthalmicus, viral conjunctivitis, viral retinitis, uveitis, strabismus, retinal necrosis, scleritis, mucormycosis, dacryoductitis, acanthamoeba keratitis, toxoplasmosis, giardiasis, leishmaniasis, malaria, helminth infections, and glaucoma. [Example]

[0079] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. "Parts" means "parts by mass."

[0080] [Production Example 1] <Synthesis of modified PVOH> PVOH1A, which is a PVOH having a quaternary ammonium salt group as a cationic group, was produced by the following procedure. A reactor equipped with a reflux condenser, dropping funnel, and stirrer was charged with 20 parts of methanol, 100 parts of vinyl acetate, and 0.7 parts of a 65% by weight aqueous solution of diallyldimethylammonium chloride. Using acetyl peroxide as an initiator, the mixture was heated under reflux under a nitrogen stream to initiate polymerization. Immediately after the start of polymerization, 2.7 parts of a 65% by weight aqueous solution of diallyldimethylammonium chloride was added dropwise over 5 hours. When the polymerization rate reached 71%, m-dinitrobenzene was added as a polymerization inhibitor to terminate the polymerization. Subsequently, unreacted monomer was removed from the system by blowing in methanol vapor, yielding a methanol solution of a copolymer of vinyl acetate and diallyldimethylammonium chloride. The resulting methanol solution was then diluted with methanol to a solids concentration of 32% by mass and placed in a kneader. While maintaining the solution temperature at 35°C, a methanol solution of sodium hydroxide was added at a ratio of 4 mmol of sodium hydroxide per 1 mole of vinyl acetate units in the copolymer to carry out saponification. The resulting solid was filtered, thoroughly washed with methanol, and dried in a hot air dryer. This yielded the target product, PVOH1A. The resulting PVOH1A had a degree of polymerization of 1700 and a degree of saponification of 88 mol%. The content of diallyldimethylammonium chloride units was 1 mol% relative to the total amount of vinyl acetate units, vinyl alcohol units, and diallyldimethylammonium chloride units.

[0081] <Acetalization> 3 g of PVOH1A was added to 17 g of purified water with stirring, heated to 90 °C, and completely dissolved over 1 hour. The mixture was then slowly cooled to room temperature with stirring. 0.31 g of N-acryloylaminoacetaldehyde dimethyl acetal (NAAADA) prepared by a known method and 10.14 g of 2 mol / L hydrochloric acid (7.3% by mass) were added, and the mixture was stirred at 23 °C for 20 hours. After further stirring at 50 °C for 5 hours, the mixture was neutralized with 1.5 mol / L NaOH and placed in a 70 / 30 ethanol / water mixed solvent. The precipitate was filtered, ultrasonically washed twice using the same solvent, and dried at room temperature. This yielded PVOH1, a crosslinked PVOH. The acetal modification amount of PVOH1 was 4.7 mol%, and the degree of saponification was 91.1 mol%.

[0082] [Production Example 2] <Synthesis of unmodified PVOH> PVOH2A, an unmodified PVOH, was produced by the following procedure. A reactor equipped with a reflux condenser, dropping device, and stirrer was charged with 20 parts vinyl acetate (20% of the total amount initially charged) and 34.5 parts methanol. The temperature was raised under a nitrogen stream while stirring. After the boiling point was reached, 0.068 parts of acetyl peroxide was added to initiate polymerization. Further, 0.4 hours after the start of polymerization, 80 parts of vinyl acetate were added dropwise at a constant rate over 9.5 hours. When the conversion of vinyl acetate reached 89%, a predetermined amount of hydroquinone monomethyl ether was added to terminate the polymerization. Subsequently, unreacted vinyl acetate monomer was removed from the system by distillation while blowing in methanol vapor, yielding a methanol solution of vinyl acetate polymer. The resulting methanol solution was then diluted with methanol to a solids concentration of 50%. This methanol solution was then placed in a kneader, and while maintaining the solution temperature at 35°C, saponification was carried out by adding a 2% methanol solution of sodium hydroxide (sodium equivalent) at a ratio of 4.8 mmol per mole of vinyl acetate structural units. As the saponification proceeded, the saponified product precipitated and became particulate. At this point, 7.5 mmol of a 2% methanol solution of sodium hydroxide (sodium equivalent) per mole of vinyl acetate structural units was added for further saponification. Subsequently, 0.8 equivalents of sodium hydroxide were added for neutralization, and the mixture was filtered, thoroughly washed with methanol, and dried in a hot air dryer to obtain the target product, PVOH2A. The resulting PVOH2A had a degree of polymerization of 500 and a degree of saponification of 88 mol%.

[0083] <Acetalization> Except for using PVOH2A instead of PVOH1A, the same procedure as in <Acetalization> of Production Example 1 was carried out to obtain PVOH2, a crosslinking group-containing PVOH. The acetal modification amount of PVOH2 was 3.8 mol %, and the degree of saponification was 97.2 mol %.

[0084] [Production Example 3] <Synthesis of unmodified PVOH> PVOH3A, an unmodified PVOH, was produced by the following procedure. A reactor equipped with a reflux condenser, dropping device, and stirrer was charged with 28 parts vinyl acetate (28% of the total amount initially charged) and 30 parts methanol. The temperature was raised under a nitrogen stream while stirring. After the boiling point was reached, 0.060 parts of acetyl peroxide was added to initiate polymerization. Further, 0.4 hours after the start of polymerization, 72 parts of vinyl acetate were added dropwise at a constant rate over 9.5 hours. When the conversion of vinyl acetate reached 92%, a predetermined amount of hydroquinone monomethyl ether was added to terminate the polymerization. Subsequently, unreacted vinyl acetate monomer was removed from the system by distillation while blowing in methanol vapor, yielding a methanol solution of vinyl acetate polymer. The resulting methanol solution was then diluted with methanol to a solids concentration of 50%. This methanol solution was placed in a kneader, and while maintaining the solution temperature at 35°C, a 2% methanol solution of sodium hydroxide (calculated as sodium) was added at a ratio of 6.0 mmol per mole of vinyl acetate structural units to carry out saponification. As the saponification proceeded, the saponified product precipitated. When it became particulate, it was filtered off, thoroughly washed with methanol, and dried in a hot air dryer to obtain the target product, PVOH3A. The resulting PVOH3A had a degree of polymerization of 500 and a degree of saponification of 98.5 mol%.

[0085] <Acetalization> Except for using PVOH3A instead of PVOH1A, the same procedure as in <Acetalization> of Production Example 1 was carried out to obtain PVOH3, a crosslinking group-containing PVOH. The acetal modification amount of PVOH3 was 3 mol %, and the degree of saponification was 99.8 mol %.

[0086] [Production Example 4] <Synthesis of unmodified PVOH> PVOH4A, an unmodified PVOH, was produced by the following procedure. A reactor equipped with a reflux condenser, a dropping device, and a stirrer was charged with 100 parts of vinyl acetate and 33 parts of methanol, and the temperature was raised under a nitrogen stream while stirring. After the temperature reached the boiling point, 1.3 parts of acetyl peroxide was added to initiate polymerization. When the conversion of vinyl acetate reached 81%, a predetermined amount of hydroquinone monomethyl ether was added to terminate the polymerization. Subsequently, unreacted vinyl acetate monomer was removed from the system by distillation while blowing in methanol vapor, yielding a methanol solution of vinyl acetate polymer. The resulting methanol solution was then diluted with methanol to a solids concentration of 47% by mass and placed in a kneader. While maintaining the solution temperature at 35°C, a methanol solution of sodium hydroxide was added at a ratio of 7 mmol of sodium hydroxide per mole of vinyl acetate units in the copolymer to carry out saponification. As the saponification proceeded, the saponified product precipitated. Once it became particulate, it was filtered off, thoroughly washed with methanol, and dried in a hot air dryer to obtain the target product, PVOH4A. The resulting PVOH4A had a degree of polymerization of 1800 and a degree of saponification of 98.5 mol%.

[0087] <Acetalization> Except for using PVOH4A instead of PVOH1A, the same procedure as in <Acetalization> of Production Example 1 was carried out to obtain PVOH4, a crosslinking group-containing PVOH. The acetal modification amount of PVOH4 was 3.6 mol %, and the degree of saponification was 99.6 mol %. After acetalization, PVOH4 was insoluble in water, so it could not be used to manufacture contact lenses.

[0088] [Example 1, Comparative Examples 1 and 2] <Contact lens production> The PVOH listed in Table 1 was added to purified water with stirring, heated to 90°C, and stirred for 1 hour to completely dissolve. The mixture was slowly cooled to room temperature with stirring to obtain an aqueous solution with a 15% PVOH concentration by mass. To 2 mL of this solution, 0.1 mL of a 100 mg / mL aqueous solution of nucleic acid as a drug and 0.09 mL of a 1% aqueous solution of Omnirad2959 by mass as a photoinitiator were added and mixed. The nucleic acid used was a Malat1 antisense oligonucleotide represented by CdsTdsAdsGdsTdsTdsCdsAdsCdsTdsGdsAdsAdsTdsGdsCd (wherein the nucleic acid bases are represented by A = adenine, T = thymine, G = guanine, and C = cytosine, the sugar moiety is represented by d = 2'-deoxyribose, and the internucleoside bond is represented by s = phosphorothioate). The resulting solution was injected into a contact lens mold with a diameter of 11 mm and a base curve (BC) of 6.5, which was then sandwiched between a male and female mold and irradiated with UV light (365 nm, 140 mW) for 2 minutes to obtain a hydrogel contact lens containing crosslinked PVOH and a drug.

[0089] 〔evaluation〕 The following sustained release test was carried out on each of the contact lenses.

[0090] <Sustained release test> Contact lenses were placed in a 24-well cell culture plate, and 1000 μL of phosphate-buffered saline (hereinafter also referred to as "PBS") was added. After standing at 37°C for 15 minutes, the entire PBS was collected. Next, another 1000 μL of PBS was added, and after standing at 37°C for 15 minutes (a total of 30 minutes), the entire PBS was collected. Next, another 1000 μL of PBS was added, and after standing at 37°C for 30 minutes (a total of 1 hour), the entire PBS was collected. This process was repeated, and PBS samples were collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after the initial addition of PBS. The drug concentration was determined by high-performance liquid chromatography (hereinafter also referred to as "HPLC"), and the cumulative elution amount at each time point was calculated. Here, the "cumulative amount of elution" is the mass percentage of the "total amount of drug eluted up to each time point" relative to the "drug content in the contact lens."

[0091] The ratio (mass%) of the cumulative elution amount at each time point to the cumulative elution amount after 24 hours was calculated, and this value was used as the release ratio for each time point. The release ratio for each time point is shown in Figure 1. The release ratio after 1 hour (cumulative elution amount after 1 hour / cumulative elution amount after 24 hours x 100) is also shown in Table 1. In Table 1, the amount of acetal modification corresponds to the amount of crosslinking group modification, and the degree of saponification is the value after acetalization.

[0092] [Table 1]

[0093] The contact lenses of Example 1 showed a gradual release of the drug, with the cumulative amount of drug eluted after 1 hour being 55% of that after 24 hours. On the other hand, the contact lenses of Comparative Examples 1 and 2 showed almost the same cumulative amount of drug eluted after 1 hour as after 24 hours, indicating that they did not have sustained release properties.

Claims

1. An ophthalmic medical device comprising a crosslinked polyvinyl alcohol-based resin obtained by crosslinking a crosslinkable group-containing polyvinyl alcohol-based resin having a monomer unit having an ionic group and a crosslinkable group-containing structure represented by the following formula (1): 【Chemical 1】 where R is an alkylene group, R １ is a hydrogen atom, an alkyl group, or a cycloalkyl group, R ２ is a hydrogen atom or an alkyl group, R ３ is a single bond or -C(R ５ ) (R ６ )-NH-C(=O)-, R ４ is a hydrogen atom or an alkyl group, R ５ and R ６ are each independently a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group. The wavy lines indicate the bonding sites with the polyvinyl alcohol resin.

2. 2. The ophthalmic medical device of claim 1, wherein the ionic group is a cationic group.

3. 3. The ophthalmic medical device of claim 2, wherein the cationic group is a quaternary ammonium salt group.

4. 4. The ophthalmic medical device according to claim 1, wherein the degree of polymerization of the crosslinking group-containing polyvinyl alcohol resin is 1,000 or more.

5. The ophthalmic medical device according to any one of claims 1 to 3, which contains a drug.

6. The ophthalmic medical device according to claim 5, wherein in the sustained release test described below, the cumulative amount of the drug dissolved after 1 hour is 80% by mass or less of the cumulative amount dissolved after 24 hours. Sustained release test: The ophthalmic medical device was placed in a 24-well cell culture plate, 1000 μL of phosphate-buffered saline was added, and the ophthalmic medical device was left to stand at 37° C. for 15 minutes, after which the entire amount of the phosphate-buffered saline was collected. Next, another 1000 μL of phosphate-buffered saline was added, and the device was left to stand at 37° C. for 15 minutes (a total of 30 minutes), after which the entire amount of the phosphate-buffered saline was collected. Next, another 1000 μL of phosphate-buffered saline was added, and the device was left to stand at 37° C. for 30 minutes (a total of 1 hour), after which the entire amount of the phosphate-buffered saline was collected. This process was repeated, and the phosphate-buffered saline samples were collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after the initial addition of the phosphate-buffered saline. These samples were used as measurement samples to determine the concentration of the drug, and the cumulative amount of elution at each time point was calculated.

7. The ophthalmic medical device according to any one of claims 1 to 3, which is a contact lens.

8. A polyvinyl alcohol-based resin having a monomer unit having an ionic group is reacted with a crosslinking group-containing compound represented by the following formula (2) to obtain a crosslinking group-containing polyvinyl alcohol-based resin, preparing a composition containing the crosslinking group-containing polyvinyl alcohol-based resin, a drug, and water; The method for producing an ophthalmic medical device includes irradiating the composition with active energy rays to crosslink the crosslinking group-containing polyvinyl alcohol-based resin. 【Chemistry 2】 wherein R′ and R″ are each independently a hydrogen atom, an alkyl group, or an alkanoyl group; R is an alkylene group; R １ is a hydrogen atom, an alkyl group, or a cycloalkyl group, R ２ is a hydrogen atom or an alkyl group, R ３ is a single bond or -C(R ５ ) (R ６ )-NH-C(=O)-, R ４ is a hydrogen atom or an alkyl group, R ５ and R ６ are each independently a hydrogen atom, an alkyl group, a cycloalkyl group, or an aryl group.

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