Pharmaceuticals (6)

Abstract

To provide a technique for suppressing crystal precipitation during low-temperature storage of an aqueous composition containing a halogenated isoquinoline derivative.SOLUTION: There is provided a pharmaceutical preparation for the prevention or treatment of one or more diseases selected from ocular hypertension and glaucoma, where an aqueous composition containing a compound represented by the general formula (1) in the figure [where X represents a halogen atom] or a salt thereof, or a solvate of them, is contained in a container made of a polyester-based resin.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical preparations and the like. [Background technology]

[0002] The following structural formula:

[0003] [ka]

[0004] Ripasudil (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline) represented by the following structural formula:

[0005] [ka]

[0006] Halogenated isoquinoline derivatives such as 4-bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline represented by the formula (I) have pharmacological effects such as Rho kinase inhibitory activity (e.g., Patent Documents 1 and 2), and are known to be useful for the prevention and treatment of ocular diseases. Specifically, they have been reported to be useful for the prevention or treatment of ocular hypertension, glaucoma, and the like (e.g., Patent Document 3), or for the prevention or treatment of ocular fundus diseases such as age-related macular degeneration (e.g., Patent Document 4).

[0007] Therefore, it would be extremely useful to establish a technique for stably formulating these halogenated isoquinoline derivatives into, for example, ophthalmic agents. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent No. 4212149 [Patent Document 2] International Publication No. 2006 / 115244 Brochure [Patent Document 3] International Publication No. 2006 / 068208 Pamphlet [Patent Document 4] Patent No. 5557408 Summary of the Invention [Problem to be solved by the invention]

[0009] Ophthalmic preparations and the like are usually compositions containing water (aqueous compositions), and need to be stored in a container to prevent the contents from dissipating and the inclusion of impurities from the outside air. Therefore, when formulating Ripasudil, a halogenated isoquinoline derivative, as an ophthalmic preparation and the like, the present inventors investigated the material of the container for storing the aqueous composition. However, it was found that when an aqueous composition containing Ripasudil is stored in a container made of a specific material, a problem occurs in that crystals precipitate in the aqueous composition when stored at low temperatures. Therefore, an object of the present invention is to provide a technique for suppressing crystal precipitation in an aqueous composition containing a halogenated isoquinoline derivative during storage at low temperatures. [Means for solving the problem]

[0010] Therefore, the present inventors conducted extensive research to solve the above-mentioned problems and discovered that when an aqueous composition containing a halogenated isoquinoline derivative such as Ripasudil is stored in a container, if the container is made of a polyester-based resin, crystal precipitation can be specifically suppressed even after storage at low temperatures, and thus the present invention was completed.

[0011] That is, the present invention provides a compound represented by the following general formula (1):

[0012] [ka]

[0013] [In the formula, X represents a halogen atom.] or a salt thereof, or a solvate thereof, is contained in a polyester resin container. The present invention also provides a method for suppressing crystal precipitation in an aqueous composition, the method comprising the step of placing an aqueous composition containing a compound represented by general formula (1) or a salt thereof, or a solvate of the compound or the salt in a polyester resin container. [Effects of the Invention]

[0014] According to the present invention, crystal precipitation can be suppressed when an aqueous composition containing a halogenated isoquinoline derivative such as Ripasudil is stored at low temperature. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present specification discloses the following aspects of the invention, for example, but is not limited to these. [1] The following general formula (1)

[0016] [ka]

[0017] [In the formula, X represents a halogen atom.] or a salt thereof, or a solvate thereof, is contained in a polyester resin container. [2] The pharmaceutical formulation according to [1], wherein the compound represented by the general formula (1) is ripasudil. [3] The pharmaceutical formulation according to [1] or [2], wherein the polyester resin is polyethylene terephthalate. [4] The pharmaceutical preparation according to any one of [1] to [3], wherein the polyester resin container is an eye drop container. [5] A method for suppressing crystal precipitation in an aqueous composition, comprising the step of placing an aqueous composition containing a compound represented by the general formula (1) or a salt thereof, or a solvate of the compound or the salt in a polyester resin container. [6] The method according to [5], wherein the compound represented by the general formula (1) is ripasudil. [7] The method according to [5] or [6], wherein the polyester resin is polyethylene terephthalate. [8] The method according to any one of [5] to [7], wherein the polyester resin container is an eye drop container.

[0018] [9] The pharmaceutical formulation according to any one of [1] to [4], wherein the aqueous composition further contains one or more selected from the group consisting of α1 receptor blockers, α2 receptor agonists, β-blockers, carbonic anhydrase inhibitors, prostaglandin F2α derivatives, sympathomimetics, parasympathomimetics, calcium channel blockers, and cholinesterase inhibitors.

[10] The pharmaceutical formulation according to any one of [1] to [4], wherein the aqueous composition further contains one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol, and salts thereof.

[11] The method according to any one of [5] to [8], wherein the aqueous composition further contains one or more selected from the group consisting of α1 receptor blockers, α2 receptor agonists, β-blockers, carbonic anhydrase inhibitors, prostaglandin F2α derivatives, sympathomimetics, parasympathomimetics, calcium channel blockers, and cholinesterase inhibitors.

[12] The method according to any one of [5] to [8], wherein the aqueous composition further contains one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, and timolol, and salts thereof.

[0019] In the general formula (1), examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, etc. In the general formula (1), examples of the halogen atom include a fluorine atom and a bromine atom, and a fluorine atom is particularly preferred. In addition, in the general formula (1), the carbon atom constituting the homopiperazine ring substituted with a methyl group is an asymmetric carbon. Therefore, stereoisomerism occurs, but the compound represented by the general formula (1) includes any stereoisomer, and may be a single stereoisomer or a mixture of various stereoisomers in any ratio. As the compound represented by the general formula (1), a compound having an S-configuration as its absolute configuration is preferred.

[0020] The salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt, and specific examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide; and organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate, with hydrochloride being preferred. Furthermore, the compound represented by the general formula (1) or a salt thereof may be a solvate such as a hydrate or alcohol solvate, and is preferably a hydrate.

[0021] Specific examples of the compound represented by the general formula (1) or a salt thereof, or a solvate thereof include: Ripasudil (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline) or its salts or solvates; 4-bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline or its salt, or a solvate thereof; etc.

[0022] The compound represented by the general formula (1) or a salt thereof or a solvate thereof is preferably Ripasudil or a salt thereof or a solvate thereof, 4-bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline or a salt thereof or a solvate thereof, more preferably Ripasudil or a salt thereof or a solvate thereof, and even more preferably Ripasudil or its hydrochloride or a hydrate thereof, and is represented by the following structural formula:

[0023] [ka]

[0024] Ripasudil hydrochloride hydrate (Ripasudil monohydrochloride dihydrate) represented by the following formula is particularly preferred.

[0025] The compound represented by the general formula (1), its salt, or solvate thereof is known and can be produced by known methods. Specifically, for example, Ripasudil, its salt, or solvate thereof can be produced by the methods described in WO 1999 / 020620 and WO 2006 / 057397. Furthermore, 4-bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline, its salt, or solvate thereof can be produced by the method described in WO 2006 / 115244.

[0026] The content of the compound represented by formula (1) or a salt thereof, or a solvate thereof in the aqueous composition is not particularly limited and may be determined appropriately depending on the disease to be treated, the patient's sex, age, symptoms, etc., but from the viewpoint of obtaining an excellent pharmacological effect, the content is preferably 0.01 to 10 w / v%, more preferably 0.02 to 8 w / v%, and particularly preferably 0.04 to 6 w / v%, of the compound represented by formula (1) in free form relative to the total volume of the aqueous composition. In particular, when ripasudil is used as the compound represented by formula (1), from the viewpoint of obtaining an excellent pharmacological effect, the content is preferably 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v%, and particularly preferably 0.1 to 2 w / v%, of ripasudil or a salt thereof, or a solvate thereof in free form relative to the total volume of the aqueous composition.

[0027] As used herein, the term "aqueous composition" refers to a composition containing at least water, and its form may be liquid (solution or suspension) or semi-solid (ointment). The water in the composition may be, for example, purified water, water for injection, or sterilized purified water. The content of water in the aqueous composition is not particularly limited, but is preferably 5% by mass or more, more preferably 20% by mass or more, even more preferably 50% by mass or more, even more preferably 90% by mass or more, and particularly preferably 90 to 99.8% by mass.

[0028] The aqueous composition can be made into various dosage forms according to known methods, for example, as described in the General Provisions for Preparations of the Japanese Pharmacopoeia, Sixteenth Edition. The dosage form is not particularly limited as long as it can be accommodated in a container as described below, and examples include injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal solutions, enemas, topical solutions, sprays, ointments, gels, oral solutions, and syrups. From the viewpoint of advantageously utilizing the pharmacological action of the compound represented by general formula (1), the dosage form is preferably an agent for ophthalmic diseases, specifically eye drops and eye ointments, with eye drops being particularly preferred.

[0029] In addition to the above, the aqueous composition may contain additives used in pharmaceuticals, quasi-drugs, etc., depending on the dosage form. Examples of such additives include inorganic salts, isotonicity agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, thickening agents, surfactants, solubilizers, suspending agents, refreshing agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, etc. Specific examples of such additives include ascorbic acid, potassium aspartate, sodium hydrogen sulfite, alginic acid, sodium benzoate, benzyl benzoate, epsilon-aminocaproic acid, fennel oil, ethanol, ethylene-vinyl acetate copolymer, sodium edetate, tetrasodium edetate, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride solution, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, Xylitol, citric acid hydrate, sodium citrate hydrate, glycerin, gluconic acid, L-glutamic acid, sodium L-glutamate, creatinine, chlorhexidine gluconate solution, chlorobutanol, crystalline sodium dihydrogen phosphate, geraniol, sodium chondroitin sulfate, acetic acid, potassium acetate, sodium acetate hydrate, titanium dioxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzododecinium bromide, tartaric acid, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol Solution, sorbic acid, potassium sorbate, taurine, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyloxapol, sodium dehydroacetate, trometamol, concentrated glycerin, concentrated mixed tocopherols, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride solution 50, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin, hydroxyethyl cellulose, hydroxypropyl cellulose, Promellose, glacial acetic acid, sodium metabisulfite, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalkonium chloride, benzalkonium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, borax, boric acid, povidone, polyoxyethylene (200), polyoxypropylene glycol (70), sodium polystyrene sulfonate, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl alcohol (partially saponified), d-borneol, macrogol 4000,Examples include macrogol 6000, D-mannitol, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methanesulfonic acid, methylcellulose, l-menthol, monoethanolamine, aluminum monostearate, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, ryuuno, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, malic acid, and petrolatum.

[0030] Preferred examples of additives include potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, concentrated glycerin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, borax, boric acid, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified), macrogol 4000, macrogol 6000, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, monoethanolamine, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium hyaluronate, glucose, and l-menthol.

[0031] The aqueous composition may further contain other medicinal ingredients in addition to those mentioned above, depending on the disease to be treated, etc. Examples of such medicinal ingredients include α1 receptor blockers including bunazosin such as bunazosin hydrochloride, or a salt thereof, or a solvate thereof; brimonidine such as brimonidine tartrate, or a salt thereof, or a solvate thereof; α2 receptor blockers including apraclonidine, or a salt thereof, or a solvate thereof; carteol such as carteol hydrochloride, or a salt thereof, or a solvate thereof; nipradilol, or a salt thereof, or a solvate thereof; and timolol such as timolol maleate, or a salt thereof, or a solvate thereof. beta-blockers including betaxolol or a salt thereof or a solvate thereof such as betaxolol hydrochloride, levobunolol or a salt thereof or a solvate thereof such as levobunolol hydrochloride, befunolol or a salt thereof or a solvate thereof, metipranolol or a salt thereof or a solvate thereof; dorzolamide or a salt thereof or a solvate thereof such as dorzolamide hydrochloride, brinzolamide or a salt thereof or a solvate thereof, acetazolamide or a salt thereof or a solvate thereof, dichlorphenamide or or a solvate thereof, carbonic anhydrase inhibitors including methazolamide or a salt thereof or a solvate thereof; isopropyl unoprostone or a salt thereof or a solvate thereof, tafluprost or a salt thereof or a solvate thereof, travoprost or a salt thereof or a solvate thereof, bimatoprost or a salt thereof or a solvate thereof, latanoprost or a salt thereof or a solvate thereof, cloprostenol or a salt thereof or a solvate thereof, fluprostenol or a salt thereof or a solvate thereof prostaglandin F2α derivatives including; sympathomimetics including dipivefrin such as dipivefrin hydrochloride or its salts or solvates thereof, epinephrine, epinephrine borate, epinephrine hydrochloride or its salts or solvates thereof; parasympathomimetics including distigmine bromide or its salts or solvates thereof, pilocarpine such as pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate or its salts or solvates thereof, carbachol or its salts or solvates thereof;Calcium antagonists including lomerizine, such as lomerizine hydrochloride, or a salt thereof, or a solvate thereof; cholinesterase inhibitors including demecarium, a salt thereof, or a solvate thereof, echothiophate, a salt thereof, or a solvate thereof, and physostigmine, a salt thereof, or a solvate thereof, and the like, and one or more of these can be combined; The other active ingredient is preferably at least one selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol, and salts thereof.

[0032] The pH of the aqueous composition is not particularly limited, but is preferably 4 to 9, more preferably 4.5 to 8, and particularly preferably 5 to 7. The osmotic pressure ratio relative to physiological saline is not particularly limited, but is preferably 0.6 to 3, and particularly preferably 0.6 to 2.

[0033] As used herein, the term "container" refers to a package that directly contains the aqueous composition. The term "container" encompasses any of the terms "sealed container," "airtight container," and "sealed container" defined in the General Rules of the Japanese Pharmacopoeia, 16th Edition.

[0034] The shape of the container is not particularly limited as long as it can accommodate the aqueous composition, and may be appropriately selected and set depending on the dosage form, the use of the pharmaceutical preparation, etc. Specific examples of such container shapes include containers for injections, containers for inhalants, containers for sprays, bottle-shaped containers, tube-shaped containers, containers for eye drops, containers for nasal drops, containers for ear drops, and bag-shaped containers.

[0035] As used herein, a "polyester resin container" refers to a container in which at least the portion of the container that comes into contact with the aqueous composition is "made of a polyester resin." Therefore, for example, a container having a polyester resin layer as the inner layer that comes into contact with the aqueous composition and a resin of another material laminated on the outer surface also falls under the category of a "polyester resin container." The dicarboxylic acids and diols that constitute the polyester resin are not particularly limited. Examples of dicarboxylic acids include phthalic acid, terephthalic acid, and 2,6-naphthalenedicarboxylic acid. Examples of diols include ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,4-cyclohexanedimethanol, and bisphenol. The polyester resin may be a polymer of a single type of polyester unit or a polymer of multiple types of polyester units. In the case of a polymer of multiple types of polyester units, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization. Furthermore, the stereoregularity (tacticity) is not particularly limited. Specific examples of such polyester-based resins include homopolyesters such as polyalkylene terephthalates (e.g., polyethylene terephthalate, polybutylene terephthalate, etc.), polyalkylene naphthalates (e.g., polyethylene naphthalate, polybutylene naphthalate, etc.), polycycloalkylene terephthalates (e.g., poly(1,4-cyclohexylene dimethylene terephthalate)), and polyarylates (e.g., resins composed of bisphenol and phthalic acid), as well as copolyesters containing these homopolyester units as the main component, and copolymers of the homopolyesters, and these can be used alone or in combination of two or more. As the polyester-based resin, polyethylene terephthalate is preferred from the viewpoint of suppressing crystal precipitation. In this specification, "made of polyester-based resin" means that at least a portion of the material contains polyester-based resin, and for example, a mixture of two or more resins, such as polyester-based resin and other resins (polymer alloy), is also included in "made of polyester-based resin."

[0036] It is preferable to further incorporate a substance that blocks the transmission of ultraviolet light, such as an ultraviolet absorber or an ultraviolet scattering agent, into the polyester resin container. This improves the stability of the compound represented by general formula (1) against light. Specific examples of such substances include titanium oxide as an ultraviolet scattering agent;Examples include zinc oxide. Examples of ultraviolet absorbers include 2-(2H-benzotriazol-2-yl)-p-cresol (e.g., Tinuvin P, manufactured by BASF), 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol (e.g., Tinuvin 234, manufactured by BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)benzotriazole (e.g., Tinuvin 320, manufactured by BASF), 2-[5-chloro(2H)-benzotriazol-2-yl]-4-methyl-6-(tert-butyl)phenol (e.g., Tinuvin 326, manufactured by BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)-5-chlorobenzotriazole (e.g., Tinuvin 327, manufactured by BASF), and 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (e.g., Tinuvin PA328: BASF), 2-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol (e.g., Tinuvin 329: BASF), 2,2'-methylenebis[6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol] (e.g., Tinuvin 360: BASF), reaction products of methyl 3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionate with polyethylene glycol 300 (e.g., Tinuvin 213: BASF), 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol (e.g., Tinuvin 571: BASF), benzotriazole-based ultraviolet absorbers such as 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole, 2-[2'-hydroxy-3'-(3'',4'',5'',6''-tetrahydrophthalimidomethyl)-5'-methylphenyl]benzotriazole, and 2,2'-methylenebis[4-(1,1,3,3-tetramethylbutyl)-6-(2H-benzotriazol-2-yl)phenol];Cyanoacrylate-based UV absorbers such as 2,2-bis{[2-cyano-3,3-diphenylacryloyloxy]methyl}propane-1,3-diyl bis(2-cyano-3,3-diphenylacrylate) (e.g., Uvinul 3030 FF: BASF), ethyl 2-cyano-3,3-diphenylacrylate (e.g., Uvinul 3035: BASF), and 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (e.g., Uvinul 3039: BASF); triazine-based UV absorbers such as 2-(4,6-diphenyl-1,3,5-triazin-2-yl)-5-[(hexyl)oxy]phenol (e.g., Tinuvin 1577 ED: BASF); octabenzone (e.g., Chimassorb Benzophenone-based ultraviolet absorbers such as benzophenone-based UV absorbers such as 2,2'-dihydroxy-4,4'-dimethoxybenzophenone (e.g., Uvinul 3049: BASF), 2,2'-4,4'-tetrahydrobenzophenone (e.g., Uvinul 3050: BASF), oxybenzone, hydroxymethoxybenzophenone sulfonic acid, hydroxymethoxybenzophenone sodium sulfonate, dihydroxydimethoxybenzophenone, dihydroxydimethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, and tetrahydroxybenzophenone; methyl diisopropylcinnamate, cinoxate, glyceryl di-p-methoxycinnamate mono-2-ethylhexanoate, isopropyl p-methoxycinnamate / diisopropyl cinnamate mixture, 2-ethylhexyl p-methoxycinnamate, and cinnamic acid benzyl ester. Cinnamic acid-based UV absorbers such as para-aminobenzoic acid, ethyl para-aminobenzoate, glyceryl para-aminobenzoate, amyl para-dimethylaminobenzoate, 2-ethylhexyl para-dimethylaminobenzoate, and ethyl 4-[N,N-di(2-hydroxypropyl)amino]benzoate; salicylic acid-based UV absorbers such as ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, and methyl salicylate; guaiazulene; 2-ethylhexyl dimethoxybenzylidene dioxoimidazolidinepropionate;Examples include 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,5-triazine; parahydroxyanisole; 4-tert-butyl-4'-methoxydibenzoylmethane; phenylbenzimidazole sulfonic acid; 2-(4-diethylamino-2-hydroxybenzoyl)-hexyl benzoate;

[0037] When a substance that blocks ultraviolet light transmission is kneaded into the container, the mixing ratio varies depending on the type of substance, etc., but may be, for example, about 0.001 to 50 mass %, preferably 0.002 to 25 mass %, and particularly preferably 0.01 to 10 mass % in the container.

[0038] It is preferable that the interior of the container is visible (observable) with the naked eye. If the interior is visible, it is possible to inspect for the presence of foreign matter during the manufacturing process of the pharmaceutical preparation, and it is possible for users of the pharmaceutical preparation to check the remaining amount of the contents (aqueous composition). Here, visibility is sufficient as long as at least a portion of the container surface is ensured (for example, even if the side of an eye drop container is obscured by a shrink film or the like, it can be said that visibility is possible as long as the bottom surface is visible). If the interior is visible from a portion of the container surface, this makes it possible to check the aqueous composition in the container.

[0039] The means for storing the aqueous composition in the container is not particularly limited, and the aqueous composition may be filled in a conventional manner according to the shape of the container.

[0040] The indications for the pharmaceutical preparation are not particularly limited, and may be appropriately selected depending on the pharmacological action of the compound represented by the general formula (1) above. Specifically, for example, the compound represented by general formula (1) can be used as an agent for preventing or treating ocular hypertension or glaucoma, based on its Rho kinase inhibitory activity and intraocular pressure-reducing activity. More specific examples of glaucoma include primary open-angle glaucoma, normal-tension glaucoma, excessive aqueous humor production glaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma, steroid-induced glaucoma, lenticular capsular glaucoma, pigmentary glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma.

[0041] Furthermore, as disclosed in Japanese Patent No. 5557408, ocular fundus diseases (lesions that mainly occur in the retina and / or choroid. Specific examples thereof include fundus changes due to hypertension and arteriosclerosis, retinal vein occlusions such as central retinal artery occlusion, central retinal vein occlusion, and branch retinal vein occlusion, congenital retinal vascular abnormalities such as diabetic retinopathy, diabetic macular edema, diabetic maculopathy, Eales disease, and Coats disease, von Hippel disease, pulseless disease, macular diseases (central serous chorioretinopathy, cystoid macular edema, age-related macular degeneration, macular hole, myopic macular atrophy), and other diseases. The present invention can be used as a prophylactic or therapeutic agent for diabetic retinopathy, diabetic macular edema, or age-related macular degeneration, more preferably diabetic retinopathy, diabetic macular edema, or age-related macular degeneration, and ... retinopathy, diabetic macular edema, or age-related macular degeneration, and more preferably diabetic retinopathy, diabetic retinopathy, diabetic macular edema, or age-related macular degeneration, and more preferably diabetic retinopathy, diabetic retinopathy, diabetic macular edema, or age-related macular degeneration, and more preferably diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, [Example]

[0042] The present invention will now be further described with reference to examples, but the present invention is not limited to these examples. In the following test examples, Ripasudil monohydrochloride dihydrate can be produced, for example, by the method described in WO 2006 / 057397.

[0043] [Test Example 1] Preservation test Part 1 Aqueous compositions having the formulations shown in Table 1 were prepared by a conventional method, and then placed in polyethylene terephthalate (PET) or polyvinyl chloride (PVC) containers to prepare pharmaceutical preparations. Each of the obtained pharmaceutical preparations was stored at 0°C for 2 days, and then visually evaluated for the presence or absence of crystal precipitation. The case where no crystal precipitation was observed was marked with ○, and the case where crystal precipitation was observed was marked with ×. The results are shown in Table 2.

[0044] [Table 1]

[0045] [Table 2]

[0046] As shown in the results in Table 2, when an aqueous composition containing Ripasudil was placed in a container made of a polyester resin such as polyethylene terephthalate (PET), no crystal precipitation was observed even when stored at low temperatures, whereas when placed in a container made of polyvinyl chloride (PVC), crystal precipitation was observed.

[0047] [Test Example 2] Preservation test No. 2 The aqueous compositions shown in Table 3 were prepared by a conventional method and then placed in polyethylene terephthalate (PET) containers to prepare pharmaceutical preparations. The obtained pharmaceutical preparation was stored at 0°C for 21 days, and then visually evaluated for the presence or absence of crystal precipitation. The case where no crystal precipitation was observed was marked with ◯, and the case where crystal precipitation was observed was marked with ×. The results are shown in Table 4.

[0048] [Table 3]

[0049] [Table 4]

[0050] As shown in Table 4, even when the formulation of the aqueous composition was changed, no crystal precipitation was observed when the composition was stored in a container made of a polyester resin such as polyethylene terephthalate (PET) or at low temperatures.

[0051] The results of the above test examples 1 and 2 revealed that when an aqueous composition containing a compound represented by general formula (1), including Ripasudil, or a salt thereof, or a solvate thereof, is placed in a polyester resin container, crystals are relatively unlikely to precipitate even when stored at low temperatures, and the composition has excellent storage stability.

[0052] [Manufacturing Examples 1 to 27] Aqueous compositions containing the ingredients and amounts (amounts (g) per 100 mL of aqueous composition) shown in Tables 5 to 7 are prepared by a conventional method and placed in polyethylene terephthalate eye drop containers to produce the pharmaceutical preparations of Preparation Examples 1 to 27.

[0053] [Table 5]

[0054] [Table 6]

[0055] [Table 7]

[0056] [Manufacturing Examples 28-54] Pharmaceutical preparations of Preparation Examples 28 to 54 can be produced by conventional methods by using the same amount of 4-bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline in place of Ripasudil monohydrochloride dihydrate in Preparation Examples 1 to 27. [Industrial Applicability]

[0057] According to the present invention, a pharmaceutical preparation having excellent storage stability can be provided, and can be suitably used in the pharmaceutical industry and the like.

Claims

[Claim 1] The invention described herein.

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