Water-based components

Abstract

Suppresses discoloration of halogenated isoquinoline derivative-containing aqueous compositions during high-temperature storage. Providing new technologies. [Solution] The following general formula (1) TIFF2026105000000014.tif39170 [In the formula, X represents a halogen atom.] Compounds represented by or salts thereof or solvates thereof, and biguanide compounds and their An aqueous composition containing one or more selected from the group consisting of salts and solvates thereof.

Description

[Technical Field]

[0001] This invention relates to aqueous compositions, etc. [Background technology]

[0002] The following structural formula:

[0003] [ka]

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

[0005] [ka]

[0006] Represented as 4-bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl Halogenated isoquinoline derivatives such as sulfonyl isoquinoline inhibit Rho kinase It has pharmacological effects such as harmful effects (for example, Patent Documents 1 and 2) and is useful for the prevention and treatment of eye diseases. It is known that this can be done. Specifically, for example, in the prevention or treatment of conditions such as ocular hypertension and glaucoma (for example) , Patent Document 3), or prevention or treatment of fundus diseases such as age-related macular degeneration (for example, Patent Document 3) 4) It has been reported to be useful in this regard.

[0007] Therefore, these halogenated isoquinoline derivatives are stably used, for example, as ophthalmic agents. Establishing the technology for formulation is extremely useful. Ophthalmic preparations are usually compositions containing water (aqueous compositions). However, halogenated compounds When an aqueous composition containing repasodil, which is an isoquinoline derivative, is prepared and stored at a high temperature, it is known that the aqueous composition discolors over time. Several means for suppressing discoloration have been proposed so far (for example, Patent Documents 5 to 8).

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Summary of the Invention

Problems to be Solved by the Invention

[0009] An object of the present invention is to provide a new technique for suppressing discoloration of an aqueous composition containing a halogenated isoquinoline derivative during high-temperature storage.

Means for Solving the Problems

[0010] Therefore, the present inventors conducted intensive studies to solve the above problems, and as a result, in an aqueous composition containing a halogenated isoquinoline derivative such as repasodil, a biguanide such as chlorhexidine was further added. ​​​ It contains one or more selected from the group consisting of anido compounds, their salts, and solvates thereof. We discovered that by providing this feature, discoloration during high-temperature storage can be suppressed, thus completing the present invention. .

[0011] In other words, the present invention relates to the following general formula (1)

[0012] [ka]

[0013] [In the formula, X represents a halogen atom.] Compounds represented by or salts thereof or solvates thereof, and biguanide compounds and their An aqueous composition containing one or more selected from the group consisting of salts and solvates thereof. It is something that is provided. Furthermore, the present invention relates to a compound represented by the general formula (1) above, or a salt thereof, or a solvent thereof. An aqueous composition containing a Japanese compound contains biguanide compounds and their salts, and their solvates. A method for suppressing discoloration of an aqueous composition, comprising the step of including one or more selected from the group of essential elements. This provides... [Effects of the Invention]

[0014] According to the present invention, an aqueous composition containing a halogenated isoquinoline derivative such as lipasudil This can suppress discoloration during high-temperature storage. [Modes for carrying out the invention]

[0015] In this specification, "w / v%" means mass-to-volume percentage, specifically 100 m This refers to the mass (g) of each component contained in composition L.

[0016] In the general formula (1) above, the halogen atoms are fluorine, chlorine, and bromine atoms. Examples include the following. In the above general formula (1), the halogen atoms are fluorine and bromine. Atoms are preferred, and fluorine atoms are particularly preferred. Furthermore, in the general formula (1) above, the carbon constituting the homopiperazine ring substituted with a methyl group The primary atom is a chiral carbon. Therefore, stereoisomerism occurs, but the compound is represented by general formula (1). A substance can contain any stereoisomer, or it may have only one stereoisomer, or it may have various stereoisomers. A mixture of any proportion is also acceptable. The compound represented by the general formula (1) is one in which the absolute configuration is S A compound with a specific configuration is preferred.

[0017] The salt of the compound represented by the general formula (1) is not limited to any pharmaceutically acceptable salt. It is not specified, and specifically, for example, hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide Inorganic salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, etc. Hacitate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluene Examples include organic salts such as sulfonates, naphthalene sulfonates, and camphor sulfonates. Hydrochloride salts are preferred. Furthermore, the compound represented by the general formula (1) or its salt is a hydrate or an alcoholic, etc. It may be a solvate, but a hydrate is preferred.

[0018] The compound represented by the general formula (1) above, or a salt thereof, or a solvate thereof, is: Physically, for example, Lipasdil (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepa [I-1-yl]sulfonyl]isoquinoline) or its salts or solvates thereof; 4-Bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl Isoquinoline or its salts or solvates thereof; These are some examples.

[0019] The compounds represented by the general formula (1) above, their salts, or their solvates include: Pasudil or its salts or their solvates, 4-bromo-5-[[(2S)-2-methyl [Tyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline or its salt or These solvates are preferred, and lipasudil or its salts or their solvates are more preferred. Furthermore, lipasudil or its hydrochloride or hydrate thereof is more preferable, and the following structure formula:

[0020] [ka]

[0021] Lipasdil hydrochloride hydrate (lipasdil 1-hydrochloride dihydrate) represented by [formula] is particularly preferred.

[0022] Compounds represented by the general formula (1) above, salts thereof, or solvates thereof are known. It can be manufactured by known methods. Specifically, for example, lipasudil or its salts or the These solvates are described in International Publication No. 1999 / 020620, International Publication No. 200 It can be manufactured using the methods described in the 6 / 057397 pamphlet. Also, 4- Bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl] Soquinoline or its salts or solvates thereof, International Publication No. 2006 / 115244 It can be manufactured using the methods described in the pamphlet.

[0023] Compounds represented by the general formula (1) or salts thereof in aqueous compositions or solvations thereof The amount of substance contained is not particularly limited and should be considered as appropriate depending on the applicable disease, the patient's gender, age, symptoms, etc. It is fine to decide by doing so, but from the viewpoint of obtaining excellent pharmacological effects, the amount of the aqueous composition relative to the total volume is generally It is preferable to contain 0.01 to 10 w / v% of the compound represented by formula (1) in terms of its free form. It is preferable to contain 0.02-8 w / v%, and more preferably 0.04-6 w / v%. It is particularly preferable to use lipasudil as the compound represented by general formula (1). In some cases, from the viewpoint of obtaining excellent pharmacological effects, lipasdi is added to the total volume of the aqueous composition. Contains 0.05-5 w / v% of the free form of 170 It is preferable to have it, more preferably to contain 0.1-3 w / v%, and 0.15-2 w / A content of v% is particularly preferred.

[0024] Furthermore, in the present invention, "biguanide compound" has a biguanide residue in its molecule. While not particularly limited to compounds, from the viewpoint of inhibiting discoloration, the following general formula (2) is used. A group consisting of compounds and polymers having repeating units represented by the following general formula (3) One or more of these are preferred, and the compound represented by general formula (2) is more preferred. Polymers having repeating units represented by general formula (3) include homopolymers and other repeating polymers. Copolymers with units are also acceptable, but homopolymers are preferred. Also, the general formula (3) is used. The number-average molecular weight of a polymer having repeating units is 300, from the viewpoint of discoloration suppression. A value of ~15000 is preferred, and 500~5000 is more preferred.

[0025] [ka]

[0026] [In the formula, R 1 This indicates a hydrogen atom, or a substituted or unsubstituted monovalent hydrocarbon group having 1 to 20 carbon atoms. death, R 2 This represents a substituted or unsubstituted monovalent hydrocarbon group having 1 to 20 carbon atoms. R 3 This represents a substituted or unsubstituted divalent hydrocarbon group having 1 to 20 carbon atoms. n represents either 0 or 1.

[0027] [ka]

[0028] [In the formula, R 4 This represents a substituted or unsubstituted divalent hydrocarbon group having 1 to 20 carbon atoms.

[0029] In formula (2), n is preferably 1 from the viewpoint of inhibiting discoloration.

[0030] R in equation (2) 1 , R 2 The "monovalent hydrocarbon group" shown is an alkyl group, an alkyl group. Aralkyl groups are preferred. The alkyl group described above may be linear or branched. Furthermore, the alkyl group may have a number of carbon atoms. Alkyl groups with 2 to 16 carbon atoms are preferred, and alkyl groups with 3 to 12 carbon atoms are more preferred. Alkyl groups with 4 to 8 alkyl groups are particularly preferred. Examples of alkyl groups include methyl groups and ethyl groups. n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl Examples include n-nonyl groups, n-decanyl groups, n-octadecanyl groups, etc. As the above aryl group, an aryl group having 6 to 12 carbon atoms is preferable, and an aryl group having 6 to 9 carbon atoms is more preferable. For example, a phenyl group, a tolyl group, a dimethylphenyl group, a naphthyl group, etc. can be mentioned. For example, a phenyl group, a tolyl group, a dimethylphenyl group, a naphthyl group, etc. can be mentioned. As the above aralkyl group, an aralkyl group having 7 to 12 carbon atoms is preferable, and an aralkyl group having 7 to 10 carbon atoms is more preferable. For example, a benzyl group, a phenethyl group, etc. can be mentioned. For example, a benzyl group, a phenethyl group, etc. can be mentioned.

[0031] Also, as the substituent which the monovalent hydrocarbon group represented by R 1 , R 2 may have, halogen atoms such as a chlorine atom and a bromine atom; a hydroxy group, etc. can be mentioned, but a halogen atom is preferable. The substitution position and number of substituents are arbitrary, and when having two or more substituents, the substituents may be the same or different. As the monovalent hydrocarbon group having such a substituent, specifically, haloaryl groups such as a chlorophenyl group and a dichlorophenyl group; haloaralkyl groups such as a chlorobenzyl group and a dichlorobenzyl group, etc. can be mentioned. Also, as the substituent which the monovalent hydrocarbon group represented by R may have, halogen atoms such as a chlorine atom and a bromine atom; a hydroxy group, etc. can be mentioned, but a halogen atom is preferable. The substitution position and number of substituents are arbitrary, and when having two or more substituents, the substituents may be the same or different. As the monovalent hydrocarbon group having such a substituent, specifically, haloaryl groups such as a chlorophenyl group and a dichlorophenyl group; haloaralkyl groups such as a chlorobenzyl group and a dichlorobenzyl group, etc. can be mentioned. As such a monovalent hydrocarbon group having such a substituent, specifically, haloaryl groups such as a chlorophenyl group and a dichlorophenyl group; haloaralkyl groups such as a chlorobenzyl group and a dichlorobenzyl group, etc. can be mentioned.

[0032] As R 1 in formula (2), a hydrogen atom, a substituted or unsubstituted alkyl group having 2 to 16 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms are preferable, a hydrogen atom, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms are more preferable, and a substituted or unsubstituted aryl group having 6 to 12 carbon atoms is particularly preferable. As R in formula (2), a hydrogen atom, a substituted or unsubstituted alkyl group having 2 to 16 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms are preferable, a hydrogen atom, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms are more preferable, and a substituted or unsubstituted aryl group having 6 to 12 carbon atoms is particularly preferable. As R in formula (2), a hydrogen atom, a substituted or unsubstituted alkyl group having 2 to 16 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms are preferable, a hydrogen atom, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms are more preferable, and a substituted or unsubstituted aryl group having 6 to 12 carbon atoms is particularly preferable. Also, as R 2 in formula (2), a substituted or unsubstituted alkyl group having 2 to 16 carbon atoms, a substituted or unsubstituted aryl group having 6 to 12 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms As R ​​​A kill group is preferred, and substituted or unsubstituted aryl groups having 6 to 12 carbon atoms, substituted or unsubstituted carbon A more preferred aralkyl group has 7 to 12 prime atoms, and a substituted or unsubstituted ally group has 6 to 12 carbon atoms. The 'L' group is particularly preferred.

[0033] R in equation (2) 3 , R in equation (3) 4 The "divalent hydrocarbon group" shown is a linear Alternatively, branched alkanediyl groups are preferred. The number of carbon atoms in the alkanediyl group is preferably 1 or more, more preferably 2 or more, and particularly preferably 2 or more. The value is 3 or more, preferably 16 or less, more preferably 12 or less, and particularly preferably It is 8 or less. For example, methane-1,1-diyl group, ethane-1,1-diyl group, ethane n-1,2-diyl group, propane-1,1-diyl group, propane-1,2-diyl group, pu Ropan-1,3-diyl group, propane-2,2-diyl group, butane-1,1-diyl group, Butane-1,2-diyl group, butane-1,3-diyl group, butane-1,4-diyl group, thane-1,5-diyl group, hexane-1,6-diyl group, heptane-1,7-diyl group Examples include octane-1,8-diyl groups. Note that R in equation (2) 3 , R in equation (3) 4 Even if the divalent hydrocarbon group shown has A good substituent would be the above R. 1 , R 2 The monovalent hydrocarbon group shown may have Examples similar to those found in the conversion cycle include those found in the conversion cycle.

[0034] Examples of biguanide compounds include chlorhexidine and 1-(3,4-diclo Robenzyl)-5-octylbiguanide, 1-butylbiguanide, 1-octadecylbiguanide Anido, phenylbiguanide, 1-o-tolylbiguanide, 1-p-tolylbiguanide, Examples include 1-(2-phenylethyl) biguanide and polyhexamethylene biguanide. Of these biguanide compounds, using just one alone or combining two or more will yield results. It can be used in combination. Among these biguanide compounds, chlorhexidine, 1 -(3,4-dichlorobenzyl)-5-octyl biguanide, polyhexamethylene biguanide Nido is preferred, and chlorhexidine is particularly preferred.

[0035] Furthermore, in this specification, "biguanide compounds and their salts and their solvates" "One or more selected from the group" includes biguanide compounds and their pharmaceutically acceptable salts. Furthermore, examples include solvates of these compounds or pharmaceutically acceptable salts with water, alcohol, etc. These can be used in combination of one or more types. Pharmaceutically acceptable salts are not particularly limited, but specifically include, for example, hydrochloride salts and sulfuric acid salts. Inorganic salts such as salts, nitrates, hydrofluorides, and hydrobroms; acetates, tartrates, lactates, Citrate, fumarate, maleate, succinate, methanesulfonate, ethansulfonate Honate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, Examples include organic acid salts such as sulfonates and glucons. One or more selected from the group consisting of biguanide compounds, their salts, and their solvates. The above includes biguanide compounds, hydrochloride salts of biguanide compounds, and biguanide compounds Selected from the group consisting of gluconates, acetates of biguanide compounds, and solvates thereof. Preferably one or more of the following: chlorhexidine, chlorhexidine hydrochloride, chlorhexidine A group consisting of cidin gluconate, chlorhexidine acetate, and their solvates. One or more of the following are more preferable, including chlorhexidine listed in the 17th edition of the Japanese Pharmacopoeia. One or more selected from the group consisting of hydrochloride and chlorhexidine gluconate solution is more preferred. In particular, chlorhexidine gluconate solution, as listed in the 17th edition of the Japanese Pharmacopoeia, is preferred. Furthermore, these ingredients are publicly known and may be manufactured by publicly known methods, or commercially available products may be used. You can.

[0036] From the group consisting of biguanide compounds and their salts in aqueous compositions and their solvates The amount of one or more selected ingredients is not particularly limited, but from the viewpoint of discoloration suppression, aqueous composition Preferably, it contains 0.00001 to 5 w / v% of the total volume, and 0.0001 to 1 It is more preferable to contain w / v%, and particularly preferable to contain 0.001 to 0.1 w / v%. Furthermore, when chlorhexidine is used as a biguanide compound, discoloration occurs. From the viewpoint of inhibitory effect, it is contained in an amount of 0.00005 to 3 w / v% relative to the total volume of the aqueous composition. It is preferable that it contains 0.0005 to 0.5 w / v%, and more preferably 0.002 to It is particularly preferable to contain 0.05 w / v%. Furthermore, the compound represented by the general formula (1) or its salt in the aqueous composition or the same Selected from the group consisting of solvates, biguanide compounds and their salts, and their solvates. The mass ratio of one or more of these is not particularly limited, but from the viewpoint of discoloration suppression, the general formula ( 1) For every 1 part by mass of the free form of the compound represented by 1), a biguanide compound and the One or more selected from the group consisting of salts and solvates thereof, in an amount of 0.00001 to 1 by mass It is preferable to contain parts, more preferably 0.0001 to 0.1 parts by mass, and 0. It is particularly preferable to contain 0.01 to 0.01 parts by mass of the compound represented by general formula (1). When using lipasudil as the substance and chlorhexidine as the biguanide compound: In this regard, from the viewpoint of inhibiting discoloration, when converted to the free form of lipasudil, per 1 part by mass, One or more selected from the group consisting of chlorhexidine, its salts, and their solvates. Preferably containing 0.00005 to 0.5 parts by mass, and preferably containing 0.0005 to 0.05 parts by mass. It is more preferable to have it, and particularly preferable to contain 0.003 to 0.008 parts by mass.

[0037] In this specification, “aqueous composition” means a composition containing at least water, and In terms of properties, it can be liquid (solution or suspension) or semi-solid (ointment), with liquid being preferred. For example, purified water, sterile water for injection, or sterile purified water may be used as the water in the composition. can. The water content in the aqueous composition is not particularly limited, but is preferably 5% by mass or more. 0% by mass or more is more preferable, 50% by mass or more is even more preferable, and 90% by mass or more is even more preferable. More preferably, and particularly preferably 90 to 99.8% by mass.

[0038] Aqueous compositions are prepared, for example, according to known methods described in the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia, etc. It can be manufactured in various dosage forms. Examples of dosage forms include injections and inhalation solutions. Eye drops, eye ointments, ear drops, nasal drops, enemas, topical solutions, sprays, ointments, creams Examples include powders, gels, oral solutions, syrups, etc. The general dosage form is (1) From the perspective of advantageously utilizing the pharmacological effects of the compounds expressed, ophthalmic preparations, specifically eye drops, A preparation or ointment is preferred, and eye drops are particularly preferred.

[0039] In addition to those mentioned above, aqueous compositions are used in pharmaceuticals, quasi-drugs, etc., depending on the dosage form. It may contain additives. Examples of such additives include inorganic salts, isotonic agents, Chelating agent, stabilizer, pH adjuster, preservative, antioxidant, viscosity modifier, surfactant, solubilizer Examples include fertilizers, suspending agents, cooling agents, dispersants, preservatives, oily bases, emulsion bases, and water-soluble bases. It is possible. Examples of such additives include, for instance, ascorbic acid and potassium aspartate. Sodium bisulfite, alginic acid, sodium benzoate, benzyl benzoate, ip Silon-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, Ruboxyvinyl polymer, anhydrous sodium sulfite, anhydrous sodium carbonate, d-camphor, dl-camphor, xylitol, citric acid hydrate, sodium citrate hydrate, glycerin Gluconic acid, L-glutamic acid, L-sodium glutamate, creatinine, chloroglycerides Lobutanol, sodium dihydrogen crystalline phosphate, geraniol, sodium chondroitin sulfate Um, acetic acid, potassium acetate, sodium acetate hydrate, titanium dioxide, gellan gum, Djibouti Hydroxytoluene, potassium bromide, benzododecinium bromide, tartaric acid, sodium hydroxide Um, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol Liquid, taurine, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate Thimerosal, tyroxapol, sodium dehydroacetate, trometamol, concentrated glycerin Phosphorus, concentrated mixed tocopherol, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium Chloride solution 50, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, parahydroxybenzoate Propyl benzoate, methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin N, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, ice Acetic acid, sodium pyrosulfite, phenylethyl alcohol, glucose, propylene glyco Benzyl phosphate, bergamot oil, benzalkonium chloride, benzalkonium chloride solution, benzyl Alcohol, benzethonium chloride, benzethonium chloride solution, borax, boric acid, povidone Polyoxyethylene (200), polyoxypropylene glycol (70), polystyrene Sodium lensulfonate, polysorbate 80, polyoxyethylene hydrogenated castor oil 60 Polyvinyl alcohol (partially saponified), d-borneol, macrogol 4000, Macrogol 6000, D-mannitol, anhydrous citric acid, anhydrous sodium monohydrogen phosphate Anhydrous sodium dihydrogen phosphate, methanesulfonic acid, methylcellulose, l-menthol Monoethanolamine, aluminum monostearate, polyethylene monostearate Glycol, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin N, dragon's manure, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, phosphoric acid Examples include sodium dihydrogen, sodium dihydrogen phosphate monohydrate, malic acid, and petrolatum. ru.

[0040] Examples of additives include potassium chloride, calcium chloride hydrate, sodium chloride, and salt. Magnesium chloride, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, water Sodium oxide, sodium bicarbonate, sodium carbonate hydrate, concentrated glycerin, hydrochloride Cethylcellulose, hydroxypropylcellulose, hypromellose, borax, boric acid Povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, monostearate Polyethylene glycol, polyvinyl alcohol (partially saponified), macrogol 400 0, Macrogol 6000, Anhydrous Citric Acid, Anhydrous Sodium Monohydrogen Phosphate, Anhydrous Dihydrogen Phosphate Sodium hydrogen, methylcellulose, monoethanolamine, phosphoric acid, sodium hydrogen phosphate Potassium dihydrogen hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate Monohydrate, sodium hyaluronate, glucose, l-menthol, etc. are preferred.

[0041] The aqueous composition may also contain other active ingredients depending on the disease or other condition being treated, in addition to those mentioned above. It is acceptable to have it. Examples of such medicinal ingredients include bunazosin hydrochloride and other bunazosin compounds. α1 receptor blockers containing salts thereof or solvates thereof; brimonidine tartrate, etc. Any brimonidine or its salts or their solvates, apraclonidine or its α2 receptor agonists containing salts or solvates thereof; such as carteolol hydrochloride Roll or its salts or solvates thereof, nipradilol or its salts or the Solvates of timolol, timolol maleate, timolol or its salts, or their solvents Betaxol or its salts, such as betaxolol hydrochloride, or their solvates. levovunol or its salts, such as levovunol hydrochloride, or their solvates, Funolol or its salts or solvates thereof, methypranolol or its salts or Beta-blockers containing those solvates; dorzolamide hydrochloride or similar dorzolamide or its Salts or solvates thereof, brinzolamide or its salts or solvates thereof, aceta Zolamide or its salts or their solvates, dichlorphenamide or its salts or Carbonic anhydrase containing those solvates, metazolamide or its salts, or those solvates Isopropyl unoprostone or its salts or their solvates, taflup Rost or its salts or their solvates, travoprost or its salts or their solvates of bimatoprost or its salts or their solvates, latanoprost or Prostaglandins, including their salts or solvates; omidenepaguisopropyl EP2 receptor agonists containing dipivefrin hydrochloride or its salts or solvates thereof; dipivefrin hydrochloride dipivephrine or its salts or solvates thereof, epinephrine, epinephrine Epinephrine or its salts, such as borate and epinephrine hydrochloride, or their solvates. Sympathomimetic agents containing; distigmine bromide or its salts or solvates thereof, pyro Pilocarpine or its salts, such as pilocarpine hydrochloride, pilocarpine nitrate, etc. or a combination of the solvates thereof, carbachol or its salts, or the solvates thereof Neurostimulants; lomerizine or its salts, such as lomerizine hydrochloride, or their solvates. Contains calcium channel blockers; demepotassium or its salts or their solvates, ecothiof ate or its salts or solvates thereof, physostigmine or its salts or the Examples include cholinesterase inhibitors containing solvates of these, and one or two of these. The above can be combined. Other active ingredients include latanoprost, nipradilol, timolol, and omidenepag. One or more selected from the group consisting of isopropyl and its salts and their solvates preferable.

[0042] The pH of the aqueous composition at 25°C is not particularly limited, but is preferably 4 to 9, and 4.5 to 9. 8 is more preferred, and 5 to 7 is particularly preferred. Also, the osmotic pressure ratio to physiological saline is not particularly limited. While not fixed, 0.6 to 3 is preferred, and 0.6 to 2 is particularly preferred.

[0043] Aqueous compositions are preferably housed in containers from the viewpoint of storage stability and portability. In this specification, "container" means a package that directly contains the aqueous composition. The container is defined as a "sealed container," "airtight container," or "sealed container" in the General Rules of the Sixteenth Revised Japanese Pharmacopoeia. It is a concept that encompasses all aspects of "vessel."

[0044] The form of the container is not particularly limited, as long as it is capable of containing the aqueous composition, and the dosage form, etc. You can select and set it as appropriate depending on the situation. Examples of such container forms include, for example... , containers for injections, containers for inhalants, containers for sprays, bottle-shaped containers, tube-shaped containers, point Examples include containers for eye drops, nasal drops, ear drops, and bag containers. The container may be further packaged in a box, bag, or the like.

[0045] The material of the container is not particularly limited and should be selected appropriately according to the shape of the container. Examples of such materials include glass, plastic, cellulose, pulp, rubber, and metal. Among these, plastic is preferred from the standpoint of processability, squeezeability, and durability. It is preferable that the resin used for the plastic container be a thermoplastic resin, for example, Low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density Polyolefin resins such as polyethylene, polypropylene, and cyclic polyolefins; Polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, poly Butylene naphthalate, poly(1,4-cyclohexylenedimethyleneterenaphthalate) Polyester resins such as; polyphenylene ether resins; polycarbonate resins; Examples include resulfone resins, polyamide resins, polyvinyl chloride resins, and styrene resins. These may be mixtures (polymer alloys). The material of the container is not particularly limited, but from the viewpoint of preventing discoloration, polyolefin is preferred. It is preferable that it be a resin, and particularly preferable that it be polypropylene.

[0046] In this specification, "polyolefin resin container" means a container that has at least an aqueous component This refers to a container in which the part that comes into contact with the product is made of "polyolefin resin". Therefore, for example A polyolefin layer is provided in the inner layer that comes into contact with the aqueous composition, and a resin of another material is provided on the outside thereof. Containers made by laminating or other similar methods also fall under the category of "polyolefin resin containers." Here, polio The refin resin is not particularly limited and is a polymer (homopolymer) of a single monomer. It may also be a copolymer of multiple types of monomers. In such cases, the polymerization mode is not particularly limited, and can be random polymerization or block polymerization. Good. Furthermore, its three-dimensional regularity (tacticity) is not particularly limited. Examples of such polyolefin resins include, specifically, polyethylene (more details For example, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene Polyethylene (including medium-density polyethylene), polypropylene, cyclic polyolefin, poly(4-methyl) Tylpentene, polytetrafluoroethylene, ethylene-propylene copolymer, ethylene α-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid Examples include copolymers, ethylene-vinyl acetate copolymers, and ethylene-ethyl acrylate copolymers. These can be used in combination of one or more types. Polyolefin resins are also available. Therefore, from the standpoint of suppressing discoloration, polyethylene, polypropylene, and cyclic polyolefins are used. Polyethylene is preferred, polypropylene is more preferred, and polypropylene is particularly preferred. stomach. In this specification, "made of polyolefin resin" means at least a part of its material. This means that it contains polyolefin resin, for example, polyolefin resin and other A mixture of two or more resins (polymer alloy) with the resin is also classified as "made from polyolefin resin". It is included.

[0047] Polyolefin resin containers also contain UV absorbers and UV scatterers to counteract ultraviolet light. It is preferable to incorporate a substance that inhibits permeation. This prevents the compound represented by general formula (1) from permeating. The stability of these materials to light is improved. Specifically, such materials include, for example, ultraviolet radiation Examples of disruptors include titanium dioxide and zinc oxide. Also, examples of UV absorbers include 2 -(2H-benzotriazol-2-yl)-p-cresol (e.g., Tinuvin P:B ASF Corporation, 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl -1-phenylethyl)phenol (e.g., Tinuvin 234: BASF), 2-(3, 5-di-t-butyl-2-hydroxyphenyl)benzotriazole (e.g., Tinuvin3 20: BASF, 2-[5-chloro(2H)-benzotriazol-2-yl]-4- Methyl-6-(tert-butyl)phenol (e.g., Tinuvin 326: BASF), 2- (3,5-di-t-butyl-2-hydroxyphenyl)-5-chlorobenzotriazole (For example, Tinuvin327: BASF), 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'-methyllenbis[6-( 2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl) Phenol (e.g., Tinuvin 360: BASF), methyl 3-(3-(2H-benzo Riazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionate The reaction product of polyethylene glycol 300 (e.g., Tinuvin 213: BASF), 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol For example, Tinuvin 571 (BASF), 2-(2'-hydroxy-3',5'-di-t-amine) (ruphenyl)benzotriazole, 2-[2'-hydroxy-3'-(3'',4'',5'', 6''-Tetrahydrophthalimidomethyl)-5'-methylphenyl]benzotriazole ,2,2'-methylenebis[4-(1,1,3,3-tetramethylbutyl)-6-(2H Benzotriazole-based UV absorbers such as [benzotriazole-2-yl)phenol] ;2,2-bis{[2-cyano-3,3-diphenylacryloyloxy]methyl}pro Pan-1,3-diyl=bis(2-cyano-3,3-diphenylacrylate) (for example) Uvinul 3030 FF (BASF), 2-cyano-3,3-diphenylacrylate ethyl ( For example, Uvinul 3035 (BASF), 2-cyano-3,3-diphenylacrylic acid 2- Cyanoacrylate-based ultraviolet light such as ethylhexyl (e.g., Uvinul 3039: BASF). Absorbent; 2-(4,6-diphenyl-1,3,5-triazine-2-yl)-5-[(he Triadioxyphenol (e.g., Tinuvin 1577 ED: BASF) UV absorbers; octabenzone (e.g., Chimassorb 81: BASF), 2,2'- Dihydroxy-4,4'-dimethoxybenphenone (e.g., Uvinul 3049: BASF) , 2,2'-4,4'-tetrahydrobenphenone (e.g., Uvinul 3050: BASF) , oxybenzone, hydroxymethoxybenzophenone sulfonic acid, hydroxymethoxy Sodium benzophenone sulfonate, dihydroxydimethoxybenzophenone, dihydro Sodium roxydimethoxybenzophenone disulfonate, dihydroxybenzophenone , benzophenone-based UV absorbers such as tetrahydroxybenzophenone; diisopropyl Methyl cinnamate, cinoxate, diparamethoxycinnamate mono-2-ethylhexanoate Lyceryl, isopropyl paramethoxycinnamate / diisopropyl cinnamate mixture , 2-ethylhexyl paramethoxycinnamate, benzyl cinnamate, and other cinnamic acid-based UV absorbers Astringents: para-aminobenzoic acid, ethyl para-aminobenzoate, glyceryl para-aminobenzoate amyl paradimethylaminobenzoate, 2-ethylhexyl paradimethylaminobenzoate , benzoic acid ethyl 4-[N,N-di(2-hydroxypropyl)amino]benzoate, etc. Stellate-type UV absorbers; ethylene glycol salicylate, octyl salicylate, salicyl Dipropylene glycol acid, phenyl salicylate, homomenthyl salicylate, salicylic acid Methyl salicylic acid-based UV absorbers; guaiazulene; dimethoxybenzylidene dioxy 2-ethylhexyl soimidazolidinepropionate; 2,4,6-tris[4-(2-E [Tylhexyloxycarbonyl)anilino]1,3,5-triazine; parahydroxy Nisol; 4-tert-butyl-4'-methoxydibenzoylmethane; phenylbenzi Dazole sulfonic acid; 2-(4-diethylamino-2-hydroxybenzoyl)-benzoic acid Examples include hexyl acid.

[0048] Furthermore, when incorporating a substance that inhibits the transmission of ultraviolet light into the container, the proportion of that substance should be... Although it varies depending on the type, for example, the amount in the container is usually 0.001 to 50% by mass, preferably The amount should be approximately 0.002 to 25% by mass, and particularly preferably 0.01 to 10% by mass.

[0049] The container should preferably allow the inside to be visible (observable) to the naked eye. Therefore, it becomes possible to inspect for the presence or absence of foreign matter contamination in the manufacturing process of pharmaceutical products. This offers advantages such as allowing the user to check the remaining amount of the contents (aqueous composition). Recognition only needs to be ensured on at least a portion of the container surface (for example, eye drops) Even if the sides of the container are obscured by shrink film or the like, the bottom can still be seen. If it is visible, then it can be said to be visible. If the inside is visible from a part of the container surface, then This makes it possible to confirm the aqueous composition inside the container. In this specification, "pharmaceutical preparation" refers to an aqueous composition contained in a container. It refers to.

[0050] The means of containing the aqueous composition in the container are not particularly limited and can be filled by conventional methods according to the form of the container, etc. Fill it in.

[0051] The diseases to which aqueous compositions and pharmaceutical preparations can be applied are not particularly limited, and the compounds represented by the general formula (1) above... The appropriate choice should be made according to the pharmacological effects and other properties of the substance. Specifically, for example, the Rho kinase inhibitory effect of the compound represented by general formula (1), and Based on its intraocular pressure-lowering effect, it can be used as a preventive or therapeutic agent for ocular hypertension and glaucoma. Glaucoma can be further categorized into, for example, primary open-angle glaucoma, normal-tension glaucoma, and aqueous humor glaucoma. Hyperglaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed Combined glaucoma, steroid glaucoma, lens capsule glaucoma, pigment glaucoma, amyloid glaucoma, Examples include neovascular glaucoma and malignant glaucoma.

[0052] Furthermore, as disclosed in Japanese Patent Publication No. 5557408, it is represented by general formula (1) Based on the effects of the compound, fundus diseases (diseases that primarily manifest in the retina and / or choroid) Strange. Specifically, for example, fundus changes due to hypertension and arteriosclerosis, central retinal artery occlusion, retinal Cardiovascular vein occlusion (central retinal vein occlusion) and branch retinal vein occlusion (branch retinal vein occlusion) Retinal vein occlusion (such as al vein occlusion), diabetic retinopathy, diabetic macular edema, diabetic macula Congenital retinal vascular anomalies such as Eales disease and Coats disease, Hippel disease (von Hippel disease), pulseless disease, macular disease (center) Central serous chorioretinopathy, cystoid macular edema Age-related macular degeneration, macular hole ole), myopic macular degeneration, retinovitreous interface macular degeneration, Drug-toxic macular degeneration, hereditary macular degeneration, etc., retinal detachment (rhegmatogenous, tractional, exudative, etc.) Examples include retinitis pigmentosa and retinopathy of prematurity.) A preventive or therapeutic agent for these conditions, more preferably sugar It may also be used as a preventive or therapeutic agent for urinary retinopathy, diabetic macular edema, or age-related macular degeneration.

[0053] Furthermore, aqueous compositions and pharmaceutical preparations can be used to treat eye diseases (preferably ocular hypertension, glaucoma, and retinal diseases). Diseases to be selected: Particularly preferred are diseases selected from ocular hypertension and glaucoma) prevention and / or When used as a therapeutic agent, it should be administered 1 to 3 times a day.

[0054] This specification is not limited to these, but for example, the following embodiments Disclose. [1A] The following general formula (1)

[0055] [ka]

[0056] [In the formula, X represents a halogen atom.] Compounds represented by or salts thereof or solvates thereof, and biguanide compounds and their An aqueous composition containing one or more selected from the group consisting of salts and solvates thereof. [2A] The compound represented by the general formula (1) is lipasudil, as described in [1A]. Aqueous composition. [3A] The biguanide compound is defined by the following general formula (2)

[0057] [ka]

[0058] [In the formula, R 1 This indicates a hydrogen atom, or a substituted or unsubstituted monovalent hydrocarbon group having 1 to 20 carbon atoms. death, R 2 This represents a substituted or unsubstituted monovalent hydrocarbon group having 1 to 20 carbon atoms. R 3 This represents a substituted or unsubstituted divalent hydrocarbon group having 1 to 20 carbon atoms. n represents either 0 or 1. Compounds represented by the following general formula (3)

[0059] [ka]

[0060] [In the formula, R 4 This represents a substituted or unsubstituted divalent hydrocarbon group having 1 to 20 carbon atoms. [1A] is one or more polymers selected from the group consisting of polymers having repeating units represented by the symbol [1A The aqueous composition described in [2A] or [2A].

[0061] [4A] The biguanide compound is chlorhexidine, as in [1A]~[3A]. Any of the aqueous compositions described. [5A] From the group consisting of the biguanide compounds and their salts and solvates One or more of the selected substances are chlorhexidine, chlorhexidine hydrochloride, and chlorhexidine Selected from the group consisting of gluconates and chlorhexidine acetates and their solvates. An aqueous composition containing one or more of the following: [1A] to [4A]. [6A] From the group consisting of the biguanide compounds and their salts and their solvates One or more of the selected types are chlorhexidine gluconate, among [1A] to [5A] Any of the aqueous compositions listed below.

[0062] [7A] An aqueous composition according to any one of [1A] to [6A], which is an ophthalmic preparation. [8A] An aqueous composition described in [7A], which is an eye drop. [9A] A preventive and / or therapeutic agent for a disease selected from ocular hypertension, glaucoma, and retinal diseases. An aqueous composition as described in any of [1A] to [8A].

[0063] [10A] In addition, α1 receptor blockers, α2 receptor agonists, β-blockers, carbonic anhydrase Inhibitors, prostaglandins, EP2 receptor agonists, sympathetic agonists, parasympathetic agonists One or more drugs selected from the group consisting of drugs, calcium channel blockers, and cholinesterase inhibitors. An aqueous composition containing any of the following: [1A] to [9A]. [11A] In addition, latanoprost, nipradilol, timolol, omidenepagyu It contains one or more selected from the group consisting of sopropyl and its salts and their solvates. An aqueous composition having any of the descriptions in [1A] to [9A].

[0064] [12A] The aqueous composition described in any of [1A] to [11A] is polyolefin-based A pharmaceutical preparation housed in a resin container. [13A] The polyolefin resin is polyethylene or polypropylene. [12A] A pharmaceutical preparation as described in [12A]. [14A] The polyolefin resin container is a container for eye drops, [12A] or [13A] is a pharmaceutical preparation.

[0065] [1B] The compound represented by the general formula (1) above, or a salt thereof, or a solvate thereof The aqueous composition contains biguanide compounds and their salts and their solvates. A method for suppressing discoloration of an aqueous composition, comprising the step of including one or more substances selected from a group. [2B] The compound represented by the general formula (1) is lipasudil, as described in [1B]. method. [3B] The biguanide compound is the compound represented by the general formula (2), and the One or more polymers selected from the group consisting of polymers having repeating units represented by general formula (3) A method described in [1B] or [2B].

[0066] [4B] The biguanide compound is chlorhexidine, as in [1B]~[3B]. The method of notation. [5B] From the group consisting of the biguanide compounds and their salts and their solvates One or more of the selected substances are chlorhexidine, chlorhexidine hydrochloride, and chlorhexidine Selected from the group consisting of gluconates and chlorhexidine acetates and their solvates. One or more types that can be detected, described in one of the following ways: [1B] to [4B]. [6B] From the group consisting of the biguanide compounds and their salts and their solvates One or more of the selected ingredients are chlorhexidine gluconate, among [1B] to [5B] Please describe the method.

[0067] [7B] The aqueous composition is an ophthalmic agent, according to any one of [1B] to [6B]. method. [8B] The method according to [7B], wherein the ophthalmic agent is an eye drop. [9B] The aqueous composition provides for the prevention of a disease selected from ocular hypertension, glaucoma, and retinal disease. The method described in any of [1B] to [8B], which is and / or a therapeutic agent.

[0068] [10B] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, and a β blocker. Drugs, carbonic anhydrase inhibitors, prostaglandins, EP2 receptor agonists, sympathomimetic drugs Selected from the group consisting of parasympathetic agonists, calcium channel blockers, and cholinesterase inhibitors. A method described in any of [1B] to [9B], containing one or more types of [unclear]. [11B] The aqueous composition further comprises latanoprost, nipradilol, and timolol Selected from the group consisting of omidenepagisopropyl and their salts and their solvates. A method described in any of [1B] to [9B], containing one or more of the above.

[0069] [12B] The further step includes housing the aqueous composition in a polyolefin resin container. One of the methods described in [1B] to [11B]. [13B] The polyolefin resin is polyethylene or polypropylene. The method described in [12B]. [14B] The polyolefin resin container is a container for eye drops, [12B] or The method described in [13B]. [Examples]

[0070] Next, the present invention will be further described with reference to examples, but the present invention is not limited in any way to these examples. isn't it. In the following test examples, ripasudil 1-hydrochloride dihydrate is used, for example, in International Publication No. 2. It can be manufactured using the method described in pamphlet No. 006 / 057397.

[0071] [Test Example 1] Preservation Test The aqueous mixtures of Example 1 and Comparative Example 1, containing the components and quantities shown in Table 1 per 100 mL. The finished product was prepared by conventional methods and placed in a polypropylene container. Each of the resulting aqueous compositions was stored at 80°C for one week. The degree of discoloration (yellowing) before and after storage was as follows: The color difference (ΔYI) of the aqueous composition before and after storage was measured using a colorimeter (spectrophotometer CM-700d: Koni The results were evaluated by measuring using Caminolta Sensing Co., Ltd. The results are shown in Table 1.

[0072] [Table 1]

[0073] As shown in Table 1, the aqueous composition containing lipasudil was further treated with chlorhexidine. When chlorhexidine is included, ΔYI is lower compared to when chlorhexidine is not included. The values ​​were significantly lower, revealing that discoloration after high-temperature storage was suppressed.

[0074] Based on the above test results, compounds represented by general formula (1), such as lipasudil, or An aqueous composition containing the salt or solvate thereof, further comprising chlorhexidine One selected from the group consisting of biguanide compounds and their salts and their solvates. When the above is included, discoloration (yellowing) is relatively less likely to occur even when stored at high temperatures. It was found to have excellent storage stability.

[0075] [Manufacturing Examples 1-27] The following ingredients and quantities (amount per 100 mL of aqueous composition (g)) are included in Tables 2 to 4. The aqueous composition can be manufactured by conventional methods.

[0076] [Table 2]

[0077] [Table 3]

[0078] [Table 4]

[0079] [Manufacturing Examples 28-54] In manufacturing examples 1-27, the same amount of 4-bromo- was used instead of lipasudil 1-hydrochloride dihydrate. 5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoli Products using this method can be manufactured by conventional methods as aqueous compositions as shown in manufacturing examples 28 to 54.

[0080] [Manufacturing Examples 55-108] By housing the aqueous compositions of Production Examples 1 to 54 in polypropylene eye drop containers, The pharmaceutical formulations described in manufacturing examples 55-108 can be manufactured by conventional methods.

[0081] [Manufacturing Examples 109-162] By housing the aqueous compositions of Production Examples 1 to 54 in polyethylene eye drop containers, The pharmaceutical formulations described in manufacturing examples 109-162 can be manufactured by conventional methods. [Industrial applicability]

[0082] According to the present invention, aqueous compositions and pharmaceutical formulations with excellent storage stability can be provided, which are useful for the pharmaceutical industry, etc. It can be suitably used in the following applications.

Claims

[Claim 1] The invention described in the specification.

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