Aqueous composition

Abstract

To provide a technique for enhancing stability of brimonidine in an aqueous composition.SOLUTION: By further incorporating a halogenated isoquinoline derivative represented by ripasudil in an aqueous composition containing brimonidine, a decrease in the content of brimonidine in the aqueous composition is suppressed.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an aqueous composition and the like. [Background technology]

[0002] Brimonidine, such as brimonidine tartrate (chemical name: 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxaline-6-amine mono-(2R,3R)-tartrate), is a type of adrenergic α2 receptor agonist that inhibits aqueous humor production and promotes aqueous humor outflow from the uveoscleral outflow pathway, and exhibits excellent intraocular pressure-reducing effects. Therefore, it is used as an active ingredient in ophthalmic agents, such as drugs for treating ocular hypertension and glaucoma (Non-Patent Document 1). Ophthalmic agents are usually compositions containing water (aqueous compositions), and various studies have been conducted on aqueous compositions containing brimonidine (e.g., Patent Documents 1 and 2).

[0003] By the way, the following structural formula:

[0004] [ka]

[0005] Ripasudil (chemical name: 4-fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline) represented by the following structural formula:

[0006] [ka]

[0007] 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 3 and 4), and are known to be useful for the prevention and treatment of eye diseases. Specifically, for example, they have been reported to be useful for the prevention or treatment of ocular hypertension, glaucoma, and the like (e.g., Patent Document 5), and Glanatec (registered trademark) eye drops 0.4% containing ripasudil as an active ingredient has been marketed in Japan as a treatment for ocular hypertension and glaucoma. However, there have been no specific reports so far on aqueous compositions containing brimonidine or a salt thereof, or a solvate thereof, and a halogenated isoquinoline derivative. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Special Publication No. 2004-504279 [Patent Document 2] Japanese Patent Application Laid-Open No. 2012-246304 [Patent Document 3] Patent No. 4212149 [Patent Document 4] International Publication No. 2006 / 115244 Brochure [Patent Document 5] International Publication No. 2006 / 068208 Pamphlet [Non-patent literature]

[0009] [Non-Patent Document 1] Aiphagan (registered trademark) eye drops 0.1% Pharmaceutical Interview Form, Senju Pharmaceutical Co., Ltd., May 2013 (revised 4th edition) Summary of the Invention [Problem to be solved by the invention]

[0010] Aqueous compositions have the advantages of being gentle to living organisms such as ocular tissues and being highly safe because they contain water, and are easy to handle during production and use, but the active ingredient is prone to destabilization due to reactions mediated by water, etc. By improving the stability of aqueous compositions containing brimonidine, it is possible to provide pharmaceuticals and the like of higher quality. Therefore, an object of the present invention is to provide a technique for improving the stability of brimonidine in an aqueous composition. [Means for solving the problem]

[0011] Therefore, the present inventors have conducted extensive research to solve the above-mentioned problems and have surprisingly found that by further adding a halogenated isoquinoline derivative, typified by Ripasudil, to an aqueous composition containing brimonidine, the decrease in the brimonidine content in the aqueous composition can be suppressed, thereby completing the present invention.

[0012] That is, the present invention provides a composition comprising the following components (A) and (B): (A) brimonidine or a salt thereof or a solvate thereof; (B) General formula (1)

[0013] [ka]

[0014] [In the formula, X represents a halogen atom.] a compound represented by the formula (I) or a salt thereof, or a solvate thereof; The present invention provides an aqueous composition comprising:

[0015] The present invention also provides the following component (A): (A) brimonidine or a salt thereof or a solvate thereof; to an aqueous composition containing the following component (B): (B) a compound represented by the general formula (1) or a salt thereof, or a solvate thereof; The present invention provides a method for stabilizing brimonidine, a salt thereof, or a solvate thereof in an aqueous composition, the method comprising: [Effects of the Invention]

[0016] According to the present invention, it is possible to prevent a decrease in the brimonidine content in an aqueous composition and to provide an aqueous composition having excellent stability. DETAILED DESCRIPTION OF THE INVENTION

[0017] <Brimonidine or its salt or solvate thereof> As used herein, "brimonidine or a salt thereof, or a solvate thereof" includes not only brimonidine but also pharmacologically acceptable salts of brimonidine, as well as solvates of brimonidine or a pharmacologically acceptable salt thereof with water, alcohol, etc. Specific examples of pharmacologically acceptable salts include, but are not limited to, 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 tartrate being preferred.

[0018] Brimonidine, a salt thereof, or a solvate thereof is preferably brimonidine or brimonidine tartrate (brimonidine monotartrate) (chemical name: 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxaline-6-amine mono-(2R,3R)-tartrate). Brimonidine, a salt thereof, or a solvate thereof is known and may be produced by a known method, or a commercially available product may be used.

[0019] The content of brimonidine 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 sex, age, symptoms, etc. of the patient. From the viewpoint of obtaining an excellent pharmacological effect, the content is preferably 0.01 to 10 w / v%, more preferably 0.02 to 1 w / v%, and particularly preferably 0.06 to 0.5 w / v%, relative to the total volume of the aqueous composition.

[0020] <Compound represented by general formula (1), a salt thereof, or a solvate thereof> 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.

[0021] 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.

[0022] 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 a salt thereof, or a solvate thereof; etc.

[0023] 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:

[0024] [ka]

[0025] Ripasudil hydrochloride hydrate (Ripasudil monohydrochloride dihydrate) represented by the following formula is particularly preferred.

[0026] 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.

[0027] 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, but from the viewpoint of the effect of suppressing a decrease in the content of brimonidine or a salt thereof, or a solvate thereof, the content is preferably 0.01 to 10 w / v%, more preferably 0.1 to 8 w / v%, and particularly preferably 0.25 to 6 w / v%, calculated as the free form of the compound represented by formula (1), 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 the effect of suppressing a decrease in the content of brimonidine or a salt thereof, or a solvate thereof, the content is preferably 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v%, even more preferably 0.1 to 2 w / v%, and particularly preferably 0.25 to 1 w / v%, calculated as the free form of ripasudil or a salt thereof, or a solvate thereof, relative to the total volume of the aqueous composition.

[0028] Furthermore, the mass ratio of brimonidine or a salt thereof, or a solvate thereof to the compound represented by the general formula (1), or a salt thereof, or a solvate thereof in the aqueous composition is not particularly limited, but from the viewpoint of inhibiting a decrease in the content of brimonidine or a salt thereof, or a solvate thereof, the aqueous composition preferably contains 0.01 to 1.5 parts by mass, more preferably 0.04 to 0.8 parts by mass, and particularly preferably 0.08 to 0.4 parts by mass of brimonidine or a salt thereof, or a solvate thereof per part by mass of the compound represented by the general formula (1) converted into its free form. In particular, when the compound represented by general formula (1) or a salt thereof or a solvate thereof is Ripasudil or a salt thereof or a solvate thereof, from the viewpoint of inhibiting a decrease in the content of brimonidine or a salt thereof or a solvate thereof, it is preferable to contain 0.02 to 1 part by mass of brimonidine or a salt thereof or a solvate thereof per 1 part by mass of Ripasudil converted to its free form, more preferably 0.06 to 0.5 parts by mass, and particularly preferably 0.1 to 0.3 parts by mass.

[0029] 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), with liquid being preferred. The water in the composition may be, for example, purified water, water for injection, sterilized purified water, etc. 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.

[0030] 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 Sixteenth Edition of the Japanese Pharmacopoeia. Examples of dosage forms 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 effects of brimonidine and the compound represented by general formula (1), preferred dosage forms are ophthalmic preparations, specifically eye drops and eye ointments, with eye drops being particularly preferred.

[0031] Depending on the dosage form, the aqueous composition may contain additives used in pharmaceuticals, quasi-drugs, etc. 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, chitosan, methylparaben ... Ciritol, 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 oxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzododecinium bromide, tartaric acid, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution, 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, hypromellose, glacial acetic acid, sodium metabisulfite Um, 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, macrogol 6000, D-mannitol,Examples of the additive include anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methanesulfonic acid, methylcellulose, 1-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, sodium dihydrogen phosphate dihydrate, malic acid, and petrolatum.

[0032] 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, D-mannitol, 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 dihydrogen phosphate dihydrate, sodium hyaluronate, glucose, and l-menthol.

[0033] 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; α2 receptor agonists including apraclonidine, or a salt thereof, or a solvate thereof; carteolol such as carteolol hydrochloride, or a salt thereof, or a solvate thereof; nipradilol, or a salt thereof, or a solvate thereof; timolol such as timolol maleate, or a salt thereof, or a solvate thereof; and betaxolol such as betaxolol hydrochloride, or a salt thereof, or a solvent thereof. beta-blockers including levobunolol or its salts or solvates thereof such as levobunolol hydrochloride, befunolol or its salts or solvates thereof, metipranolol or its salts or solvates thereof; dorzolamide or its salts or solvates thereof such as dorzolamide hydrochloride, brinzolamide or its salts or solvates thereof, acetazolamide or its salts or solvates thereof, dichlorphenamide or its salts or solvates thereof, methazolamide or its salts or solvates thereof carbonic anhydrase inhibitors including; prostaglandins including isopropyl unoprostone or its salts or solvates thereof, tafluprost or its salts or solvates thereof, travoprost or its salts or solvates thereof, bimatoprost or its salts or solvates thereof, latanoprost or its salts or solvates thereof, cloprostenol or its salts or solvates thereof, fluprostenol or its salts or solvates thereof; dipivefrin or its salts such as dipivefrin hydrochloride or solvates thereof, sympathomimetics containing epinephrine or its salts or solvates thereof, such as epinephrine, epinephrine borate, epinephrine hydrochloride; parasympathomimetics containing distigmine bromide or its salts or solvates thereof, pilocarpine or its salts or solvates thereof, such as pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, etc., carbachol or its salts or solvates thereof; calcium channel blockers containing lomerizine or its salts or solvates thereof, such as lomerizine hydrochloride;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, may be used alone or in combination of two or more of these; The other active ingredient is preferably one or more selected from the group consisting of latanoprost, timolol, nipradilol, dorzolamide, brinzolamide, and salts thereof.

[0034] The pH (25°C) of the aqueous composition is not particularly limited, but is preferably 4 to 8.5, more preferably 5 to 8, and particularly preferably 6 to 7.5. The osmotic pressure ratio relative to physiological saline is not particularly limited, but is preferably 0.6 to 3, and more preferably 0.6 to 2.

[0035] The aqueous composition is preferably housed in a container from the viewpoints of storage stability, portability, etc. The shape of the container is not particularly limited as long as it can house the aqueous composition, and may be appropriately selected and set depending on the dosage form, etc. Specific examples of such container shapes include containers for injections, inhalants, sprays, bottle-shaped containers, tube-shaped containers, eye drops, nasal drops, ear drops, and bag-shaped containers. These containers may also be packaged in boxes, bags, etc.

[0036] The material of the container is not particularly limited and may be appropriately selected depending on the shape of the container. Specific examples include glass, plastic, cellulose, pulp, rubber, metal, etc. From the viewpoints of processability, squeezability, and durability, plastic is preferred. The resin for the plastic container is preferably a thermoplastic resin, and examples thereof include polyolefin-based resins such as low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, polypropylene, and cyclic polyolefin; polyester-based resins such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, and poly(1,4-cyclohexylene dimethylene terenaphthalate); polyphenylene ether-based resins; polycarbonate-based resins; polysulfone-based resins; polyamide-based resins; polyvinyl chloride resins; and styrene-based resins, and mixtures thereof (polymer alloys) may also be used.

[0037] The disease to which the aqueous composition is applied is not particularly limited, and may be appropriately selected depending on the pharmacological action of brimonidine or the compound represented by the general formula (1). Specifically, for example, based on the adrenergic α2 receptor activating activity and intraocular pressure-reducing activity of brimonidine, and based on the Rho kinase inhibitory activity and intraocular pressure-reducing activity of the compound represented by general formula (1), brimonidine can be used as a preventive or therapeutic agent for ocular hypertension and glaucoma. In this case, the intraocular pressure-reducing activity of brimonidine and the intraocular pressure-reducing activity of the compound represented by general formula (1) are combined to provide an excellent intraocular pressure-reducing effect, thereby providing excellent preventive and / or therapeutic effects for ocular hypertension and glaucoma, which is preferable. 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.

[0038] Furthermore, as disclosed in Japanese Patent No. 5557408, based on the action of the compound represented by general formula (1), it is possible to treat ocular fundus diseases (lesions occurring mainly in the retina and / or choroid, specifically, for example, 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, diabetic retinopathy, diabetic macular edema, diabetic maculopathy, congenital retinal vascular abnormalities such as Eales disease and Coats disease, von Hippel disease, pulseless disease, macular diseases (central serous chorioretinopathy, cystoid macular edema, age-related macular degeneration, macular hole, etc.), and the like. Examples of the prophylactic or therapeutic agent include retinal detachment (rhegmatogenous, tractional, exudative, etc.), myopic macular atrophy (myopic macular degeneration), vitreoretinal interface macular degeneration, drug-toxic macular degeneration, hereditary macular degeneration, etc.), retinal detachment (rhegmatogenous, tractional, exudative, etc.), retinitis pigmentosa, retinopathy of prematurity, etc.), more preferably diabetic retinopathy, diabetic macular edema, or age-related macular degeneration. Furthermore, the prophylactic or therapeutic agent may be used as a therapeutic agent for postoperative complications of cataract surgery, such as secondary cataract and anterior capsule contraction, or as a therapeutic agent for corneal edema.

[0039] When the aqueous composition is used as a preventive and / or therapeutic agent for an eye disease (preferably a disease selected from ocular hypertension, glaucoma, and ocular fundus disease; particularly preferably a disease selected from ocular hypertension and glaucoma), an appropriate amount (for example, about one drop in the case of eye drops) may be administered about 1 to 3 times a day, preferably about 1 to 2 times a day, depending on the expected level of efficacy.

[0040] The present specification discloses the following aspects of the invention, for example, but is not limited to these. [1] The following components (A) and (B): (A) brimonidine or a salt thereof or a solvate thereof; (B) General formula (1)

[0041] [ka]

[0042] [In the formula, X represents a halogen atom.] a compound represented by the formula (I) or a salt thereof, or a solvate thereof; An aqueous composition comprising: [2] The aqueous composition according to [1], wherein the compound represented by the general formula (1) is Ripasudil. [3] The aqueous composition according to [1] or [2], wherein component (A) is brimonidine tartrate. [4] The aqueous composition according to any one of [1] to [3], wherein component (B) is ripasudil hydrochloride hydrate (ripasudil monohydrochloride dihydrate). [5] The aqueous composition according to any one of [1] to [4], wherein the content of component (A) is 0.01 to 10 (preferably 0.02 to 1, particularly preferably 0.06 to 0.5) w / v% relative to the total volume of the aqueous composition. [6] The aqueous composition according to any one of [1] to [5], wherein the content of component (B) is 0.01 to 10 (preferably 0.1 to 8, particularly preferably 0.25 to 6) w / v% calculated as the free form of the compound represented by general formula (1) relative to the total volume of the aqueous composition. [7] The aqueous composition according to any one of [1] to [6], which is an ophthalmic agent. [8] The aqueous composition according to [7], which is an eye drop. [9] The aqueous composition according to any one of [1] to [8], which is an agent for preventing and / or treating a disease selected from the group consisting of ocular hypertension and glaucoma.

[0043]

[10] The aqueous composition according to any one of [1] to [9], further comprising one or more members selected from the group consisting of alpha-1 receptor blockers, alpha-2 receptor agonists, beta-blockers, carbonic anhydrase inhibitors, prostaglandins, sympathomimetics, parasympathomimetics, calcium antagonists, and cholinesterase inhibitors.

[11] The aqueous composition according to any one of [1] to [9], further comprising one or more selected from the group consisting of latanoprost, timolol, nipradilol, dorzolamide, brinzolamide, salts thereof, and solvates thereof.

[0044]

[12] The following component (A): (A) brimonidine or a salt thereof or a solvate thereof; to an aqueous composition containing the following component (B): (B) a compound represented by the general formula (1) or a salt thereof, or a solvate thereof; A method for stabilizing (preferably suppressing a decrease in content of) brimonidine or a salt thereof, or a solvate thereof in an aqueous composition, comprising:

[13] The method according to

[12] , wherein the compound represented by the general formula (1) is ripasudil.

[14] The method according to

[12] or

[13] , wherein component (A) is brimonidine tartrate.

[15] The method according to any one of

[12] to

[14] , wherein component (B) is ripasudil hydrochloride hydrate (ripasudil monohydrochloride dihydrate).

[16] The method according to any one of

[12] to

[15] , wherein the content of component (A) in the aqueous composition is 0.01 to 10 (preferably 0.02 to 1, particularly preferably 0.06 to 0.5) w / v% relative to the total volume of the aqueous composition.

[17] The method according to any one of

[12] to

[16] , wherein the content of component (B) in the aqueous composition is 0.01 to 10 (preferably 0.1 to 8, particularly preferably 0.25 to 6) w / v% in terms of the free form of the compound represented by general formula (1) relative to the total volume of the aqueous composition.

[18] The method according to any one of

[12] to

[17] , wherein the aqueous composition is an ophthalmic agent.

[19] The method according to

[18] , wherein the ophthalmic agent is an eye drop.

[20] The method according to any one of

[12] to

[19] , wherein the aqueous composition is an agent for preventing and / or treating a disease selected from the group consisting of ocular hypertension and glaucoma.

[0045]

[21] The method according to any one of

[12] to

[20] , 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, prostaglandins, sympathomimetics, parasympathomimetics, calcium channel blockers, and cholinesterase inhibitors.

[22] The method according to any one of

[12] to

[20] , wherein the aqueous composition further contains one or more compounds selected from the group consisting of latanoprost, timolol, nipradilol, dorzolamide, brinzolamide, salts thereof, and solvates thereof. [Example]

[0046] 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.

[0047] [Test Example 1] Storage test (evaluation of brimonidine stability) In order to evaluate the stability of brimonidine in the aqueous compositions, aqueous compositions of Example 1 and Comparative Example 1 containing the ingredients and amounts shown in Table 1 per 100 mL were prepared by a conventional method. Each of the resulting aqueous compositions was stored at 80°C for 1 day, and the remaining percentage of brimonidine after storage was measured as follows. That is, for each aqueous composition before the start of storage and after 1 day of storage, the peak height was measured using an HPLC device, and the remaining rate (%) of brimonidine was calculated according to the following formula, which was used as an index of content reduction.

[0048] Residual brimonidine rate (%) = peak height of brimonidine after storage / peak height of brimonidine before storage × 100

[0049] The results are shown in Table 1.

[0050] [Table 1]

[0051] The results shown in Table 1 indicate that the aqueous composition containing only brimonidine (Comparative Example 1) exhibited a decrease in brimonidine content, with the residual rate of brimonidine reaching approximately 96.5% after storage at 80°C for 1 day. On the other hand, the aqueous composition containing ripasudil in addition to brimonidine (Example 1) showed substantially no decrease in brimonidine content even after storage at 80°C for 1 day.

[0052] [Test Example 2] Storage test (Evaluation of brimonidine stability Part 2) In order to confirm the stability of brimonidine in a system containing additives commonly used in ophthalmic preparations, aqueous compositions of Example 2 and Comparative Example 2 containing the ingredients and amounts shown in Table 2 per 100 mL were prepared by a conventional method. The resulting aqueous compositions were stored at 80°C for 1 day, and the residual percentage of brimonidine after storage was measured in the same manner as in Test Example 1. The results are shown in Table 2.

[0053] [Table 2]

[0054] The results shown in Table 2 indicate that the brimonidine content decreased significantly in systems containing additives commonly used in ophthalmic preparations, and that the aqueous composition containing only brimonidine (Comparative Example 2) showed a significant decrease in brimonidine residual rate of 92.3% after storage at 80°C for 1 day, resulting in a decrease in content. On the other hand, the aqueous composition containing ripasudil in addition to brimonidine (Example 2) showed a significant decrease in brimonidine residual rate of 97.3% even after storage at 80°C for 1 day, confirming that the decrease in brimonidine content was suppressed, as in Test Example 1.

[0055] The results of the above Test Examples 1 and 2 revealed that the decrease in the brimonidine content can be suppressed by further adding a compound represented by general formula (1), such as Ripasudil, or a salt thereof, or a solvate thereof to an aqueous composition containing brimonidine, a salt thereof, or a solvate thereof.

[0056] [Manufacturing Examples 1 to 27] Aqueous compositions containing the ingredients and amounts (amounts (g) per 100 mL of aqueous composition) shown in Tables 3 to 5 can be produced by conventional methods.

[0057] [Table 3]

[0058] [Table 4]

[0059] [Table 5]

[0060] [Manufacturing Examples 28-54] The aqueous compositions of Preparation Examples 28 to 54 can be prepared by a conventional method 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]

[0061] According to the present invention, an aqueous composition having excellent stability can be provided, which can be suitably used in the pharmaceutical industry and the like.

Claims

[Claim 1] The invention described herein.

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