Package body

Abstract

To provide a package body in which a drug can be supported by an ophthalmic medical device during storage, and the drug is released from the ophthalmic medical device during use.SOLUTION: A package body includes an ophthalmic medical device, a drug, and a preservation solution. The ophthalmic medical device includes a hydrogel including a resin including a constitutional unit derived from a monomer including an amine structure. The pH of the preservation solution is 6.5 or less.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a package containing an ophthalmic medical device, a medication and a preservative solution. [Background technology]

[0002] Ophthalmic medical devices with sustained drug release properties have been investigated, so that by wearing an ophthalmic medical device containing a therapeutic drug, the drug can be delivered to the affected area in the eye over a long period of time. One such ophthalmic medical device known is a hydrogel contact lens carrying a drug (Patent Document 1).

[0003] Hydrogel contact lenses are typically stored in sealed packages with a storage solution. It has been proposed that adding a specific polymer to the storage solution can impart hydrophilicity and lubricity to the surface of a hydrogel contact lens (Patent Document 2). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2008-539837 [Patent Document 2] Japanese Patent Publication No. 2022-151117 Summary of the Invention [Problem to be solved by the invention]

[0005] The present inventors have investigated how to package a drug together with an ophthalmic medical device containing a hydrogel and a preservative solution, thereby allowing the drug to be carried by the hydrogel during storage. However, hydrogels with sustained-release properties have the problem that the drug is difficult to impregnate. Furthermore, even if the drug is impregnated, it is not carried by the hydrogel and dissolves into the preservative solution.

[0006] An object of the present invention is to provide a package that can hold a drug in an ophthalmic medical device during storage and that allows the drug to be released from the ophthalmic medical device when it is used. [Means for solving the problem]

[0007] The present invention has the following aspects. [1] A package containing an ophthalmic medical device, a drug, and a preservative solution, the ophthalmic medical device comprises a hydrogel containing a resin including a constituent unit derived from a monomer including an amine structure, A package characterized in that the pH of the preservative solution is 6.5 or less. [2] The package described in [1] above, wherein the preservative solution contains phosphate-buffered saline. [3] The package according to [1] or [2], wherein the amine structure is a tertiary amine structure. [4] The package according to any one of [1] to [3] above, wherein the monomer containing an amine structure is represented by the following formula (1): [ka] However, R 1 is a hydrogen atom or an alkyl group, and R 2 is an alkylene group, and R 3 and R 4 are each independently an alkyl group. [5] The resin contains a structural unit derived from a monomer other than the monomer having an amine structure, The package according to any one of [1] to [4], wherein the content of the structural units derived from the monomer having an amine structure is 10 to 90 mol % relative to the total of the structural units derived from the monomer having an amine structure and the other monomer. [6] The package according to any one of [1] to [5] above, wherein the drug comprises an anionic drug. [7] The package according to any one of [1] to [6] above, wherein the preservative solution is supplied with carbon dioxide. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide a package that can hold a drug in an ophthalmic medical instrument during storage and that allows the drug to be released from the ophthalmic medical instrument when used. DETAILED DESCRIPTION OF THE INVENTION

[0009] As used herein, the term "hydrogel" refers to a structure that has a network structure formed by physical or chemical crosslinking of polymer molecular chains, and that swells by absorbing water into this network structure. A "monomer" is a compound having one polymerizable unsaturated group. Examples of the polymerizable unsaturated group include an acryloyl group in which the hydrogen atom bonded to the α-position carbon atom may be substituted with a substituent (e.g., an alkyl group) (hereinafter also referred to as an (α-substituted) acryloyl group), a vinyl group, and an allyl group. An "acrylic monomer" is a monomer having an (α-substituted) acryloyl group as a polymerizable unsaturated group. "(Meth)acrylate" is a general term for acrylate and methacrylate. The same applies to "(meth)acrylic acid," "(meth)acrylonitrile," "(meth)acrylamide," and "(meth)acryloyl group." The symbol "to" indicating a range of values ​​means that the values ​​before and after it are included as the lower and upper limits.

[0010] [Packaging] A package according to one embodiment of the present invention contains an ophthalmic medical device, a medication, and a preservative solution.

[0011] <Ophthalmic medical devices> In this embodiment, the ophthalmic medical device includes a hydrogel, and the hydrogel includes a resin including constitutional units derived from a monomer containing an amine structure.

[0012] When such an ophthalmic medical device comes into contact with a storage solution of pH 6.5 or less, the pH of the hydrogel decreases, the amine structure is protonated, and drugs, especially anionic drugs, are easily adsorbed to the hydrogel and are less likely to leach from the hydrogel. This allows the drug to be loaded onto the ophthalmic medical device and maintained in that state during storage. The lower the pH, the higher the rate of protonation, and the greater the effect. On the other hand, when the package is opened and the ophthalmic medical device is attached to the affected area at the time of use, the pH increases due to contact with body fluids and the evaporation of carbon dioxide (described below), which reduces the proportion of protonated amine structures and facilitates the release of the drug from the hydrogel.

[0013] The amine structure may be, for example, a tertiary amine structure, a secondary amine structure, or a primary amine structure. In terms of drug adsorption due to protonation when the pH is lowered, a tertiary amine structure is preferred. The amine structure-containing monomer may have one or more amine structures.

[0014] Examples of the monomer containing an amine structure include a compound represented by the following formula (1), an acrylic monomer such as (meth)acrylamide or dimethylaminopropyl(meth)acrylamide; a vinyl monomer such as N-vinylpyrrolidone or N-vinyl-ε-caprolactam; and a styrene derivative such as dimethylaminostyrene.

[0015] [ka] However, R 1 is a hydrogen atom or an alkyl group, and R 2 is an alkylene group, and R 3 and R 4 are each independently an alkyl group.

[0016] In formula (1), R 1 The alkyl group may be linear or branched. The number of carbon atoms in the alkyl group is, for example, 1 to 3. 1 is preferably a hydrogen atom or a methyl group. R2 The alkylene group may be linear or branched. The alkylene group has, for example, 1 to 4 carbon atoms. R 3 and R 4 The alkyl group preferably has a size that does not cause steric hindrance when the drug is adsorbed. The alkyl group may be linear or branched, and linear alkyl groups are preferred from the viewpoint of steric hindrance. The number of carbon atoms in the alkyl group is preferably 1 to 4, and more preferably 1 to 3. Examples of the compound represented by formula (1) include 2-(dimethylamino)ethyl (meth)acrylate, 2-(diethylamino)ethyl (meth)acrylate, 2-(dipropylamino)ethyl (meth)acrylate, 2-(diisopropylamino)ethyl (meth)acrylate, 2-(di-t-butylamino)ethyl (meth)acrylate, 3-(dimethylamino)propyl (meth)acrylate, and 3(dibutylamino)propyl (meth)acrylate.

[0017] As the monomer containing an amine structure, an acrylic monomer is preferred because of its high polymerizability, and a compound represented by the formula (1) is more preferred because it is easily protonated when the pH is lowered and has little steric hindrance, so that it does not inhibit drug adsorption. The monomers containing an amine structure may be used alone or in combination of two or more.

[0018] The resin may further contain structural units derived from monomers other than the monomer containing an amine structure. The other monomer may be any monomer that is copolymerizable with the monomer containing an amine structure, and may be appropriately selected from known monomers. Examples of other monomers include compounds represented by the following formula (2), acrylic monomers such as 2,3-dihydroxypropyl(meth)acrylate, and siloxane-containing vinyl monomers such as tris(trimethylsilyloxy)silylpropyl(meth)acrylate, [3-(meth)acryloxy-2-hydroxypropyloxy]propylbis(trimethylsiloxy)methylsilane, [3-(meth)acryloxy-2-hydroxypropyloxy]propylbis(trimethylsiloxy)butylsilane, and 3-(meth)acryloxy-2-(2-hydroxyethoxy)-propyloxy)propylbis(trimethylsiloxy)methylsilane.

[0019] [ka] However, R 5 is a hydrogen atom or an alkyl group, and R 6 is an alkylene group, m is an integer of 0 to 3, and R 7 is an ethylene group, and R 8 is a hydrogen atom or an alkyl group.

[0020] In formula (2), R 5 The alkyl group may be linear or branched. The number of carbon atoms in the alkyl group is, for example, 1 to 3. 5 is preferably a hydrogen atom or a methyl group. R 6 The alkylene group may be linear or branched. The alkylene group has, for example, 1 to 4 carbon atoms. R 8 The alkyl group may be linear or branched and may have, for example, 1 to 3 carbon atoms. Examples of the compound represented by formula (2) include 2-(2-methoxyethoxy)ethyl (meth)acrylate, 2-methoxyethyl (meth)acrylate, 2-hydroxyethyl (meth)acrylate, and hydroxypropyl (meth)acrylate.

[0021] When the monomer containing an amine structure includes a compound represented by formula (1), the other monomer is preferably an acrylic monomer from the viewpoint of polymerizability, and more preferably a compound represented by formula (2) from the viewpoint of gelation without impairing hydrophilicity when copolymerized with the compound represented by formula (1). The other monomers may be used alone or in combination of two or more.

[0022] The resin typically contains structures derived from the crosslinker. The crosslinking agent is preferably a compound having two or more polymerizable unsaturated groups, and examples thereof 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, methylene bis(meth)acrylamide, 2-hydroxy-1,3-di(meth)acryloxypropane, and trimethylolpropane tri(meth)acrylate. The crosslinking agent may be used alone or in combination of two or more kinds.

[0023] In the resin, the content of constitutional units derived from monomers containing an amine structure is preferably 10 to 90 mol %, more preferably 20 to 80 mol %, and even more preferably 30 to 70 mol %, relative to the total (100 mol %) of the monomers containing an amine structure and constitutional units derived from other monomers. When the content of constitutional units derived from monomers containing an amine structure is equal to or greater than the lower limit, the drug is easily carried during storage in a preservative solution, and the drug is easily released during use of the ophthalmic medical device. When the content of constitutional units derived from monomers containing an amine structure is equal to or less than the upper limit, the drug is easily released during use of the ophthalmic medical device.

[0024] In the resin, the content of the structure derived from the crosslinking agent is preferably 1 to 90 mol %, more preferably 5 to 80 mol %, and even more preferably 10 to 75 mol %, relative to the total (100 mol %) of the monomer containing the amine structure and the structural units derived from other monomers. When the content of the structure derived from the crosslinking agent is equal to or greater than the lower limit, the shape stability of the gel is superior. When the content of the structure derived from the crosslinking agent is equal to or less than the upper limit, the drug can be easily carried during storage in a preservative solution.

[0025] Hydrogels typically contain water. When an ophthalmic medical device, a drug, and a preservative solution are packaged together, the drug is carried in the hydrogel that constitutes the ophthalmic medical device, but the hydrogel may contain the drug in the ophthalmic medical device before it is packaged. The hydrogel may further contain other components in addition to the resin, water, and drug, as required.

[0026] Examples of ophthalmic medical devices include medical contact lenses, implantable sustained drug release devices, punctal plugs, and conjunctival rings. Among these, medical contact lenses are preferred because of their convenience for patients, non-invasiveness, and the fact that they do not require the physician to become accustomed to them.

[0027] The ophthalmic medical device may consist solely of the hydrogel, or may consist of the hydrogel and other materials. The other materials may be materials known as constituent materials for ophthalmic medical devices. For example, in the case of medical contact lenses, lens materials known in the field of contact lenses may be used as the other materials. The other lens material may be a hydrogel.

[0028] The ophthalmic medical device can be manufactured by a known method. For example, a composition containing a monomer, such as a monomer containing an amine structure, a crosslinking agent, a polymerization initiator, and an organic solvent is placed in a mold and polymerized to obtain a gel containing a resin. The resulting gel is then contacted with water to replace at least a portion of the organic solvent with water. If necessary, the resulting gel is dried to remove any remaining organic solvent. This process allows for the production of an ophthalmic device made of a hydrogel. Any known polymerization initiator can be used. The polymerization reaction can be carried out by, for example, irradiation with active energy rays or heating. Examples of active energy rays include ultraviolet rays, electron beams, etc. Heating conditions include, for example, at 40 to 80°C for 3 to 24 hours. The polymerization reaction may be carried out in the air, but is preferably carried out in an inert gas atmosphere such as nitrogen or argon in order to prevent inhibition of polymerization by oxygen. An example of a method for contacting a resin molded body with water is to wash the resin molded body with a cleaning liquid containing water. By washing the resin molded body, at least a portion of the liquid medium can be replaced with water, and unreacted monomers and the like can be removed. The cleaning liquid may be water or a mixture of water and an organic solvent. An example of the organic solvent is an alcohol such as ethanol.

[0029] <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.

[0030] Examples of drugs used for ophthalmic diseases include 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.

[0031] Antibacterial agents include, for example, bacitracin, chloramphenicol, ciprofloxacin, erythromycin, moxifloxacin, gatifloxacin, gentamicin, levofloxacin, sulfacetamide, polymyxin B, vancomycin, tobramycin, or combinations thereof. Antiviral agents include, for example, trifluridine, vidarabine, acyclovir, valacyclovir, famciclovir, foscarnet, ganciclovir, formivirsen, cidofovir, or combinations thereof. Antifungal agents include, for example, amphotericin B, natamycin, fluconazole, itraconazole, ketoconazole, miconazole, or combinations thereof. Antiprotozoal agents include, for example, polymyxin B, neomycin, clotrimazole, miconazole, ketoconazole, propamidine, polyhexamethylene biguanide, chlorhexidine, itraconazole, or combinations thereof. Anti-inflammatory agents include, for example, any known steroidal anti-inflammatory drug (SAID), any known non-steroidal anti-inflammatory drug (NSAID), or a combination thereof. Examples of SAIDs include glucocorticoids such as dexamethasone, prednisolone, fluorometholone, loteprednol, medrysone, and rimexolone. NSAIDs include, for example, diclofenac, flurbiprofen, ketorolac, bromofenac, nepafenac, or combinations thereof. Anti-neoplastic agents include chemotherapeutic agents well known in the art. Anesthetic agents include, for example, aminoamides, aminoesters, or combinations thereof. Aminoamides include, for example, lidocaine, prilocaine, mepivacaine, ropivacaine, or combinations thereof. Aminoesters include, for example, benzocaine, procaine, proparacaine, tetracaine, or combinations thereof. Autonomic agents include, for example, 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. Antihistamines include, for example, pheniramine, antazoline, naphazoline, emedastine, levocarbastine, cromolyn, or combinations thereof. Mast cell stabilizers include, for example, lodoxamide, pemirolast, nedocromil, olopatadine, ketotifen, azelastine, epinastine, or combinations thereof.

[0032] As the drug, an anionic drug, an amphoteric drug or a cationic drug is preferred, and an anionic drug is more preferred, since it is easily adsorbed to a protonated amine structure.

[0033] Anionic drugs are drugs that have anionic groups and exhibit a negative charge in water. Examples of anionic drugs include nucleic acids, tranilast, acitazanolast hydrate, sodium cromoglycate, glutathione, pranoprofen, bromfenac sodium, diclofenac sodium, bevotastine besilate, and combinations thereof.

[0034] 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.

[0035] 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.

[0036] 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. Amphoteric drugs include, for example, 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.

[0037] Cationic drugs are drugs that have a cationic group and exhibit a positive charge in water. The cationic agent may be a cationic polymer, such as epsilon polylysine (εPLL), an antimicrobial peptide containing multiple arginine and / or lysine groups, or polyquat. The cationic drug may be a drug containing a guanidinium group. Examples of drugs containing at least one guanidinium 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 antibacterial peptides such as defensin and indolicidin, and biguanide antibacterial 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, echothiopate iodide, epinepherine, epinepherine bitartrate, carteolol hydrochloride, befunolol hydrochloride, and ripasudil. The cationic drug may be used in combination with other drugs.

[0038] The amount of drug contained in the package is determined taking into consideration the dosage, release amount, etc. of the drug. The content of the drug is not particularly limited, but can be set, for example, in the range of 0.1 to 20% by mass relative to the total mass of the hydrogel.

[0039] <Preservation solution> The pH of the storage solution is 6.5 or less, preferably 6 or less, more preferably 5.7 or less, and preferably 3 or more, more preferably 4 or more, and more preferably 4.5 or more. When the pH is below the upper limit, the proportion of protonated amine structures increases, making it easier for the drug to be carried by the hydrogel. When the pH is above the lower limit, the drug release and wearing comfort are better. The pH is measured at 25°C.

[0040] The preservative solution may be any known preservative solution for ophthalmic medical devices, as long as it does not impair the effects of the present invention, except that the pH is 6.5 or less. The preservative solution typically contains a buffer solution. Examples of the buffer solution include a phosphate buffer solution, a borate buffer solution, etc. As the buffer solution, phosphate buffered saline is preferred from the viewpoints of shape stability and wearing comfort. The preservative solution may further contain a preservative, an isotonicity agent, a surfactant, a thickener, a humectant, a stabilizer, a disinfectant, a pH adjuster, etc. Examples of preservatives include methylparaben, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, potassium sorbate, thimerosal, phenylmercuric nitrate, and borate. Examples of isotonicity agents include sodium chloride, potassium chloride, and boric acid. Examples of humectants include polyvinyl alcohol, methylcellulose, hydroxypropylmethylcellulose, 2-methacryloyloxyethyl phosphorylcholine, trehalose, and hyaluronic acid. Examples of stabilizers include edetate. Examples of disinfectants include polyhexanide hydrochloride and polydronium chloride.

[0041] Preferably, the preservation solution is carbon dioxide supplied. When carbon dioxide is supplied to the preservative solution, the carbon dioxide dissolves and the pH decreases. Because the package is sealed, the carbon dioxide remains dissolved in the preservative solution while the package is stored. When the package is opened to use the ophthalmic medical device, the carbon dioxide evaporates from the preservative solution, causing the pH to increase. Instead of carbon dioxide, acetic acid, folic acid, propionic acid, butyric acid, etc. may be supplied, but carbon dioxide is preferred because it volatilizes at room temperature and is a gas.

[0042] In the package, the content of the preservative solution is, in mass terms, preferably 10 to 500 times, more preferably 50 to 300 times, and even more preferably 100 to 200 times the dry mass of the ophthalmic medical device. When the content is 10 times or more, the ophthalmic medical device can be sufficiently immersed in the preservative solution. When the content is 500 times or less, there is a tendency for less drug to leach out during storage.

[0043] <Container> In the package, containers for packaging the ophthalmic medical instruments, the medicine and the preservative solution can be the same as known containers for ophthalmic medical instruments. The container is preferably sealable, from the viewpoint of preventing the release of the drug in the container due to an increase in the pH of the preservative solution caused by the evaporation of carbon dioxide during storage of the package. Examples of sealable containers include those described in Japanese Patent No. 4928583.

[0044] <Manufacturing method of packaging body> The package of this embodiment can be produced by, for example, adjusting the pH of the storage solution to 6.5 or less, packaging it together with the ophthalmic medical instrument and the drug, and storing it.

[0045] As a method for adjusting the pH of the preservation solution to 6.5 or less, the method of supplying carbon dioxide is preferred, as described above. When carbon dioxide is supplied to the preservation solution, the carbon dioxide dissolves in the preservation solution and the pH decreases over time, so carbon dioxide is supplied until the pH of the preservation solution reaches a desired value. The pH of the preservation solution before carbon dioxide is supplied varies depending on the composition of the preservation solution, but is typically 7.0 to 7.6. Carbon dioxide can be supplied, for example, by bubbling carbon dioxide with a purity of 99% or higher into the preservation solution at a rate of 10 mL / min or higher for 5 minutes or longer. The temperature at which carbon dioxide is supplied is, for example, 15 to 30°C.

[0046] After packaging, during storage of the package, the drug adsorbs onto the protonated amine structures of the hydrogel, resulting in a drug-containing ophthalmic medical device. The storage time is preferably 24 hours or more, more preferably 72 hours or more. The upper limit of the storage time is not particularly limited, but is, for example, 5 years, preferably 3 years, and more preferably 1 year. The storage temperature is, for example, 10 to 30°C.

[0047] <Application> The ophthalmic medical device removed from the package is used to treat ophthalmic diseases. When the ophthalmic medical device is brought into contact with the cornea or conjunctiva, the drug gradually elutes from the ophthalmic medical device into tears. 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.

[0048] <Other embodiments> Another embodiment of the present invention is a method for making a drug-containing ophthalmic medical device. In the method for manufacturing a drug-containing ophthalmic medical device of this embodiment, the ophthalmic medical device, the drug, and a preservative solution are placed in a sealable container, carbon dioxide is supplied to the preservative solution to adjust the pH to 6.5 or less, and the container is then sealed and stored. The ophthalmic medical instruments and drugs are the same as those described above. The preferred range of pH after carbon dioxide supply is also the same as that described above. The pH of the preservation solution before carbon dioxide supply varies depending on the composition of the preservation solution, but is, for example, 7.0 to 7.6.

[0049] Another embodiment of the present invention is a method for storing ophthalmic medical instruments. In the method for manufacturing an ophthalmic medical device of this embodiment, the ophthalmic medical device, a drug, and a preservative solution are placed in a sealable container, carbon dioxide is supplied into the preservative solution to adjust the pH to 6.5 or less, and the container is then sealed and stored. The ophthalmic medical instruments and drugs are the same as those described above. The preferred range of pH after carbon dioxide supply is also the same as that described above. The pH of the preservation solution before carbon dioxide supply varies depending on the composition of the preservation solution, but is, for example, 7.0 to 7.6. [Example]

[0050] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0051] (Examples 1 to 4, Comparative Examples 1 to 6) <Preparation of hydrogel> 2-(dimethylamino)ethyl methacrylate was used as the monomer containing an amine structure, and 2-(2-methoxyethoxy)ethyl methacrylate was used as the other monomer. The amounts of the amine structure-containing monomer and other monomers shown in Table 1, 1 mmol of diethylene glycol dimethacrylate as a crosslinker, and 0.05 mmol of 4,4'-azobis(4-cyanovaleric acid) as an initiator were dissolved in 5 mL of N,N-dimethylformamide to obtain a monomer mixture solution. 5 mL of the monomer mixture solution was purged with nitrogen gas for 30 minutes, then heated to 60°C and polymerized for 20 hours. The resulting gel was then purified by washing with an aqueous ethanol solution (ethanol / water = 50 / 50 (volume ratio)) and water, and dried under reduced pressure to obtain a hydrogel.

[0052] <Preparation of drug-containing hydrogel> 5 mL of Dulbecco's phosphate-buffered saline (PBS) (Nacalai Tesque, Inc.) was placed in a lidded container, and 10 mg of the hydrogel was immersed in the PBS and allowed to stand overnight. 5 mL of PBS containing 250 μg of salmon sperm-derived deoxyribonucleic acid (Fujifilm Wako Pure Chemical Industries, Ltd.) as a model drug was added to the container. A carbon dioxide substitution treatment was performed by bubbling carbon dioxide gas (purity 99.5% or higher, Tokai Acetylene Co., Ltd.) at a flow rate of 30 mL / min for 20 minutes at room temperature (25°C), and then the container was sealed with the lid. Note that the carbon dioxide substitution treatment was not performed for Comparative Examples 2 to 6. The container was then stored in a sealed state. The storage was performed at 25°C for 3 days.

[0053] <Evaluation of drug adsorption and drug release amounts> After storage, the lid of the container was removed, and 1.5 mL of PBS was collected. The collected PBS was designated as sample A, and its absorbance at a wavelength of 260.5 nm was measured using an ultraviolet-visible spectrophotometer (JASCO Corporation, V-650). Sample A was then returned to its original container. Next, a release test was conducted by leaving the container with the lid removed in air at 25°C for 5 days. After the test, 1.5 mL of PBS was collected. The collected PBS was designated as sample B, and its absorbance at a wavelength of 260.5 nm was measured in the same manner as above. Using a calibration curve prepared in advance, the drug concentrations of Sample A and Sample B were determined from the measured absorbance, and the amount of drug adsorption (μg) during storage and the amount of drug released (μg) during the release test were calculated. The amount of drug adsorption and the amount of drug released were calculated using the following formulas. In this example, the amount of drug in the PBS in the container before the carbon dioxide replacement treatment was 250 μg. The amount of drug in the PBS in the container after storage was calculated from the drug concentration of Sample A. The amount of drug adsorption in the PBS in the container after the release test was calculated from the drug concentration of Sample B. Drug adsorption amount (μg) = [drug amount in PBS in the container before carbon dioxide replacement treatment (μg)] - [drug amount in PBS in the container after storage (μg)] Drug release amount (μg) = [drug amount in PBS in the container after release test (μg)] - [drug amount in PBS in the container after storage (μg)] Table 1 shows the drug adsorption amount (μg / mg) per 1 mg of the hydrogel and the drug release amount (μg / mg) per 1 mg of the hydrogel. For Comparative Examples 1 and 6 where the drug adsorption amount was 0 μg, and Comparative Examples 2 to 5 where carbon dioxide substitution treatment was not performed, the drug release amount was not measured.

[0054] <pH measurement> 9 mL of Dulbecco's phosphate buffered saline (PBS) (Nacalai Tesque, Inc.) and a stirrer chip were placed in a 20 mL collection vial. A pH meter (Eutech pH meter pH2700, Nikkoh Hansen Co., Ltd.) was immersed in the PBS in the collection vial, and carbon dioxide gas (purity 99.5% or higher, Tokai Carbon Co., Ltd.) was bubbled at a flow rate of 30 mL / min at room temperature. The pH at each measurement time was recorded every 1 minute up to 20 minutes. The same measurement was performed 3 times. Table 1 shows the pH 20 minutes after the start of bubbling. The pH of the PBS before bubbling was 7.2.

[0055]

Table 1

[0056] In Examples 1 to 4, the drug was adsorbed by the hydrogel during storage in the preservation solution. Also, when the container was opened, the drug was released from the hydrogel. This is considered to be because carbon dioxide was released and the pH of the preservation solution increased. In Example 1, the drug release amount is higher than the drug adsorption amount, but this is within the range of measurement error. On the other hand, in Comparative Examples 1 and 6 that did not use a monomer containing an amine structure, the drug was not adsorbed by the hydrogel regardless of the pH of the preservation solution. Comparative Examples 2 to 5 where the pH of the preservation solution during storage was higher than 6.5 had less drug adsorption amount compared to Examples 1 to 4 with the same monomer composition.

Claims

1. A package containing an ophthalmic medical device, a medication, and a preservative solution, the ophthalmic medical device comprises a hydrogel containing a resin including a constituent unit derived from a monomer including an amine structure, A package characterized in that the pH of the preservative solution is 6.5 or less.

2. The package of claim 1 , wherein the preservative solution comprises phosphate buffered saline.

3. The package according to claim 1 or 2, wherein the amine structure is a tertiary amine structure.

4. The packaging body according to claim 1 or 2, wherein the monomer containing an amine structure is represented by the following formula (1): 【Chemistry 1】 However, R １ is a hydrogen atom or an alkyl group, and R ２ is an alkylene group, and R ３ and R ４ are each independently an alkyl group.

5. the resin contains a constituent unit derived from a monomer other than the monomer having an amine structure, 3. The packaging body according to claim 1, wherein the content of the structural units derived from the monomer having an amine structure is 10 to 90 mol % based on the total content of the structural units derived from the monomer having an amine structure and the other monomer.

6. The package of claim 1 or 2, wherein the drug comprises an anionic drug.

7. 3. The package of claim 1, wherein the preservative solution is supplied with carbon dioxide.

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