Printing ink for ophthalmic medical devices, ophthalmic medical devices, method for manufacturing ophthalmic medical devices, and method for manufacturing drug-containing ophthalmic medical devices

Abstract

This invention provides a printing ink for ophthalmic medical instruments that prevents drug leaching during the cleaning and storage process. [Solution] A printing ink for ophthalmic medical devices, wherein the ophthalmic medical device comprises a lens layer and a functional layer having the function of releasing a drug slowly, the printing ink for ophthalmic medical devices is used to form the functional layer, and the printing ink for ophthalmic medical devices comprises an ionic monomer and a monomer having a hydroxyl group.

Description

[Technical Field]

[0001] This invention relates to printing ink for ophthalmic medical devices, ophthalmic medical devices, methods for manufacturing ophthalmic medical devices, and methods for manufacturing drug-containing ophthalmic medical devices. [Background technology]

[0002] To enable the delivery of medication to the affected area of ​​the eye over a long period of time, ophthalmic medical devices containing medication have been investigated for therapeutic purposes. Patent Document 1 discloses a product in which a coating including a drug accumulation layer and a barrier layer is formed on the surface of a medical device such as a contact lens by printing. The drug accumulation layer contains the drug, and the barrier layer regulates the release of the drug from the drug accumulation layer. Patent Document 1 also discloses a method in which a drug receiving layer is formed in advance by printing, and the drug is incorporated into the drug receiving layer to form a drug accumulation layer. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Japanese Patent Publication No. 2015-232707 [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] Contact lenses are generally cleaned and stored in a storage solution after manufacturing. However, in the product described in Patent Document 1, the drug dissolves into the washing solution and storage solution during the washing and storage process, resulting in a decrease in the drug content. Patent Document 1 addresses the problems of inability to control release from the coating, the alteration of the physical properties of the lens material and the resulting impairment of optical properties when the drug is dispersed inside the lens, and the release of the drug from both directions of the lens by sequentially providing a drug accumulation layer and a barrier layer on one side of the lens layer. However, the elution of the drug during the cleaning and storage process has not been considered.

[0005] The present invention aims to provide a printing ink for ophthalmic medical devices that does not release drugs during the washing and storage process, an ophthalmic medical device that does not release drugs during the washing and storage process, a method for manufacturing the same, and a method for manufacturing a drug-containing ophthalmic medical device using the ophthalmic medical device. [Means for solving the problem]

[0006] The present invention has the following aspects. [1] Printing ink for ophthalmic medical devices, The aforementioned ophthalmic medical device includes a lens layer and a functional layer having the function of releasing a drug slowly. The aforementioned printing ink for ophthalmic medical devices is used to form the functional layer. The aforementioned printing ink for ophthalmic medical devices comprises an ionic monomer and a monomer having a hydroxyl group. [2] The printing ink for ophthalmic medical devices according to [1], wherein the functional layer has the function of adsorbing a water-soluble agent in an aqueous solution and slowly releasing the adsorbed water-soluble agent. [3] The printing ink for ophthalmic medical devices according to [1] or [2], wherein the water-soluble agent is an ionic agent. [4] A printing ink for ophthalmic medical devices according to any one of [1] to [3] above, which can be cured by active energy rays. [5] A printing ink for ophthalmic medical devices according to any of [1] to [4] above, which is capable of inkjet printing. [6] The printing ink for ophthalmic medical devices according to [5], wherein the viscosity at 23°C is 0.1 to 50 mPa·s. [7] Ophthalmic medical devices, It comprises a lens layer and a functional layer having the function of releasing the drug slowly. The functional layer includes a printed layer formed from the printing ink for ophthalmic medical devices described in any of [1] to [6] above, an ophthalmic medical device. [8] The ophthalmic medical device according to [7], wherein the average maximum thickness of the printed layer is 70 μm or less. [9] A method for manufacturing an ophthalmic medical device, comprising forming a printed layer on a lens layer using a printing ink for ophthalmic medical devices described in any of [1] to [6] above.

[10] A method for manufacturing a drug-containing ophthalmic medical device, comprising immersing the ophthalmic medical device described in [7] or [8] above in a preservation solution containing a drug to adsorb the drug onto the printed layer. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide a printing ink for ophthalmic medical devices that does not release drugs during the washing and storage process, an ophthalmic medical device that does not release drugs during the washing and storage process, a method for manufacturing the same, and a method for manufacturing a drug-containing ophthalmic medical device using the ophthalmic medical device. [Brief explanation of the drawing]

[0008] [Figure 1] These are TOF-SIMS ion images of contact lenses from Examples 1 and 2 (upper panel: Example 1, lower panel: Example 2). [Figure 2] This graph shows the results of the sustained-release test. [Modes for carrying out the invention]

[0009] In this specification, "monomer" is a compound having one polymerizable unsaturated group. Examples of polymerizable unsaturated groups include (meth)acryloyl, vinyl, and allyl groups. "Acrylic monomers" are monomers that have a (meth)acryloyl group as a polymerizable unsaturated group. "(meth)acryloyl group" is a general term for acryloyl and methacryloyl groups. The same applies to "(meth)acrylate," "(meth)acrylic acid," "(meth)acrylonitrile," and "(meth)acrylamide." Viscosity is measured using an E-type viscometer. The "average maximum thickness" of the printed layer is measured by the method described in the examples below. A "hydrogel" is a structure that has a network structure formed by physical or chemical cross-linking of polymer molecular chains and takes in water and swells in this network structure. The "~" indicating a numerical range means that the numerical values described before and after it are included as the lower limit value and the upper limit value. Hereinafter, embodiments of the present invention will be described.

[0010] 〔Printing Ink for Ophthalmic Medical Devices〕 The printing ink for ophthalmic medical devices of this embodiment (hereinafter, also simply referred to as "ink") is used for manufacturing an ophthalmic medical device including a lens layer and a functional layer. By performing printing using the ink of this embodiment, a functional layer having a function of gradually releasing a drug is formed. Hereinafter, the functional layer formed from the ink of this embodiment is also referred to as a printing layer. The ophthalmic medical device will be described in detail later.

[0011] The ink of this embodiment includes an ionic monomer and a monomer having a hydroxyl group (hereinafter, also referred to as a "hydroxyl group-containing monomer"). Thereby, a printing layer can be formed that adsorbs a drug during storage of the ophthalmic medical device and gradually releases the adsorbed drug during use of the ophthalmic medical device.

[0012] Examples of the ionic monomer include at least one selected from the group consisting of a cationic monomer, an anionic monomer, and an amphoteric ionic monomer.

[0013] A cationic monomer is a monomer having a cationic group (however, excluding amphoteric ionic monomers). Examples of the cationic group include a quaternary ammonium group. The cationic monomer may be an acrylic monomer, a monomer other than an acrylic monomer, or a combination thereof. It is preferable that at least a part of the cationic monomer is an acrylic monomer. <Examples of cationic monomers include trimethyl[3-((meth)acryloylamino)propyl]ammonium, 2-(meth)acryloyloxyethyltrimethylammonium, 2-(meth)acryloyloxyethyldimethylethylammonium, 2-(meth)acryloyloxyethyldimethyln-pentylammonium, and (meth)acryloyloxyethyldimethylbenzylammonium. Free anions for charge compensation may be further included. Cationic monomers may be used individually or in combination of two or more.

[0014] Anionic monomers are monomers that have an anionic group (excluding amphoteric monomers). Examples of anionic groups include carboxylic acid groups, sulfonic acid groups, and phosphate groups. The anionic monomer may be an acrylic monomer, a monomer other than an acrylic monomer, or a combination of these. Preferably, at least a portion of the anionic monomer is an acrylic monomer. Examples of anionic monomers include monocarboxylic acids such as (meth)acrylic acid, 2-methacryloyloxyethyl succinic acid, 2-methacryloyloxyethyl hexahydrophthalic acid, vinylbenzoic acid or allyl acetic acid; unsaturated carboxylic acid monomers such as dicarboxylic acids such as (anhydride) maleic acid, fumaric acid, and itaconic acid; unsaturated hydrocarbons having a sulfonic acid group such as vinyl sulfonic acid and styrene sulfonic acid; 2-(meth)acryloyloxyethanesulfonic acid, 2-(meth)acryloyloxypropanesulfonic acid, 3-(meth)acryloyloxypropanesulfonic acid, Examples include (meth)acrylates having a sulfonic acid group, such as 2-(meth)acryloyloxybutanesulfonic acid, 4-(meth)acryloyloxybutanesulfonic acid, 2-(meth)acryloyloxy-2,2-dimethylethanesulfonic acid, or p-(meth)acryloyloxymethylbenzenesulfonic acid; unsaturated sulfonic acid monomers such as (meth)allylsulfosuccinate esters having 5 to 20 carbon atoms; unsaturated phosphoric acid monomers such as 2-(meth)acryloyloxyethyl acid phosphate and bis(2-(meth)acryloyloxyethyl) acid phosphate. Anionic monomers may be used individually or in combination of two or more.

[0015] Amphoteric monomers are monomers that have both a cationic group and an anionic group. Examples of cationic groups include those similar to those found in cationic monomers. Examples of anionic groups include those similar to those found in anionic monomers. The amphoteric monomer may be an acrylic monomer, a monomer other than an acrylic monomer, or a combination of these. Preferably, at least a portion of the amphoteric monomer is an acrylic monomer. Examples of amphoteric monomers include [2-((meth)acryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, [3-((meth)acryloylamino)propyl]dimethyl(3-sulfopropyl)ammonium hydroxide, 2-((meth)acryloyloxy)ethyl-2-(triethylammonio)ethyl phosphate, and [[2-((meth)acryloyloxy)ethyl](dimethyl)ammonio]acetate. The amphoteric monomer may be used alone or in combination of two or more types.

[0016] Hydroxyl group-containing monomers are typically nonionic monomers. Examples of hydroxyl group-containing monomers include hydroxyalkyl (meth)acrylates such as 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, 5-hydroxypentyl (meth)acrylate, 6-hydroxyhexyl (meth)acrylate, and 8-hydroxyoctyl (meth)acrylate; caprolactone-modified monomers such as caprolactone-modified 2-hydroxyethyl (meth)acrylate; and diethylene glycol (meth)acrylate. Examples include oxyalkylene-modified monomers such as acrylate and polyethylene glycol (meth)acrylate; primary hydroxyl group-containing monomers such as 2-acryloyloxyethyl-2-hydroxyethylphthalic acid; secondary hydroxyl group-containing monomers such as 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 3-chloro-2-hydroxypropyl (meth)acrylate, and 2-hydroxy-3-acryloyloxypropyl (meth)acrylate; and tertiary hydroxyl group-containing monomers such as 2,2-dimethyl-2-hydroxyethyl (meth)acrylate. Hydroxyl group-containing monomers may be used individually or in combination of two or more.

[0017] The ink of this embodiment may further contain other monomers other than ionic monomers and hydroxyl group-containing monomers. Other monomers include, for example, (meth)acrylates such as glycidyl (meth)acrylate, dimethylaminoethyl (meth)acrylate, and diethylaminoethyl (meth)acrylate; and acrylamides such as (meth)acrylamide, hydroxyethyl (meth)acrylamide, hydroxymethyl (meth)acrylamide, dimethyl (meth)acrylamide, diethyl (meth)acrylamide, N-methyl (meth)acrylamide, dimethylaminopropyl (meth)acrylamide, and isopropyl (meth)acrylamide. Other monomers may be used individually or in combination of two or more.

[0018] The content of ionic monomers in the ink is preferably 1 to 40 mol%, and more preferably 5 to 30 mol%, based on 100 mol% of the total monomers. If the content of ionic monomers is above the lower limit, the printed layer is more likely to adsorb the chemical. If the content of ionic monomers is below the upper limit, the chemical is more likely to be released from the printed layer.

[0019] When an anionic monomer or cationic monomer is used in combination with an amphoteric monomer, the molar ratio of the anionic monomer or cationic monomer to the amphoteric monomer (anionic monomer or cationic monomer / amphoteric monomer) is preferably 90 / 10 to 30 / 70, and more preferably 70 / 30 to 40 / 60.

[0020] The content of hydroxyl group-containing monomers is preferably 20 to 99 mol%, and more preferably 40 to 90 mol%, relative to 100 mol% of the total monomers. When the content of hydroxyl group-containing monomers is above the lower limit, the adhesion to the lens layer and the shape stability after swelling are better.

[0021] The total content of ionic monomers and hydroxyl group-containing monomers is preferably 80 to 100 mol%, and more preferably 95 to 100 mol%, relative to 100 mol% of the total amount of all monomers.

[0022] The ink of this embodiment may further contain a crosslinking agent. Examples of crosslinking agents include compounds having two or more polymerizable unsaturated groups. Examples of compounds having two or more polymerizable unsaturated groups include di(meth)acrylates such as ethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, and polyethylene glycol di(meth)acrylate, as well as methylenebis(meth)acrylamide, 2-hydroxy-1,3-di(meth)acryloxypropane, and trimethylolpropane tri(meth)acrylate. In polyethylene glycol di(meth)acrylate, the average number of repeating oxyethylene groups is, for example, 1 to 8. A single crosslinking agent may be used alone, or two or more may be used in combination.

[0023] The crosslinking agent content is preferably 0.1 to 1.0 mol%, and more preferably 0.2 to 0.4 mol%, based on 100 mol% of the total monomers. When the crosslinking agent content is above the lower limit, the shape stability of the printed layer is better. When the crosslinking agent content is below the upper limit, the printed layer readily adsorbs the chemical and readily releases the adsorbed chemical.

[0024] The ink of this embodiment may further contain a polymerization initiator. Known polymerization initiators can be used. Examples of polymerization initiators include photopolymerization initiators and thermal polymerization initiators. If the ink of this embodiment is to be curable by active energy rays, it is preferable to include a photopolymerization initiator in the ink. Examples of photopolymerization initiators include alkylphenone-based initiators and acylphosphine oxide-based initiators. Polymerization initiators may be used individually or in combination of two or more. The polymerization initiator content is, for example, 0.05 to 0.8 mol%, or even 0.1 to 0.5 mol%, relative to 100 mol% of the total monomers.

[0025] The ink of this embodiment may further contain a liquid medium for purposes such as adjusting the viscosity of the ink. Examples of liquid media include alcohols such as methanol, ethanol, propanol, and isopropyl alcohol, and ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone. Alcohols are preferred as the liquid media because they can be easily removed during washing. The liquid medium may be used alone or in combination of two or more types. The liquid medium content is, for example, 1 to 100 mol%, or even 10 to 50 mol%, relative to 100 mol% of the total monomers.

[0026] The ink of this embodiment may further contain other components besides those mentioned above. Other ingredients include, for example, pharmaceuticals and moisturizing ingredients such as polyvinylpyrrolidone. Pharmaceuticals include those similar to those described later. The content of other components is, for example, 0 to 50% by mass, or even 0 to 30% by mass, relative to the total mass of the ink minus the other components.

[0027] The ink of this embodiment can be prepared by mixing an ionic monomer, a hydroxyl group-containing monomer, and, if necessary, at least one selected from the group consisting of other monomers, polymerization initiators, liquid media, and other components.

[0028] The ink of this embodiment can be cured by active energy rays or heat. When the printed ink is irradiated with active energy rays or heated, the polymerization reaction of monomers proceeds, and if a crosslinking agent is present, the crosslinking reaction also proceeds. As a result, the ink hardens and a printed layer is formed. The ink of this embodiment is preferably curable by active energy rays. Curing the ink with active energy rays allows for faster curing compared to curing by heat, resulting in superior productivity.

[0029] The viscosity of the ink in this embodiment only needs to be such that printing is possible, and can be set according to the printing method. As for the printing method, known printing methods can be applied, such as inkjet printing and pad printing. Of these, inkjet printing is preferred because it makes it easier to reduce the average maximum thickness of the printed layer. Therefore, it is preferable that the ink of this embodiment is capable of inkjet printing, and it is preferable that the printed layer formed using the ink of this embodiment is an inkjet printed layer. For inkjet printing applications, the viscosity of the ink of this embodiment is preferably 0.1 to 50 mPa·s, and more preferably 1 to 20 mPa·s, at 23°C.

[0030] [Ophthalmic medical devices] The ophthalmic medical device of this embodiment includes a lens layer and a functional layer. The functional layer includes a printed layer (hereinafter also referred to as printed layer A) formed from the above-mentioned ink.

[0031] Ophthalmic medical devices may be any known ophthalmic medical device having a lens layer, such as medical contact lenses and intraocular lenses. Among these, medical contact lenses are preferred due to their convenience for patients, non-invasiveness, and the fact that they do not require physician expertise.

[0032] (Lens layer) The material of the lens layer may be any known material, such as hydrogel or plastic. Examples of hydrogels include hydroxyethyl methacrylate (hereinafter also referred to as "HEMA"), silicone methacrylate, fluorine methacrylate, silicone, glycerol methacrylate, N,N-dimethylacrylamide, and polyvinyl alcohol. An example of a plastic is polymethyl methacrylate. The lens layer may be a commercially available lens, such as a commercially available contact lens, or one manufactured by a known method. The maximum thickness of the lens layer (for example, the thickness of the center of the contact lens) is not particularly limited, but is, for example, 50 to 500 μm.

[0033] (Functional layer) The functional layer includes the printing layer A. Printed layer A is a cured product of the ink described above and contains a resin comprising structural units derived from ionic monomers and structural units derived from hydroxyl group-containing monomers. The resin may further contain structural units derived from other monomers. The resin may be crosslinked. Printed layer A may contain other components. The printed layer A may be a hydrogel.

[0034] Since the printed layer A contains the above-mentioned resin, it has the function of slowly releasing the chemical agent. The printed layer A may, for example, release a chemical agent that is already contained in the printed layer A, or it may adsorb a chemical agent from the outside and release the adsorbed chemical agent. If the printed layer A has the function of adsorbing a chemical from the outside and slowly releasing the adsorbed chemical, the printed layer A does not need to contain the chemical before adsorbing the chemical from the outside.

[0035] Printed layer A typically has the function of adsorbing water-soluble drugs in an aqueous solution and slowly releasing the adsorbed water-soluble drugs. In this case, by packaging the ophthalmic medical device together with an aqueous solution of water-soluble drugs to form a package and storing it, the water-soluble drugs can be adsorbed onto printed layer A. Then, when the ophthalmic medical device is removed from the package and brought into contact with the cornea or conjunctiva, the water-soluble drugs gradually dissolve from printed layer A into the tear film.

[0036] If the printed layer A has the function of adsorbing a drug from the outside and slowly releasing the adsorbed drug, or adsorbing a water-soluble drug in an aqueous solution and slowly releasing the adsorbed water-soluble drug, it is preferable that, from the viewpoint of ease of drug adsorption, there is no other layer on top of the printed layer A, and that the printed layer A constitutes at least a part of the surface of the ophthalmic medical device.

[0037] The printed layer A may be formed on at least one surface of the lens layer, in contact with the lens layer, or through another layer. The printed layer A may be formed to cover the entire surface of the lens layer, or to cover only a portion of the surface of the lens layer. There may be one or more printed layers A. Any pattern may be formed by the printed layers A. On at least one surface of an ophthalmic medical instrument, the ratio of the area of ​​the printed layer A to the area of ​​the ophthalmic medical instrument is, for example, 40-100%, and even 80-100%.

[0038] The average maximum thickness of the printed layer A is preferably 70 μm or less, more preferably 60 μm or less, even more preferably 50 μm or less, and also preferably 1 μm or more, more preferably 5 μm or more, and even more preferably 10 μm or more. The above upper and lower limits can be combined as appropriate. If the average maximum thickness is below the upper limit, the oxygen permeability and optical properties of the ophthalmic medical device are less likely to be impaired. If the average maximum thickness is above the lower limit, the amount of adsorbed drug becomes sufficiently large.

[0039] The functional layer includes the printing layer A, and therefore has the same function as the printing layer A. The functional layer may consist only of the printing layer A, or it may further include functional layers other than the printing layer A. Functional layers other than the printed layer A can be any layer that has the function of releasing the drug slowly. For example, a layer with pores containing fine particles that encapsulate the drug within the pores can be used. The preferred range for the average maximum thickness of functional layers other than the printed layer A is the same as that for the printed layer A. On at least one surface of an ophthalmic medical device, the ratio of the area of ​​the functional layer to the total area of ​​the functional layer is, for example, 40-100%, or even 80-100%.

[0040] (Manufacturing method for ophthalmic medical devices) The ophthalmic medical device of this embodiment can be manufactured, for example, by forming a printed layer on a lens layer using the ink described above.

[0041] The printed layer can be formed by printing and curing the aforementioned ink. The printing method is as described above. Curing methods include curing with active energy rays and curing by heat. As mentioned above, curing with active energy rays is preferred. Examples of active energy rays include ultraviolet rays and electron beams. Examples of conditions for curing by heat include 30 to 120°C for 1 to 12 hours. Curing may be carried out in the atmosphere, but it is preferable to carry it out in an inert gas atmosphere such as nitrogen or argon from the viewpoint of suppressing polymerization inhibition by oxygen. The printing and curing process may be repeated multiple times. The average maximum thickness of the printed layer can be adjusted by the number of times the printing and curing process is performed.

[0042] After the formation of the printed layer, the resulting ophthalmic medical instrument may be washed. This removes unreacted monomers and other impurities. Alternatively, washing with a water-containing washing solution can incorporate water into the printed layer, creating a hydrogel. The water-containing washing solution may be water itself, or a mixture of water and an organic solvent. Examples of organic solvents include alcohols such as ethanol.

[0043] [Method for manufacturing drug-containing ophthalmic medical devices] By immersing the aforementioned ophthalmic medical instruments in a preservation solution containing a drug, the drug can be adsorbed onto the printed layer of the ophthalmic medical instruments, thereby creating drug-containing ophthalmic medical instruments. In this case, the ophthalmic medical device can be packaged in a container together with a preservative solution containing a drug to form a package. The packaging method may be the same as known packaging methods for ophthalmic medical devices. Before packaging, ophthalmic medical instruments, preservatives, and containers may be sterilized. After packaging, the packaging may be sterilized. Examples of sterilization conditions include high-pressure steam sterilization at 120°C and 2 atmospheres for 20 minutes.

[0044] (Medicine) There are no particular restrictions on the medications used; they can be appropriately selected from known medications depending on the disease being treated. The drug may be, for example, nucleic acids, proteins, carbohydrates (polysaccharides, etc.), other organic compounds, inorganic compounds, or a combination of two or more of these.

[0045] Drugs used for ophthalmic diseases include, for example, anti-infective agents (antibacterial agents, antiviral agents, antifungal agents, antiparasitic agents, etc.), angiogenesis inhibitors (antivascular endothelial growth factor (VEGF) agents, etc.), anti-inflammatory agents, intraocular pressure lowering agents, anti-cancer agents, anesthetics, autonomic nerve agents, steroids (corticosteroids, etc.), antihistamines, mast cell stabilizers, immunosuppressants, and mitotic inhibitors.

[0046] Examples of antibacterial agents include bacitracin, chloramphenicol, ciprofloxacin, erythromycin, moxifloxacin, gatifloxacin, gentamicin, levofloxacin, sulfacetamide, polymyxin B, vancomycin, tobramycin, or combinations thereof. Examples of antiviral agents include trifluridine, vidarabine, acyclovir, valacyclovir, famciclovir, foscarnet, ganciclovir, formivirsen, cidofovir, or combinations thereof. Examples of antifungal agents include amphotericin B, natamycin, fluconazole, itraconazole, ketoconazole, miconazole, or combinations thereof. Examples of antiparasitic agents include polymyxin B, neomycin, clotrimazole, miconazole, ketoconazole, propamidine, polyhexamethylene biguanide, chlorhexidine, itraconazole, or combinations thereof. Examples of anti-inflammatory agents include any known steroidal anti-inflammatory drugs (SAIDs), any known non-steroidal anti-inflammatory drugs (NSAIDs), or combinations thereof. Examples of SAIDs include glucocorticoids such as dexamethasone, prednisolone, fluorometholone, loteprednol, medlisone, and rimexolone. Examples of NSAIDs include diclofenac, flurbiprofen, ketrolac, bromofenac, nepafenac, or combinations thereof. Examples of anti-cancer agents include chemotherapeutic agents that are well-known in this field. Examples of anesthetics include aminoamides, aminoesters, or combinations thereof. Examples of aminoamides include lidocaine, prilocaine, mepivacaine, ropivacaine, or combinations thereof. Examples of amino esters include benzocaine, procaine, propalacaine, tetracaine, or combinations thereof. Examples of autonomic nervous system agents include acetylcholine, carbachol, pilocarpine, physostigmine, ecothiophate, atropine, scopolamine, homotrapine, cyclopentolate, tropicamide, dipivefrin, epinephrine, phenylephrine, apraclonidine, brimonidine, cocaine, hydroxyamphetamine, naphazoline, tetrahydrozoline, dapiprazole, betaxolol, carteolol, levovunolol, metipranolol, timolol, bepotastine besylate, or combinations thereof. Examples of antihistamines include pheniramine, antazoline, naphazoline, emedastine, levocarbastine, cromolyn, or combinations thereof. Examples of mast cell stabilizers include rhodoxamide, pemirolast, nedocromil, olopatadine, ketotifen, azelastine, epinastine, or combinations thereof.

[0047] When a functional layer such as printing layer A has the function of adsorbing a water-soluble agent in an aqueous solution and slowly releasing the adsorbed water-soluble agent, a water-soluble agent is preferred as the agent. As for water-soluble agents, ionic agents are preferred because they readily adsorb to the printed layer A. Examples of ionic agents include anionic agents, amphoteric agents, and cationic agents. If the ink forming the printed layer A contains a cationic monomer, it is preferable that the water-soluble agent contains an anionic agent. When the ink forming the printed layer A contains anionic monomers, it is preferable that the water-soluble agent contains a cationic agent.

[0048] Anionic drugs are drugs that possess an anionic group and exhibit a negative charge in water. Examples of anionic drugs include nucleic acids, tranilast, acitazanolase hydrate, sodium cromoglycate, glutathione, pranoprofen, bromfenac sodium, diclofenac sodium, bevotastine besilate, diquafosol sodium, or combinations thereof.

[0049] Examples of nucleic acids used as drugs include antisense oligonucleotides. Antisense oligonucleotides, also called antisense nucleic acids, are single-stranded oligonucleotides that contain a base sequence capable of hybridizing (i.e., complementary) to the transcript of a target gene or at least a part of the transcript of a target gene, and can suppress the expression of the transcript of a target gene or the level of the target transcript mainly through an antisense effect.

[0050] The target genes or target transcripts whose expression is suppressed, altered, or modified by the antisense effect are not particularly limited, but include, for example, genes of organisms into which nucleic acid complexes are introduced, such as genes whose expression is increased in various diseases. The transcript of the target gene is mRNA transcribed from the genomic DNA encoding the target gene, and also includes unmodified mRNA, unprocessed mRNA precursors, etc. 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 DNA-dependent RNA polymerase. In one embodiment, the target transcript may be, for example, metastasis-associated lungadenocarcinoma transcript 1 (malat1) non-coding RNA, scavenger receptor B1 (SR-B1) mRNA, or DMPK (dystrophia myotonica-protein kinase) mRNA. The base sequences of genes and transcripts can be obtained from publicly available databases, such as the NCBI (National Center for Biotechnology Information) database. Anionic drugs may be used in combination with other drugs.

[0051] Amphoteric drugs are drugs that possess both anionic and cationic groups and have a net charge of zero in water. Olopatadine, an ophthalmic drug, 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. Examples of amphoteric drugs include levocabastine hydrochloride, anlexanox, olopatadine, lomefloxacin hydrochloride, ofloxacin, norfloxacin, levofloxacin, tosufloxacin, pirenoxine, rapamycin, or combinations thereof. Amphoteric drugs may be used in combination with other drugs.

[0052] Cationic drugs are drugs that possess a cationic group and exhibit a positive charge in water. The cationic agent may also be a cationic polymer. Examples of cationic polymers include epsilon-polylysine (εPLL) and polyquat, which are antimicrobial peptides containing multiple arginine and / or lysine groups. Cationic drugs may also be drugs containing a guanidin group. Drugs containing at least one guanidin group include antihistamines such as epinastine and emedastine; glaucoma drugs such as apraclonidine and brimonidine; guanine derivative antiviral drugs such as ganciclovir and valganciclovir; arginine-containing antimicrobial peptides such as defensin and indolicidine; and biguanide antimicrobial agents such as chlorhexidine, alexidine, and polyhexamethylene biguanide (PHMB). Other cationic drugs include ketotifen, cationic steroids, neostigmine methylsulfate, oxybuprocaine hydrochloride, naphazoline nitrate, naphazoline hydrochloride, sodium chondroitin sulfate, pilocarpine hydrochloride, distigmine bromide, ecothiopate iodide, epinephrine, epinephrine bitartrate, carteolol hydrochloride, befnolol hydrochloride, ripasudil, and atropine. Cationic drugs may be used in combination with other drugs.

[0053] The amount of drug contained in the preservative solution is determined considering the amount of drug adsorbed onto the functional layer. The amount of the drug is not particularly limited, but for example, it can be set in the range of 0.1 to 20% by mass relative to the total mass of the functional layer.

[0054] (preservation solution) The preservation solution may be any known preservation solution for ophthalmic medical devices, except that it contains a drug. The storage solution typically contains a buffer. Examples of buffers include phosphate buffer and borate buffer. Phosphate-buffered saline is preferred as the buffer due to its shape stability and comfortable fit. The preservative solution may further contain preservatives, isotonic agents, surfactants, thickeners, humectants, stabilizers, disinfectants, pH adjusters, etc. Examples of preservatives include methylparaben, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, potassium sorbate, thimerosal, phenylmercury nitrate, and borates. Examples of isotonic agents include sodium chloride, potassium chloride, and boric acid. Examples of humectants include polyvinyl alcohol, methylcellulose, hydroxypropyl methylcellulose, 2-methacryloyloxyethyl phosphorylcholine, trehalose, and hyaluronic acid. Examples of stabilizers include edetates. Examples of disinfectants include polyhexanide hydrochloride and polydronium chloride. The pH of the preservation solution is, for example, 5-9. The pH value is for 25°C.

[0055] The mass of the preservation solution used to immerse ophthalmic medical instruments is preferably 10 to 500 times the dry mass of the ophthalmic medical instruments, more preferably 30 to 300 times, and even more preferably 50 to 200 times. If the mass is 10 times or more, the ophthalmic medical instruments can be sufficiently immersed in the preservation solution. If the mass is 500 times or less, there is a tendency for less drug leaching during storage.

[0056] (container) For packaging ophthalmic medical instruments and preservative solutions, containers similar to those used for known ophthalmic medical instruments can be used. As for the container, a sealable one, such as the one described in Japanese Patent Publication No. 4928583, is preferred.

[0057] In this embodiment, after manufacturing ophthalmic medical instruments, they are stored in a preservation solution containing a drug, and the drug in the preservation solution is adsorbed onto the printed layer. Therefore, even if washing or sterilization is performed before storage, the drug will not leach out. [Examples]

[0058] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way by these examples. "Part" refers to "parts by mass".

[0059] (Explanation of abbreviations) HEMA: A monomer containing a hydroxyl group, 2-hydroxyethyl methacrylate CMB: Amphoteric monomer, [[2-(methacryloyloxy)ethyl](dimethyl)ammonio]acetate MAPTAC: Cationic monomer, trimethyl[3-(methacryloylamino)propyl]ammonium chloride Omnirad1173: Photopolymerization initiator, 2-hydroxy-2-methyl-1-phenylpropanone EGDMA: Crosslinking agent, polyethylene glycol dimethacrylate (average number of repeating oxyethylene groups n=4) EtOH: Ethanol

[0060] (Examples 1-2) <Ink preparation> Ink A was prepared by mixing HEMA, CMB, MAPTAC, Omnirad1173, EGDMA, and EtOH. The molar ratios of HEMA, CMB, MAPTAC, and EtOH in the ink are shown in Table 1. Omnirad1173 was added at 0.2 mol% of the total monomers. EGDMA was added at 0.3 mol% of the total monomers. The viscosity of ink A at 23°C was 10 mPa·s.

[0061] <Drying of commercially available contact lenses> A commercially available HEMA hydrogel contact lens was placed in a contact lens mold with a diameter of 13 mm and a base curve (BC) of 8.2 mm, then sandwiched between male and female molds and left to dry at room temperature for at least 3 days.

[0062] <Formation of the printed layer> A printed layer was formed on each side of a dried contact lens using the following procedure. The printing equipment used was a piezo-inkjet patterning machine NanoPrinter (manufactured by Microjet), and the print head was a piezo-driven SE-128 (manufactured by FUJIFILM Dimatix). The positive and negative pressure generator was set to positive pressure: 0.30 MPa and negative pressure: 4.7 kPa. Ink was added to the liquid delivery bottle, and the pressure was switched to positive pressure to prevent air from entering the print head, and a constant amount was discharged. After confirming that the ink was discharged in a rod shape from the nozzle head, the sample ink was filled. The ink head ejects ink by driving a piezoelectric element, so the electrical pulse and voltage are set to achieve a good ejection speed. In this example, the ejection speed was set to 7.35 m / s. After determining the ink ejection conditions, a dried contact lens was placed in the printing machine and printed across its entire surface. The printing conditions at this time are shown in Table 1. Immediately after printing, the ink was cured by irradiating it with UV light from a 365 nm UV irradiator for 3 minutes. By performing the above printing and curing process multiple times (5 times per side in Example 1, and 10 times per side in Example 2), the contact lenses of Examples 1 and 2 were obtained.

[0063] <Measurement of the thickness of the printed layer> The contact lenses from Examples 1 and 2 were each cut into strips, sandwiched between polypropylene (PP) films, dried at room temperature, embedded in resin, and their cross-sections were prepared using a microtome. For any three locations on the cross-section of the contact lens, the maximum thickness of the printed layer was determined as follows, and the average of these values ​​was taken as the average maximum thickness. Using a time-of-flight secondary ion mass spectrometer (TOF-SIMS) (ION-TOF M6, manufactured by ION-TOF Corporation), the primary ion Bi3 2+ Under the following conditions, with an acceleration voltage of 30kV, irradiation current of approximately 0.07pA, collection of positive and negative secondary ions, measurement range of 500, 200μm angular scanning (beam scanning), and integration of 30 scans, the C5H of the cross-section of a contact lens was measured. 12 N + (Compatible with CMB) or C7H 15 N2O +(Corresponding to MAPTAC) The intensity was measured. In the ion image of TOF-SIMS (size: 200 μm × 200 μm), C5H 12 N + or C7H 15 N2O + The location where the intensity was detected was defined as the printing layer, and the maximum thickness of the printing layer was determined. Fig. 1 shows the ion image of TOF-SIMS. In the figure, the upper row shows the measurement results of Example 1, and the lower row shows the measurement results of Example 2. On the left side of each row, the intensity of C5H 12 N + is shown, and on the right side, the intensity of C7H 15 N2O + is shown. The average maximum thickness of the printing layer of the contact lens in Example 1 was 20 μm. The average maximum thickness of the printing layer of the contact lens in Example 2 was 54 μm.

[0064] (Comparative Example 1) The commercially available HEMA-based hydrogel contact lenses used in Examples 1 to 2 were directly used as the contact lenses in Comparative Example 1.

[0065] (Evaluation) <Preparation of Drug-Containing Contact Lenses> Each contact lens of each example was immersed in 2 mL of a 1 mg / mL aqueous solution of nucleic acid as a model drug for 24 hours to obtain a drug-containing contact lens. As the nucleic acid, Malat1 antisense, an oligonucleotide represented by CdsTdsAdsGdsTdsTdsCdsAdsCdsTdsGdsAdsAdsTdsGdsCd (where each nucleobase is represented by A = adenine, T = thymine, G = guanine, C = cytosine, each sugar moiety is represented by d = 2'-deoxyribose, and each internucleoside bond is represented by s = phosphorothioate.) was used.

[0066] <Sustained Release Test> In a 24-well cell culture plate, a contact lens containing the above-mentioned drug was placed, and 1000 μL of phosphate-buffered saline (PBS) was added to which NaCl was added to make a NaCl concentration of 2% by mass. After standing at 37°C for 15 minutes, the entire volume of PBS was collected. Next, 1000 μL of PBS containing NaCl was added, and after standing at 37°C for another 15 minutes (total 30 minutes), the entire volume of PBS was collected. Next, 1000 μL of PBS containing NaCl was added, and after standing at 37°C for 30 minutes (total 1 hour), the entire volume of PBS was collected. Thereafter, the addition of PBS containing NaCl, standing at 37°C for a total of 1 hour, 4 hours, 8 hours, and 24 hours, and the collection of the entire volume of PBS were repeated.

[0067] <Measurement of discharge amount> In the sustained-release test described above, PBS samples were collected 15 minutes, 30 minutes, 1 hour, 4 hours, 8 hours, and 24 hours after the initial addition of PBS. The absorbance at a wavelength of 260 nm was measured using a spectrophotometer [JASCO V-750 spectrophotometer manufactured by JASCO Engineering Co., Ltd.], and the drug concentration was determined using a pre-prepared calibration curve. The cumulative elution amount (μg) up to each time point was then calculated. The results are shown in Table 2 and Figure 2. In Table 2, "Loaded amount" is (Amount of drug in the original drug solution (2000 μg)) - (Amount of drug in the drug solution after adsorption to the contact lens)

[0068] [Table 1]

[0069] [Table 2]

[0070] In the sustained-release test, no drug release was observed in the contact lens of Comparative Example 1. This is thought to be because the lack of a printed layer prevented the drug from being adsorbed. In contrast, in the sustained-release test, drug elution was confirmed in the contact lenses of Examples 1 and 2, and the cumulative amount of eluted drug increased over time. From these results, it was confirmed that the contact lenses of Examples 1 and 2 can adsorb the drug onto the printed layer and release the adsorbed drug during use.

Claims

1. Printing ink for ophthalmic medical devices, The aforementioned ophthalmic medical device includes a lens layer and a functional layer having the function of releasing a drug slowly. The aforementioned printing ink for ophthalmic medical devices is used to form the functional layer. The aforementioned printing ink for ophthalmic medical devices comprises an ionic monomer and a monomer having a hydroxyl group.

2. The printing ink for ophthalmic medical devices according to claim 1, wherein the functional layer has the function of adsorbing a water-soluble drug in an aqueous solution and slowly releasing the adsorbed water-soluble drug.

3. The printing ink for ophthalmic medical devices according to claim 2, wherein the water-soluble agent is an ionic agent.

4. A printing ink for ophthalmic medical devices according to claim 1 or 2, which is curable by active energy rays.

5. A printing ink for ophthalmic medical devices according to claim 1 or 2, which is capable of inkjet printing.

6. The printing ink for ophthalmic medical devices according to claim 5, wherein the viscosity at 23°C is 0.1 to 50 mPa·s.

7. It is an ophthalmic medical device, It comprises a lens layer and a functional layer having the function of releasing the drug slowly. The functional layer includes a printed layer formed from the printing ink for ophthalmic medical devices described in claim 1 or 2, an ophthalmic medical device.

8. The ophthalmic medical device according to claim 7, wherein the average maximum thickness of the printed layer is 70 μm or less.

9. A method for manufacturing an ophthalmic medical device, comprising forming a printed layer on a lens layer using the printing ink for ophthalmic medical devices described in claim 1 or 2.

10. A method for manufacturing a drug-containing ophthalmic medical device, comprising immersing the ophthalmic medical device described in claim 7 in a preservation solution containing a drug to adsorb the drug onto the printed layer.

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