Technical field
[0001]
　The present invention relates to aqueous compositions and the like.
Background technique
[0002]
　The following structural formula:
[0003]
[Formula 1]

[0004]
In represented Ripasujiru (chemical name: 4-Fluoro -5 - {[(2S) -2- methyl-1,4-diazepan-1-yl] sulfonyl} isoquinoline) and the following structural formula:
[0005]
[Formula 2]

[0006]
In represented by 4-bromo-5 - halogenated isoquinoline derivatives such as {[(2S) -2- methyl-1,4-diazepan-1-yl] sulfonyl} isoquinoline, pharmacological actions such as Rho kinase inhibitory action ( for example, a patent document 1 and 2), are known to be useful for the prevention and treatment of eye diseases. Specifically, for example, prevention or treatment of such ocular hypertension and glaucoma (e.g., Patent Document 3), or the prevention or treatment of age-related macular degeneration, etc. fundus diseases (e.g., patent document 4) to be useful It has been reported.
[0007]
　Therefore, these halogenated isoquinoline derivatives, for example, to establish a technique for stably formulated as ophthalmic agent is very useful.
[0008]
　Meanwhile, Patent Document 5, Ripasujiru ((S) - (-) - 1- (4- fluoro-5-isoquinoline sulfonyl) -2-methyl-1,4-homopiperazine) or a salt thereof or a solvated the combination of goods and prostaglandins such as latanoprost is disclosed. However, Patent Document 5, only that the eye drop containing 0.05% solution and latanoprost containing Ripasujiru 0.4% were sequentially instilled in same eye of cynomolgus monkeys are disclosed, both these to accommodate both aqueous composition containing or it components in a container and further does not disclose at all about the temporal storage stability and the like.
CITATION
Patent Literature
[0009]
Patent Document 1: Japanese Patent No. 4212149
Patent Document 2: WO 2006/115244 pamphlet
Patent Document 3: WO 2006/068208 Pamphlet
Patent Document 4: Japanese Patent No. 5557408 discloses
Patent Document 5: WO 2012 / 105674 pamphlet
Summary of the Invention
Problems that the Invention is to Solve
[0010]
　Ophthalmic agents are usually compositions containing water (aqueous compositions). The present inventors, when formulating Ripasujiru halogenated isoquinoline derivatives as ophthalmic agent, when preparing an aqueous composition containing Ripasujiru to confirm its storage stability by storage at elevated temperatures, over time a problem that the aqueous composition is discolored occurs has been found to specifically.
　Accordingly, the present invention provides halogenated isoquinoline derivatives containing aqueous composition, and to provide a technique for suppressing discoloration at the time of high-temperature storage.
Means for Solving the Problems
[0011]
　The present inventors have revealed that intensive studies for solving the above problems, the aqueous composition containing the halogenated isoquinoline derivatives such Ripasujiru by further allowed to contain bimatoprost and prostaglandins such as latanoprost, high temperature storage It found that can suppress the discoloration of time, and have completed the present invention.
[0012]
　That is, the present invention has the following general formula (1)
[0013]
[Formula 3]

[0014]
[Wherein, X represents a halogen atom. ]
Compound or a salt thereof or a solvate thereof represented by, and containing prostaglandins, there is provided an aqueous composition.
　Further, the present invention, the compound represented by the general formula (1) or an aqueous composition containing the salt or solvate thereof, comprising the step of allowed to contain prostaglandins, discoloration of the aqueous composition there is provided a method of inhibiting.
Effect of the Invention
[0015]
　According to the present invention, it is possible to suppress the discoloration at the time of high-temperature storage of an aqueous composition that contains a halogenated isoquinoline derivatives such Ripasujiru.
DESCRIPTION OF THE INVENTION
[0016]
　Herein includes, but is not be limited thereto, discloses the invention for example, the following embodiments.
　[1] the following general formula (1)
[0017]
[Chemical Formula 4]

[0018]
[Wherein, X represents a halogen atom. ]
A compound represented by or a salt thereof or a solvate thereof, and containing prostaglandins, the aqueous compositions.
　[2] The compound represented by the general formula (1) is a Ripasujiru, [1] an aqueous composition.
　[3] prostaglandins is isopropyl unoprostone, tafluprost, travoprost, bimatoprost, one or more selected from latanoprost, and the group consisting of salts thereof as well as their solvates, [1] or [2 to an aqueous composition.
　[4] prostaglandins, tafluprost, travoprost, bimatoprost, is latanoprost and one or more selected from the salts thereof as well as the group consisting of solvates, [1] or [2] The aqueous composition according object.
　[5] is an ophthalmic agent, [1] to an aqueous composition according to any one of [4].
　[6] is eye drops, [5] The aqueous composition.
　[7] ocular hypertension, which is a prophylactic and / or therapeutic agent for a disease selected from the group consisting of glaucoma and ocular fundus diseases, [1] to an aqueous composition according to any one of [6].
[0019]
　[8] In addition, [alpha] 1 receptor blocker, [alpha] 2 receptor agonist, beta-blockers, carbonic anhydrase inhibitors, sympathomimetics, parasympathomimetics, selected from the group consisting of calcium antagonists, and cholinesterase inhibitors containing one or more, [1] to an aqueous composition according to any one of [7].
　[9] In addition, nipradilol, dorzolamide, brinzolamide, containing one or more selected from timolol and the group consisting of salts thereof as well as their solvates, [1] to an aqueous composition according to any one of [7] .
[0020]
　[10] [1] The aqueous composition according to any one of to [9] becomes housed in the polyolefin resin container, a pharmaceutical formulation.
　[11] The polyolefin resin is polyethylene or polypropylene, [10] The pharmaceutical formulation according.
　[12] The polyolefin resin vessel is a vessel for eyedrop, [10] or [11] The pharmaceutical preparation according.
[0021]
　[13] the compound represented by the general formula (1) or an aqueous composition containing the salt or solvate thereof, comprising the step of allowed to contain prostaglandins method for inhibiting discoloration of the aqueous composition .
　[14] The compound represented by the general formula (1) is a Ripasujiru, [13] The method according.
　[15] prostaglandins is isopropyl unoprostone, tafluprost, travoprost, bimatoprost, one or more selected from latanoprost, and the group consisting of salts thereof as well as their solvates, [13] or [14 the method of] described.
　[16] prostaglandins, tafluprost, travoprost, bimatoprost, latanoprost, and their salts and at least one member selected from the group consisting of solvates, [13] or [14] The method according.
　[17] The aqueous composition is an ophthalmic agent, [13] The method of any one of - [16].
　[18] The ophthalmic agent is eye drops, [17] The method according.
　[19] The aqueous composition, ocular hypertension, which is a prophylactic and / or therapeutic agent for a disease selected from the group consisting of glaucoma and ocular fundus diseases, [13] The method according to any one of - [18].
[0022]
　[20] The aqueous composition further α1 receptor blocker, [alpha] 2 receptor agonist, beta-blockers, carbonic anhydrase inhibitors, sympathomimetics, parasympathomimetics, from a calcium antagonist and a cholinesterase inhibitor containing at least one selected from the group consisting, [13] the method according to any one of - [19].
　[21] The aqueous composition further nipradilol, dorzolamide, brinzolamide, containing one or more selected from timolol and the group consisting of salts thereof as well as their solvates, any one of [13] to [19] the method described.
[0023]
　[22] further comprises the step of receiving an aqueous composition to a polyolefin-based resin container, [13] The method of any one of - [21].
　[23] The polyolefin resin is polyethylene or polypropylene, [22] The method according.
　[24] The polyolefin resin vessel is a vessel for eyedrop, [22] or [23] The method according.
[0024]
　[25] the compound represented by the general formula (1) or an aqueous composition containing the salt or solvate thereof, comprising the step of allowed to contain prostaglandins, inhibition of crystallization of the aqueous composition Method.
　[26] The compound represented by the general formula (1) is a Ripasujiru, [25] The method according.
　[27] prostaglandins is isopropyl unoprostone, tafluprost, travoprost, bimatoprost, one or more selected from latanoprost, and the group consisting of salts thereof as well as their solvates, [25] or [26 the method of] described.
　[28] prostaglandins, tafluprost, travoprost, bimatoprost, latanoprost, and their salts and at least one member selected from the group consisting of solvates, [25] or [26] The method according.
　[29] The aqueous composition is an ophthalmic agent, [25] The method according to any one of - [28].
　[30] The ophthalmic agent is eye drops, [29] The method according.
　[31] The aqueous composition, ocular hypertension, which is a prophylactic and / or therapeutic agent for a disease selected from the group consisting of glaucoma and ocular fundus diseases, [25] The method according to any one of - [30].
[0025]
　[32] The aqueous composition further α1 receptor blocker, [alpha] 2 receptor agonist, beta-blockers, carbonic anhydrase inhibitors, sympathomimetics, parasympathomimetics, from a calcium antagonist and a cholinesterase inhibitor containing at least one selected from the group consisting, [25] the method according to any one of - [31].
　[33] The aqueous composition further nipradilol, dorzolamide, brinzolamide, containing one or more selected from timolol and the group consisting of salts thereof as well as their solvates, any one of [25] - [31] the method described.
[0026]
　In the general formula (1), the halogen atom, fluorine atom, chlorine atom, and bromine atom. In the general formula (1), the halogen atom, fluorine atom, preferably a bromine atom, a fluorine atom is particularly preferred.
　Further, in the general formula (1), the carbon atoms constituting the homopiperazine ring substituted methyl group is an asymmetric carbon. Therefore, although stereoisomeric occurs, the compound represented by the general formula (1) are encompassed any stereoisomer, it may be a single stereoisomer or a mixture of any proportions of various stereoisomers . Examples of the compound represented by the general formula (1), compounds whose absolute configuration is S configuration is preferred.
[0027]
　Examples of the salt of the compound represented by the general formula (1) is not particularly limited as long as a pharmaceutically acceptable salt, specifically, for example, hydrochloride, sulfate, nitrate, hydrofluoride, inorganic acid salts such as hydrobromide, acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate , toluenesulfonate, naphthalenesulfonate, camphorsulfonic - organic acid salts such as sulfonate and the like, hydrochloride salts are preferable.
　Further, the compound represented by the general formula (1) may be a solvate such as a hydrate or alcohol solvate is preferably a hydrate.
[0028]
　Examples of the compound or a salt thereof or a solvate thereof represented by the general formula (1), specifically, for example,
Ripasujiru (chemical name: 4-Fluoro -5 - {[(2S) -2- methyl - diazepan-1-yl] sulfonyl} isoquinoline) or a salt or solvate
thereof; 4-bromo -5 - {[(2S) -2- methyl-1,4-diazepan-1-yl] sulfonyl} isoquinoline, or a salt or solvate thereof;
and the like.
[0029]
　Examples of the compound or a salt thereof or a solvate thereof represented by the general formula (1), Ripasujiru or a salt or solvate thereof, 4-bromo -5 - {[(2S) -2- methyl - diazepan-1-yl] sulfonyl} isoquinoline, or a salt thereof, or preferably their solvates, Ripasujiru or a salt thereof, or more preferably their solvates, Ripasujiru or its hydrochloride or a hydrate thereof but more preferably the following structural formula:
[0030]
[Formula 5]

[0031]
In represented by Ripasujiru hydrochloride hydrate (Ripasujiru monohydrochloride dihydrate) is particularly preferred.
[0032]
　The compound or a salt thereof or a solvate thereof represented by the general formula (1) are known, can be prepared by known methods. Specifically, for example, Ripasujiru or a salt thereof or a solvate thereof can be prepared by WO 1999/020620 pamphlet, and a method of WO 2006/057397 pamphlet described. Further, 4-bromo -5 - {[(2S) -2- methyl-1,4-diazepan-1-yl] sulfonyl} isoquinoline or a salt thereof, or a solvate, WO 2006/115244 pamphlet it can be produced by the method described.
[0033]
　The content of the general formula (1) compound or a salt thereof or a solvate thereof represented by the aqueous composition is not particularly limited, suitably studied depending on the application disease and patient's sex, age, symptoms, etc. and may be determined, but from the viewpoint of obtaining excellent pharmacological action, relative to the total volume aqueous composition formula (1) in terms of the free form of the compound represented by by 0.01 ~ 10w / v % preferably contains, more preferably to contain 0.02 ~ 8w / v%, particularly preferably contains 0.04 ~ 6w / v%. Above all, in case of using Ripasujiru compound represented by the general formula (1), from the viewpoint of obtaining excellent pharmacological action, relative to the total volume aqueous composition, the Ripasujiru or a salt or solvate thereof, preferably contains 0.05 ~ 5w / v% in terms of free form, more preferably to contain 0.1 ~ 3w / v%, particularly preferably contains 0.15 ~ 2w / v%.
[0034]
　"Prostaglandins" as used herein, refers to prostaglandins or derivatives thereof, specifically, for example, isopropyl unoprostone (chemical name: (+) - isopropyl (Z ) -7 - [(1R , 2R, 3R, 5S) -3,5 -dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoate), tafluprost (chemical name: 1-methylethyl (5Z) -7 - [(1R, 2R, 3R, 5S) -2 - [( 1E) -3,3-difluoro-4-phenoxy-1-butenyl] -3,5-dihydroxycyclopentyl] -5-heptenoate), travoprost (chemical name: Isopropyl (5Z) - 7 - ((1R, 2R, 3R, 5S) -3,5-dihydroxy-2 - [(1E, 3R) -3-hydroxy-4- [3- (trifluoromethyl) phenoxy] but-1-enyl] cyclopentyl) hept-5-enoate), bimatoprost (chemical name: (5Z) -7 - {( 1R, 2R, 3R, 5S) -3,5-dihydroxy-2 - [(1E, 3S) -3-hydroxy-5 -phenylpent-1-en-1- yl] cyclopentyl} -N-ethylhept-5-enamide), latanoprost (chemical name: (+) - Isopropyl (Z ) -7 - [(1R, 2R, 3R, 5S) - 3,5-dihydroxy-2 - [( 3R) -3-hydroxy-5-phenylpentyl] cyclopentyl] -5-hepteno ate) and their pharmaceutically acceptable salts, furthermore include solvates with these compounds and pharmaceutically acceptable salts and water or alcohol, used in combination of two or more of these it can.
　The prostaglandins, tafluprost, travoprost, bimatoprost, that is latanoprost and one or more selected from the salts thereof as well as the group consisting of solvates preferred.
　Incidentally, these prostaglandins are known, may be produced by a known method, it may be a commercially available product.
[0035]
　Incidentally, it prostaglandins Other inhibitory effect of discoloration at the time of high-temperature storage, also has the inhibitory effect of crystallization on cold storage. Compounds represented by the general formula (1) represented by Ripasujiru or an aqueous composition containing the salt or solvate thereof may place can become crystal precipitation at a low temperature storage problem, specific Test Example 2 as disclosed, by incorporating a further latanoprost to the aqueous composition, crystal precipitation during cryopreservation as compared with the case containing no latanoprost was found to be inhibited. Accordingly, the compounds represented by the general formula (1) or a salt thereof or a solvate thereof, and an aqueous composition containing prostaglandin is suppressed discoloration during high temperature storage, also at the time of cryopreservation because it is suppressed also precipitated crystals, it has an advantage of excellent storage stability.
[0036]
　The content of prostaglandins in the aqueous composition is not particularly limited, in view of discoloration inhibition and / or crystallization inhibiting action, 0.00005 ~ 1.0 w / v% relative to the total volume aqueous composition preferably contains, more preferably to contain 0.00025 ~ 0.25w / v%, particularly preferably contains 0.00075 ~ 0.075w / v%.
　Although content mass ratio of the general formula (1) compound represented by or a salt thereof or a solvate thereof and prostaglandins in the aqueous composition is not particularly limited, discoloration inhibiting effect and / or crystallization from the viewpoint of inhibitory action against 1 part by weight in terms of a free form of the compound represented by the general formula (1), it is preferred to 0.0001 to 4 mass parts prostaglandins, 0.00125 more preferably contains ~ 1.25 parts by weight, particularly preferably 0.005 to 0.5 mass parts. Among them, in view of the case the general formula (1) compound or a salt thereof or a solvate thereof represented by is Ripasujiru or a salt thereof, or a solvate, discoloration inhibition and / or crystallization inhibiting effect from respect Ripasujiru or 1 part by weight in terms of the free form of a salt or solvate thereof, preferably to 0.0005 to 2 parts by mass prostaglandins, 0.0025 to 0. more preferably contains 75 parts by weight, particularly preferably contains from 0.0075 to 0.25 parts by weight.
[0037]
　Particularly, in the case prostaglandins is tafluprost or a salt or solvate thereof, in view of discoloration inhibition and / or crystallization inhibiting action, relative to the total volume aqueous composition, tafluprost free form of preferably contains 0.0001 ~ 0.02w / v% in terms of, more preferably to contain 0.0005 ~ 0.01w / v%, to contain 0.001 ~ 0.005w / v% It is particularly preferred.
　Although content mass ratio of the general compound represented by the formula (1) or a salt or solvate thereof and tafluprost or a salt or solvate thereof in the aqueous composition is not particularly limited, discoloration inhibition Convert the viewpoint of action and / or crystallization inhibiting action, relative to 1 part by weight in terms of a free form of the compound represented by the general formula (1), the tafluprost or a salt thereof or a solvate thereof in free form preferably it contains from 0.0001 to 0.025 part by mass, more preferably to contain 0.0007 to 0.015 parts by weight, particularly preferably contains 0.002-0.005 parts by weight. Among them, in view of the case the general formula (1) compound or a salt thereof or a solvate thereof represented by is Ripasujiru or a salt thereof, or a solvate, discoloration inhibition and / or crystallization inhibiting effect from Ripasujiru or a salt or solvate thereof per 1 part by weight in terms of its free form, tafluprost or converted to .0005-.02 salt thereof or a solvate thereof in free form preferably it contains parts by weight, more preferably to contain 0.001-0.01 parts by weight, particularly preferably contains from 0.003 to 0.004 parts by weight.
[0038]
　In the case prostaglandins is travoprost or a salt or solvate thereof, in view of discoloration inhibition and / or crystallization inhibiting action, relative to the total volume aqueous composition, of travoprost preferably it contains in terms of free form 0.0001 ~ 0.05w / v%, more preferably to contain 0.0005 ~ 0.01w / v%, containing 0.001 ~ 0.005w / v% particular preference is given to.
　Although content mass ratio of the general formula (1) compound represented by or a salt thereof or a solvate thereof and travoprost or a salt or solvate thereof in the aqueous composition is not particularly limited, discoloration from the viewpoint of inhibitory action and / or crystallization inhibiting action, relative to 1 part by weight in terms of a free form of the compound represented by the general formula (1), travoprost or a salt thereof, or free form solvate thereof preferably contains from 0.00025 to 0.03 parts by weight in terms of, more preferably to contain 0.00075 to 0.07 parts by weight, particularly preferably contains from 0.0025 to 0.03 parts by weight . Among them, in view of the case the general formula (1) compound or a salt thereof or a solvate thereof represented by is Ripasujiru or a salt thereof, or a solvate, discoloration inhibition and / or crystallization inhibiting effect from Ripasujiru or a salt or solvate thereof per 1 part by weight in terms of its free form, travoprost or 0.0005 to in terms of a salt or solvate thereof in free form 0. preferably contains 1 part by weight, more preferably to contain 0.001-0.05 parts by weight, particularly preferably contains 0.005-0.02 mass parts.
[0039]
　In the case prostaglandins is bimatoprost or a salt thereof or a solvate thereof, from the viewpoint of discoloration inhibition and / or crystallization inhibiting action, relative to the total volume aqueous composition, bimatoprost free form of preferably contains 0.001 ~ 0.5w / v% in terms of, more preferably to contain 0.005 ~ 0.1w / v%, to contain 0.01 ~ 0.05w / v% It is particularly preferred.
　Although content mass ratio of the general compound represented by the formula (1) or a salt or solvate thereof and bimatoprost or a salt thereof or a solvate thereof in the aqueous composition is not particularly limited, discoloration inhibition Convert the viewpoint of action and / or crystallization inhibiting action, relative to 1 part by weight in terms of a free form of the compound represented by the general formula (1), bimatoprost or a salt thereof or a solvate thereof in free form preferably contains 0.001 to 2 parts by weight and, more preferably to contain 0.0075 to 0.75 parts by weight, particularly preferably contains 0.025 to 0.3 parts by weight. Among them, in view of the case the general formula (1) compound or a salt thereof or a solvate thereof represented by is Ripasujiru or a salt thereof, or a solvate, discoloration inhibition and / or crystallization inhibiting effect from Ripasujiru or a salt or solvate thereof per 1 part by weight in terms of its free form, bimatoprost or 0.005 to 1 part by weight in terms of a salt or solvate thereof in a free form preferably contains, more preferably to 0.01 to 0.5 part by mass, particularly preferably 0.05 to 0.1 part by weight.
[0040]
　Further, when prostaglandins are latanoprost or a salt or solvate thereof, in view of discoloration inhibition and / or crystallization inhibiting action, relative to the total volume aqueous composition, latanoprost free form of preferably contains 0.0001 ~ 0.1w / v% in terms of, more preferably to contain 0.0005 ~ 0.05w / v%, to contain 0.001 ~ 0.01w / v% It is particularly preferred.
　Although content mass ratio of the general compound represented by the formula (1) or a salt or solvate thereof and latanoprost or a salt or solvate thereof in the aqueous composition is not particularly limited, discoloration inhibition Convert the viewpoint of action and / or crystallization inhibiting action, relative to 1 part by weight in terms of a free form of the compound represented by the general formula (1), latanoprost or a salt thereof or a solvate thereof in free form preferably contains 0.0005-0.1 part by mass, more preferably to contain 0.0025 to 0.04 parts by weight, particularly preferably contains from 0.0075 to 0.03 parts by weight. Among them, in view of the case the general formula (1) compound or a salt thereof or a solvate thereof represented by is Ripasujiru or a salt thereof, or a solvate, discoloration inhibition and / or crystallization inhibiting effect from Ripasujiru or a salt or solvate thereof per 1 part by weight in terms of their free compounds, latanoprost or converted to 0.001-0.05 salt thereof or a solvate thereof in free form preferably it contains parts by weight, more preferably to contain 0.005-0.02 parts by weight, particularly preferably contains 0.01-0.015 parts by weight.
[0041]
　By "aqueous composition" herein is meant a composition containing at least water, as its properties, a liquid (solution or suspension), semi-solid (ointment) and the like, liquid is preferred . As the water in the composition for example, purified water, water for injection, it may be used sterilized purified water.
　The content of water contained in the aqueous composition is not particularly limited, preferably at least 5 wt%, more preferably at least 20 wt%, more preferably at least 50 wt%, even more preferably at least 90 wt%, 90 ~ particularly preferably 99.8% by mass.
[0042]
　The aqueous composition may, for example, according to known methods described in the sixteenth Japanese Pharmacopoeia General Rules for Preparations and the like, may have various dosage forms. Dosage forms, e.g., injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal solutions, enema, topical solutions, sprays, ointments, gels, oral solutions, syrups, etc. and the like. Dosage forms, from the viewpoint of advantageously utilize pharmacological action possessed by the compound represented by the general formula (1), ophthalmic agents, specifically eye drops, eye ointments are preferred, eye drops are especially preferred.
[0043]
　The aqueous composition, in addition to the above, depending on the dosage form may contain additives to be used in the pharmaceutical and quasi Hinto. Such additives include, for example, inorganic salts, isotonic agents, chelating agents, stabilizing agents, pH adjusting agents, preservatives, antioxidants, thickening agents, surfactants, solubilizers, suspension Nigoka agents, refreshing agents, dispersing agents, preservatives, oily base, emulsion base, and the like water-soluble bases are.
　As such additives, specifically, for example, ascorbic acid, potassium aspartate, sodium bisulfite, 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 polymers, dried sodium sulfite, dried sodium carbonate, d-camphor, dl- camphor, xylitol, citric acid hydrate, sodium hydrate citrate, glycerol, gluconic acid, L- glutamic, L- sodium glutamate, creatinine, chlorhexidine gluconate Sanshioeki, Lolo butanol, sodium dihydrogen phosphate dihydrate, geraniol, sodium chondroitin sulfate, acetate, potassium acetate, sodium acetate hydrate, titanium oxide, gellan gum, dibutylhydroxytoluene, potassium bromide, base Nzododeshiniumu, tartaric acid, sodium hydroxide , polyoxyl stearate 45, purified lanolin, D- sorbitol, sorbitol solution, taurine, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyloxapol, sodium dehydroacetate, trometamol, concentrated glycerin, concentrated mixed tocopherol, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride solution 50, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, Palau Shi benzoate, sodium hyaluronate, human serum albumin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, glacial acetic acid, sodium metabisulfite, phenylethyl alcohol, dextrose, propylene glycol, bergamot oil, benzalkonium chloride, benzalkonium product liquid chloride, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, borax, boric acid, povidone, polyoxyethylene (200) polyoxypropylene glycol (70), sodium polystyrene sulfonate, polysorbate 80, polyoxyethylene hardened castor oil 60, polyvinyl alcohol (partially saponified), d-borneol, macrogol 4000, macrogol 6000, D-mannitol, citric anhydride Acid, sodium monohydrogen phosphate anhydrous, sodium dihydrogen phosphate anhydrous, methanesulfonic acid, methylcellulose, l-menthol, monoethanolamine, aluminum monostearate, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfate, oxyquinoline sulfate, liquid paraffin, borneol, phosphate, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, malic acid, petroleum jelly and the like may be exemplified that.
[0044]
　The additives, for example, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerine, acetate, 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, macro goal 6000, anhydrous citric acid, sodium monohydrogen phosphate anhydrous, sodium dihydrogen phosphate anhydrous, methylcellulose, monoethanolamine, phosphoric acid, sodium hydrogen phosphate hydrate, phosphate monobasic potassium Beam, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium hyaluronate, glucose, l-menthol is preferable.
[0045]
　The aqueous composition further, other than the above, depending on the application diseases like, may include other medicinal ingredients. Such medicinal ingredients, e.g., bunazosin or a salt thereof or α1 receptor blockers including solvates thereof, such as bunazosin hydrochloride; Brimonidine or a salt or solvate thereof, such as brimonidine tartrate, Apra clonidine or α2 receptor agonist containing the salt or solvate thereof; carteolol or a salt or solvate thereof, such as carteolol hydrochloride, nipradilol or a salt or solvate thereof, timolol maleate timolol or a salt or solvate thereof such as salts, betaxolol or a salt or solvate thereof, levobunolol or a salt or solvate thereof, such as levobunolol hydrochloride, befunolol or a salt thereof, such as betaxolol hydrochloride or their solvents Hydrate, metipranolol or a salt thereof, or β-blockers including solvate thereof; dorzolamide dorzolamide or a salt or solvate thereof such as hydrochloride, brinzolamide or a salt or solvate thereof, acetazolamide or di such Jipibe furin hydrochloride; a salt or solvate thereof, dichlorphenamide Fe cyanamide or a salt or solvate thereof, methazolamide or a salt thereof, or carbonic anhydrase inhibitors, including their solvates pin base furin or a salt or solvate thereof, epinephrine, epinephrine borate, such as epinephrine hydrochloride epinephrine or a salt thereof, or sympathomimetics including solvate thereof; distigmine bromide or a salt thereof, or their solvate, pilocarpine, pilocarpine hydrochloride, Pirokaru Pilocarpine or a salt thereof, or a solvate of such emissions nitrate, carbachol or parasympathomimetics salts thereof or a solvate thereof; calcium containing Lomerizine or a salt thereof or a solvate of such lomerizine hydrochloride antagonists; demecarium or a salt or solvate thereof, echothiophate or a salt or solvate thereof, include such physostigmine or a salt thereof, or cholinesterase inhibitors, including their solvates, thereof 1 it species or blend of two or more.
　Other medicinal ingredients, nipradilol, dorzolamide, brinzolamide, one or more selected from timolol and the group consisting of salts thereof as well as their solvates preferred.
[0046]
　The pH of the aqueous composition is not particularly limited, but is preferably 4-9, more preferably 4.5 to 8 and particularly preferably 5-7. Also, osmotic pressure ratio against physiological saline is not particularly limited, preferably 0.6 to 3, particularly preferably from 0.6 to 2.
[0047]
　Aqueous composition, storage stability, in view of portability or the like, it is preferably contained in the container. The term "container" as used herein, refers to a package for directly accommodating said aqueous composition. Container, "closed container" as defined Sixteenth Japanese Pharmacopoeia General Rules, "airtight container" is a concept encompassing any of "sealed container".
[0048]
　Form of the container is not particularly limited that it is capable of accommodating the aqueous composition as a limit appropriately selected depending on the dosage form, etc., may be set. The form of such containers, specifically, for example, containers for injection, the container for inhalation, sprays containers, bottles shaped container, the tube-like container, the container for eye drops, container nasal drops, point ear drops containers, bags containers and the like. These container further boxes, may be packaged by such a bag.
[0049]
　Material of the container (material) is not particularly limited, it may be suitably selected depending on the form of the container. Specifically, for example, glass, plastic, cellulose, pulp, rubber, metal and the like. Processability, in terms of the squeeze and durability, preferably made of plastic. As the resin of the plastic container is preferably a thermoplastic resin, for example, (including linear low density polyethylene), low density polyethylene, high density polyethylene, medium density polyethylene, polypropylene, polyolefin resins such as cyclic polyolefins , polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, poly (1,4-cyclohexylene dimethylene terephthalate naphthalate) polyester resins and the like; polyphenylene ether resin; polycarbonate resins; polysulfone resins, polyamides system resin, polyvinyl chloride resin; a styrene-based resin and the like, may be a mixed material (polymer alloy).
　The material of the container is not particularly limited, but is preferably a polyolefin resin in view of discoloration inhibition, particularly preferably polypropylene. As described below in Test Example, in the case the container is a polyolefin resin vessel, in particular dominantly discoloration suppressed.
[0050]
　As used herein, the term "polyolefin-based resin container", at least in part in contact with the aqueous composition of the container means the container is "made polyolefin resin". Thus, for example, a layer of polyolefin is provided in an inner layer in contact with the aqueous composition, also container made of resin or the like other material on the outside thereof by stacking or the like, corresponds to the "polyolefin resin container". Here, the polyolefin resin is not particularly limited, and a polymer of a single type of monomer (homopolymers), or a copolymer of plural kinds of monomers (copolymers). Further, in the case of a copolymer, the polymerization mode is not particularly limited, and may be a block polymer at random polymerization. Furthermore, the stereoregularity (tacticity) is not particularly limited.
　Such polyolefin resins, specifically, for example, polyethylene (including more detail, for example low density polyethylene (linear low density polyethylene), high density polyethylene, medium density polyethylene), polypropylene, cyclic polyolefin , poly (4-methylpentene), polytetrafluoroethylene, ethylene-propylene copolymers, ethylene-alpha-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid copolymer, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer and the like, can be used in combination with one or more of these. As the polyolefin resin, from the viewpoint of suppressing discoloration, polyethylene, polypropylene, preferably a cyclic polyolefin, polyethylene, polypropylene, more preferably, polypropylene is particularly preferred.
　In the present specification, "made of a polyolefin resin" means that it contains a polyolefin resin on at least a portion of the material, for example, two or more resins of the polyolefin resin and another resin mixture of (polymer alloy) is also included in the "made a polyolefin resin".
[0051]
　The polyolefin resin vessel, preferably knead the material further prevents the transmission of ultraviolet light, such as ultraviolet absorbers and ultraviolet scattering agent. Thus, stability to light of the compound represented by the general formula (1) is improved. As such material, specifically, for example, as the ultraviolet scattering agent, titanium oxide; and the zinc oxide. As the ultraviolet absorber, 2-(2H-benzotriazol-2-yl)-p-cresol (e.g., Tinuvin P: BASF Corp.), 2-(2H-benzotriazol-2-yl) -4,6 - bis (1-methyl-1-phenylethyl) phenol (e.g., Tinuvin 234: BASF Corp.), 2- (3,5-di -t- butyl-2-hydroxyphenyl) benzotriazole (e.g., Tinuvin320: BASF Corporation ), 2- [5-chloro (2H) - benzotriazol-2-yl] -4-methyl-6-(tert-butyl) phenol (e.g., Tinuvin 326: BASF Corp.), 2- (3,5-di -t- butyl-2-hydroxyphenyl) -5-chloro-benzotriazole (e.g., Tinuvin327: BASF Corp.), 2-(2H-benzotriazol-2-yl) -4,6-di -tert- Emissions butylphenol (e.g., Tinuvin PA328: BASF Corp.), 2-(2H-benzotriazol-2-yl) -4- (1,1,3,3-tetramethylbutyl) phenol (e.g., Tinuvin 329: BASF Corporation ), 2,2' Mechirurenbisu [6- (2H-benzotriazol-2-yl) -4- (1,1,3,3-tetramethylbutyl) phenol (e.g., Tinuvin 360: BASF Corporation), methyl 3 - (3- (2H-benzotriazol-2-yl) -5-tert-butyl-4-hydroxyphenyl) reaction products of propionate and polyethylene glycol 300 (e.g., Tinuvin 213: BASF Corp.), 2-(2H- benzotriazol-2-yl) -6-dodecyl-4-methylphenol (e.g., Tinuvin 571: BASF Corp.), 2- (2'-hydroxy-3 ', 5'-di t- amyl phenyl) benzotriazole, 2- [2'-hydroxy-3 '- (3' ', 4' ', 5' ', 6' '- tetrahydrophthalimide-methyl) -5'-methylphenyl] benzotriazole, 2,2'-methylenebis [4- (1,1,3,3-tetramethylbutyl)-6-(2H-benzotriazol-2-yl) phenol] benzotriazole ultraviolet absorbers such as; 2,2 bis {[2-cyano-3,3-diphenyl acryloyloxy] methyl} propane-1,3-diyl = bis (2-cyano-3,3-diphenylacrylate) (e.g., Uvinul 3030 FF: BASF Corp.), 2 - cyano-3,3-diphenyl acrylate (e.g., Uvinul 3035: BASF Corporation), hexyl 2-cyano-3,3-2-ethyl-diphenyl acrylate (e.g., Uvinul 3039 Cyanoacrylate-based UV absorber from BASF Corp.); 2- (4,6-diphenyl-1,3,5-triazin-2-yl) -5 - [(hexyl) oxy] - phenol (e.g., Tinuvin 1577 ED : triazine UV absorber from BASF Corporation); Okutabenzon (e.g., Chimassorb 81: BASF), 2,2'-dihydroxy-4,4'-dimethoxy Ben phenone (e.g., Uvinul 3049: BASF), 2, 2'-4,4'-tetrahydropyran Ben phenone (e.g., Uvinul 3050: BASF Corporation), oxybenzone, hydroxymethoxybenzophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonic acid, dihydroxy dimethoxy benzophenone, sodium dihydroxy dimethoxy benzophenone disulfonic acid, dihydroxybenzophenone, Te Benzophenone ultraviolet absorbers such as tiger hydroxybenzophenone; diisopropyl cinnamate methyl, cinoxate, di p-methoxycinnamate mono-2-ethylhexanoate, glyceryl para-methoxycinnamic acid isopropyl diisopropyl cinnamate mixture paramethoxy 2-ethylhexyl, cinnamic acid UV absorbers such as benzyl cinnamate; para-aminobenzoic acid, ethyl para-aminobenzoic acid, para-aminobenzoic acid, glyceryl p-dimethylaminobenzoic acid amyl para-dimethylaminobenzoic acid 2-ethylhexyl , 4-[N, N-di (2-hydroxypropyl) amino] benzoate-based ultraviolet absorbers such as ethyl benzoate; ethylene glycol salicylate, octyl salicylate, dipropylene glycol, Sari Le acid phenyl, homomenthyl salicylate-based ultraviolet absorbers such as methyl salicylate; guaiazulene; dimethoxybenzylidene ethylidenedioxy oxoimidazolidine propionic acid 2-ethylhexyl; 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) anilino] 1,3,5-triazine; para-hydroxyanisole; 4-tert-butyl-4'-methoxydibenzoylmethane; phenyl benzimidazole sulfonic acid; 2- (4-diethylamino-2-hydroxybenzoyl) - benzoic acid hexyl and the like.
[0052]
　In the case of kneading a material that prevents the transmission of ultraviolet light to the container, the mixing ratio may vary depending on the type of the substance, for example, in a container, 0.001 to 50% by weight, preferably from 0.002 to 25 mass%, particularly preferably may be about 0.01 to 10 wt%.
[0053]
　The container, preferably the inside is visible to the naked eye (observable). Internal viewability possible, inspection of presence or absence of contamination in the manufacturing process of the pharmaceutical preparation becomes possible, benefits occur, such as the user of the pharmaceutical preparations can check the remaining contents (aqueous composition) . Here, visual recognition possibility is only to be ensured in at least a portion of the container surface (e.g., also the sides of the container for eye drops is no longer foresee the shrink film or the like, bottom visible if visible and it can be said.). Internally visible if the part of the container surface, thereby, the aqueous composition within the container is possible confirmation.
[0054]
　Housing means of the aqueous composition to the container is not particularly limited, by a conventional method may be filled such according the form of container or the like.
[0055]
　Related diseases of the aqueous composition or the pharmaceutical preparation is not particularly limited and may be appropriately selected depending on the pharmacological action and the like possessed by the compound represented by the general formula (1).
　Specifically, for example, based on the general formula (1) Rho kinase inhibitory action and intraocular pressure effect with the compounds represented by, also on the basis of the intraocular pressure effects possessed by prostaglandins, ocular hypertension and glaucoma It can be used as prophylactic or therapeutic agents. In this case, excellent intraocular pressure lowering action by the intraocular pressure effects possessed by the intraocular pressure effects and prostaglandins having the compound represented by the general formula (1) is achieved, excellent ocular hypertension, glaucoma for preventing and / or therapeutic action is obtained, preferably. Here, the glaucoma, and more particularly, for example, primary open angle glaucoma, normal tension glaucoma, aqueous humor production excessive glaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma , steroid glaucoma, cystic glaucoma of the lens, dye glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma and the like.
[0056]
　Also, as disclosed in Japanese Japanese Patent No. 5557408, based on the action with the compound represented by the general formula (1), fundus disease (primarily the retina and / or lesion expressed in the choroid. Specifically, for example, the fundus changes due hypertension and arteriosclerosis, central retinal arterial occlusion, central retinal vein occlusion (central retinal vein occlusion) and branch retinal vein occlusion (branch retinal vein occlusion) retinal vein occlusion, such as, diabetic retinopathy , diabetic macular edema, diabetic maculopathy, Eales disease (Eales disease), Coats disease (Coats disease) retinal vascular malformation, etc., Hippel disease (von Hippel disease), pulseless disease (pulseless disease), macular disease (centrality chorioretinal disease (central serous chorioretinopathy), cystoid macular edema (cystoid macular edema), age-related macular degeneration (age-related macular degeneration), macular hole (macular hole), myopic macular atrophy ( myopic macular degeneration), vitreoretinal interface macular degeneration, drug toxicity macular degeneration, inherited macular degeneration, etc.), (rhegmatogenous, traction, exudative, etc.) retinal detachment, retinitis pigmentosa, retinopathy of prematurity prophylactic or therapeutic agents of.) the diseases and the like, more preferably diabetic retinopathy, may be utilized as diabetic macular edema or age-related macular degeneration prophylactic or therapeutic agent.
[0057]
　Incidentally, an aqueous composition or pharmaceutical preparation ophthalmic diseases (preferably, the disease is selected from ocular hypertension, glaucoma and fundus diseases: particularly preferably a disease selected from ocular hypertension and glaucoma) prevention and / or treatment of as in the case of using the agent, about 1 to 3 times daily, may be administered.
Example
[0058]
　Next, the present invention further described by way of example, the present invention is not limited to these examples.
　In the following Test Examples, Ripasujiru 1 hydrochloride dihydrate can be prepared, for example, by the method of WO 2006/057397 pamphlet described.
[0059]
[Test Example 1] storage test
　The aqueous composition of Example 1 and Comparative Example 1 The ingredients and amounts shown in Table 1 containing per 100mL routinely prepared was housed in a polypropylene container.
　Each aqueous composition obtained was stored for one week at 80 ° C.. The degree of color change before and after storage (yellowing) is the color difference between the aqueous composition before and after storage (.DELTA.YI) a color difference meter: measuring with (spectrocolorimeter CM-700 d Konica Minolta Sensing Inc.) It was evaluated by.
　The results are shown in Table 1.
[0060]
[Table 1]

[0061]
　Results As shown in Table 1, when allowed to further contain bimatoprost in an aqueous composition containing Ripasujiru, values ​​of ΔYI is significantly lower as compared with the case of not containing bimatoprost, discoloration after high temperature storage is suppressed Rukoto became clear.
[0062]
[Test Example 2] Storage Test Part 2
　The aqueous composition of Example 2 the components and amounts shown in Table 2 contains per 100mL routinely prepared was housed in a polypropylene container.
　The resulting saving an aqueous composition for one week at 80 ° C., was evaluated in the same manner as in Test Example 1 the degrees of discoloration before and after storage (yellowing).
　The results are shown in Table 2.
[0063]
[Table 2]

[0064]
　Results As shown in Table 2, even when allowed to further contain a latanoprost to the aqueous composition containing Ripasujiru values ​​of ΔYI was low.
[0065]
　From the results of the above Test Examples 1 and 2, the compound or an aqueous composition containing the salt or solvate thereof represented by the general formula (1) represented by Ripasujiru, typified further bimatoprost, latanoprost If the additional inclusion of that prostaglandins relatively discoloration even when stored at high temperatures (yellowing) hardly occurs, it became clear that excellent storage stability.
[0066]
[Test Example 3] Storage Test Part 3
　and the Table 3 the components and amounts shown in Example 3 and Comparative Example 2 containing per 100mL aqueous compositions were prepared by a conventional method.
　While each aqueous composition obtained was stored at -5 ° C. it was visually evaluated periodically for crystal precipitation was confirmed whether previously crystallization is observed in any of the aqueous composition. Those previously crystal precipitation was observed 〇, it was × what earlier in the crystal precipitation was observed.
　The results are shown in Table 3.
[0067]
[table 3]

[0068]
　Table 3 Results As described, when the additional inclusion of further latanoprost in aqueous compositions containing Ripasujiru, crystal precipitation during cryopreservation as compared with the case containing no latanoprost was found to be inhibited.
[0069]
　From the above test results, for the additional inclusion of general formula (1) compound represented by or a salt thereof, or prostaglandins represented further latanoprost in aqueous compositions containing them solvates typified by Ripasujiru If, relatively crystal even when stored at a low temperature is hardly precipitated, it was found to have excellent storage stability.
[0070]
[Production Example 1-27]
　The aqueous composition containing the components and amounts described in Table 4 to Table 6 (amounts per 100mL aqueous composition (g)) can be manufactured in a conventional manner.
[0071]
[Table 4]

[0072]
[table 5]

[0073]
[Table 6]

[0074]
[Production Examples 28 to 54]
　Production Example 1-27, Ripasujiru 1 the same amount in place of the hydrochloride dihydrate 4-bromo -5 - {[(2S) -2- methyl-1,4-diazepane - that using a 1-yl] sulfonyl} isoquinoline, as an aqueous composition of preparation 28 to 54 can be manufactured in a conventional manner.
[0075]
Preparation Example 55-108]
　The aqueous compositions of Production Examples 1-54 By housing the containers made from polypropylene for eye drops, as a pharmaceutical formulation of Preparation 55 to 108, can be manufactured in a conventional manner.
[0076]
Production Example 109-162]
　by the aqueous compositions of Production Examples 1 to 54 contained in a container for polyethylene eye drops, as a pharmaceutical formulation of Preparation 109-162, can be manufactured in a conventional manner.
Industrial Applicability
[0077]
　According to the present invention, it can provide excellent aqueous composition or pharmaceutical formulation storage stability, can be suitably used in the pharmaceutical industry and the like.

claims
[Claim 1]
　Following general formula (1)
[Chemical formula 1]

[wherein, X represents a halogen atom. ]
A compound represented by or a salt thereof or a solvate thereof, and containing prostaglandins, the aqueous compositions.
[Claim 2]
　Compound represented by the general formula (1) is a Ripasujiru, aqueous composition of claim 1 wherein.
[Claim 3]
　The prostaglandins, tafluprost, travoprost, bimatoprost, latanoprost, and their salts and at least one member selected from the group consisting of a solvate thereof according to claim 1 or 2 aqueous composition.
[Claim 4]
　The aqueous composition of any one of claims 1 to 3, comprising housed in the polyolefin resin container, a pharmaceutical formulation.
[Claim 5]
　The polyolefin resin is a polypropylene, the pharmaceutical preparation according to claim 4, wherein the.
[Claim 6]
　Following general formula (1)
[Formula 2]

[In the formula, X represents a halogen atom. ]
The compound or an aqueous composition containing the salt or solvate thereof represented by, comprising the step of allowed to contain prostaglandins method for inhibiting discoloration of the aqueous composition.
[Claim 7]
　The compound represented by the general formula (1) is a Ripasujiru The method of claim 6 wherein.
[8.]
　The prostaglandins, tafluprost, travoprost, bimatoprost, latanoprost, and their salts and at least one member selected from the group consisting of a solvate thereof according to claim 6 or 7 The method according.