JP2020193174A - Aqueous composition - Google Patents

Abstract

To provide a new technique for inhibiting discoloration in a halogenated isoquinoline derivative-containing aqueous composition during high-temperature storage.SOLUTION: An aqueous composition contains: a compound represented by the general formula (1) in the figure, where X represents a halogen atom, or its salt, or their solvate; and one or more selected from the group consisting of biguanide-based compounds, their salts, and their solvates.SELECTED DRAWING: None

Description

The present invention relates to an aqueous composition or the like.

The following structural formula:

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

Halogenated isoquinoline derivatives such as 4-bromo-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline represented by 4 have pharmacological actions such as Rho kinase inhibitory action ( For example, it has Patent Documents 1 and 2) and is known to be useful for the prevention and treatment of eye diseases. Specifically, it may be useful for the prevention or treatment of ocular hypertension, glaucoma, etc. (for example, Patent Document 3), or the prevention or treatment of fundus diseases such as age-related macular degeneration (for example, Patent Document 4). It has been reported.

Therefore, it is extremely useful to establish a technique for stably formulating these halogenated isoquinoline derivatives as, for example, ophthalmic agents.
Ophthalmic agents are usually water-containing compositions (aqueous compositions). However, it is known that when an aqueous composition containing ripasudil, which is a halogenated isoquinoline derivative, is prepared and stored at a high temperature, there arises a problem that the aqueous composition discolors over time, and some discoloration suppressions have been made so far. Means have been proposed (eg, Patent Documents 5-8).

Japanese Patent No. 421149 International Publication No. 2006/115244 Pamphlet International Publication No. 2006/068208 Pamphlet Japanese Patent No. 5557408 Japanese Unexamined Patent Publication No. 2016-135759 Japanese Unexamined Patent Publication No. 2016-135779 Japanese Unexamined Patent Publication No. 2016-155871 Japanese Unexamined Patent Publication No. 2016-166198

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

Therefore, the present inventors have diligently studied to solve the above-mentioned problems, and found that an aqueous composition containing a halogenated isoquinoline derivative such as ripasudil, a biguanide compound such as chlorhexidine, a salt thereof, and a solvate thereof were used. The present invention has been completed by finding that discoloration during high-temperature storage can be suppressed by containing one or more selected from the above group.

That is, the present invention has the following general formula (1).

[In the formula, X represents a halogen atom. ]
Provided is an aqueous composition containing a compound represented by (1) or a salt thereof or a solvate thereof, and one or more selected from the group consisting of a biguanide compound and a salt thereof and a solvate thereof. is there.
In addition, the present invention comprises a group consisting of a biguanide compound, a salt thereof, and a solvate thereof in an aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof. It provides a method for suppressing discoloration of an aqueous composition, which comprises a step of containing one or more selected kinds.

According to the present invention, discoloration of an aqueous composition containing a halogenated isoquinoline derivative such as ribasudil at high temperature can be suppressed.

In the present specification, "w / v%" means a mass-to-volume percentage, and specifically, means the mass (g) of each component contained in 100 mL of the composition.

In the general formula (1), examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and the like. In the general formula (1), as the halogen atom, a fluorine atom and a bromine atom are preferable, and a fluorine atom is particularly preferable.
Further, in the general formula (1), the carbon atom constituting the methyl group-substituted homopiperazine ring is an asymmetric carbon. Therefore, steric isomers occur, but any steric isomer is included in the compound represented by the general formula (1), and it may be a single steric isomer or a mixture of various steric isomers in an arbitrary ratio. .. As the compound represented by the general formula (1), a compound having an absolute configuration of S is preferable.

The salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt, and specifically, for example, hydrochloride, sulfate, nitrate, hydrofluoride, and the like. Inorganic acid salts such as hydrobromide; acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate , Toluene sulfonate, naphthalene sulfonate, organic acid salts such as camphor sulfonate and the like, and hydrochloride is preferable.
Further, the compound represented by the general formula (1) or a salt thereof may be a solvate such as a hydrate or an alcoholic mixture, and is preferably a hydrate.

Specific examples of the compound represented by the general formula (1), a salt thereof, or a solvate thereof include, for example,
Ripasudil (chemical name: 4-fluoro-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline) or a salt thereof or a solvate thereof;
4-Bromo-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline or a salt thereof or a solvate thereof;
And so on.

Examples of the compound represented by the general formula (1) or a salt thereof or a solvate thereof include lipasudil or a salt thereof or a solvate thereof, 4-bromo-5-[[(2S) -2-methyl-. 1,4-Diazepan-1-yl] sulfonyl] isoquinolin or a salt thereof or a solvate thereof is preferable, and ribasudil or a salt thereof or a solvate thereof is more preferable, and ribasudil or a hydrochloride thereof or a hydrate thereof is preferable. Is more preferable, and the following structural formula:

Ripasudil hydrochloride hydrate represented by (ripasudil monohydrochloride dihydrate) is particularly preferable.

The compound represented by the general formula (1), a salt thereof, or a solvate thereof is known and can be produced by a known method. Specifically, for example, ripasudil or a salt thereof or a solvate thereof can be produced by the methods described in International Publication No. 1999/20620 Pamphlet, International Publication No. 2006/057397 Pamphlet and the like. In addition, 4-bromo-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline or a salt thereof or a solvate thereof is available in International Publication No. 2006/115244. It can be manufactured by the method described.

The content of the compound represented by the general formula (1) or a salt thereof or a solvate thereof in the aqueous composition is not particularly limited, and is appropriately examined according to the applicable disease, the sex, age, symptom, etc. of the patient. However, from the viewpoint of obtaining excellent pharmacological action, 0.01 to 10 w / v in terms of the free form of the compound represented by the general formula (1) with respect to the total volume of the aqueous composition. % Is preferably contained, 0.02 to 8 w / v% is more preferably contained, and 0.04 to 6 w / v% is particularly preferable. Above all, when ripasudil is used as the compound represented by the general formula (1), ripasudil or a salt thereof or a solvate thereof is added to the total volume of the aqueous composition from the viewpoint of obtaining excellent pharmacological action. It is preferably contained in an amount of 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v%, and particularly preferably 0.1 to 2 w / v% in terms of a free form.

Further, in the present invention, the "biguanide-based compound" is not particularly limited as long as it is a compound having a biguanide residue in the molecule, but from the viewpoint of discoloration suppressing action, the compound represented by the following general formula (2). And one or more selected from the group consisting of polymers having repeating units represented by the following general formula (3) are preferable, and the compound represented by the general formula (2) is more preferable. The polymer having a repeating unit represented by the general formula (3) may be a homopolymer or a copolymer having another repeating unit, but a homopolymer is preferable. The number average molecular weight of the polymer having the repeating unit represented by the general formula (3) is preferably 300 to 15,000, more preferably 500 to 5,000, from the viewpoint of discoloration suppressing action.

[During the ceremony,
R ¹ represents a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group having 1 to 20 carbon atoms.
R ² represents a substituted or unsubstituted monovalent hydrocarbon group having 1 to 20 carbon atoms.
R ³ represents a substituted or unsubstituted divalent hydrocarbon group having 1 to 20 carbon atoms.
n represents 0 or 1. ]

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

As n in the formula (2), 1 is preferable from the viewpoint of discoloration suppressing action.

As the "monovalent hydrocarbon group" represented by R ¹ and R ² in the formula (2), an alkyl group, an aryl group and an aralkyl group are preferable.
The alkyl group may be linear or branched. Further, as the alkyl group, an alkyl group having 2 to 16 carbon atoms is preferable, an alkyl group having 3 to 12 carbon atoms is more preferable, and an alkyl group having 4 to 8 carbon atoms is particularly preferable. Examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and n. -Heptyl group, n-octyl group, n-nonyl group, n-decanyl group, n-octadecanyl group and the like can be mentioned.
As the 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 and the like can be mentioned.
As the 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 and the like can be mentioned.

Examples of the substituent that the monovalent hydrocarbon group represented by R ¹ and R ² may have include a halogen atom such as a chlorine atom and a bromine atom; a hydroxy group and the like, but a halogen atom is preferable. .. The substitution position and the number of substituents are arbitrary, and when two or more substituents are present, the substituents may be the same or different. Specific examples of the monovalent hydrocarbon group having such a substituent include a haloaryl group such as a chlorophenyl group and a dichlorophenyl group; and a haloaralkyl group such as a chlorobenzyl group and a dichlorobenzyl group.

R ¹ in the formula (2) includes 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, and a substituted or unsubstituted carbon number 7 ~ 12 aralkyl groups are preferred, hydrogen atoms, substituted or unsubstituted aryl groups with 6-12 carbon atoms, substituted or unsubstituted aralkyl groups with 7-12 carbon atoms are more preferred, substituted or unsubstituted carbon atoms 6 Aryl groups of ~ 12 are particularly preferred.
In addition, R ² in the formula (2) includes an alkyl group having 2 to 16 carbon atoms substituted or unsubstituted, an aryl group having 6 to 12 carbon atoms substituted or unsubstituted, and 7 to 7 substituted or unsubstituted carbon atoms. Twelve aralkyl groups are preferred, substituted or unsubstituted aryl groups having 6 to 12 carbon atoms, substituted or unsubstituted aralkyl groups having 7 to 12 carbon atoms are more preferable, and substituted or unsubstituted aryl groups having 6 to 12 carbon atoms are preferable. Groups are particularly preferred.

R ³ in the formula (2), the "divalent hydrocarbon group" represented by R ⁴ in the formula (3), linear or branched alkanediyl group is preferred.
The number of carbon atoms of the alkanediyl group is preferably 1 or more, more preferably 2 or more, particularly preferably 3 or more, and preferably 16 or less, more preferably 12 or less, and particularly preferably 8 or less. For example, methane-1,1-diyl group, ethane-1,1-diyl group, ethane-1,2-diyl group, propane-1,1-diyl group, propane-1,2-diyl group, propane-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 , Pentan-1,5-diyl group, hexane-1,6-diyl group, heptane-1,7-diyl group, octane-1,8-diyl group and the like.
Incidentally, R ³ in the formula (2), the divalent hydrocarbon group substituents which may be possessed by represented by R ⁴ in the formula (3), represented by the above R ^1, R ² Examples thereof include the same substituents that the monovalent hydrocarbon group may have.

Specific examples of the biguanide compound include chlorhexidine, 1- (3,4-dichlorobenzyl) -5-octylbiguanide, 1-butylbiguanide, 1-octadesylbiguanide, phenylbiguanide, 1-o-tolylbiguanide, 1 Examples thereof include -p-tolylbiguanide, 1- (2-phenylethyl) biguanide, and polyhexamethylene biguanide. Of these biguanide compounds, only one type may be used alone, or two or more types may be used in combination.
Among these biguanide compounds, chlorhexidine, 1- (3,4-dichlorobenzyl) -5-octyl biguanide, and polyhexamethylene biguanide are preferable, and chlorhexidine is particularly preferable, from the viewpoint of discoloration inhibitory action.

Further, in the present specification, "one or more selected from the group consisting of a biguanide compound and a salt thereof and a solvate thereof" includes a biganide compound, a pharmaceutically acceptable salt thereof, and the compound thereof. Examples thereof include solvates of pharmaceutically acceptable salts and water, alcohol, etc., and one or a combination of two or more of these can be used.
The pharmaceutically acceptable salt is not particularly limited, but specifically, for example, an inorganic acid salt such as a hydrochloride, a sulfate, a nitrate, a hydrofluoride salt, and a hydrobromide; an acetate salt and a tartrate salt salt. , Lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalene sulfonate, camphor sulfonate, Examples thereof include organic acid salts such as gluconate.
One or more selected from the group consisting of biguanide compounds and salts thereof and their solvates include biguanide compounds, hydrochlorides of biguanides, gluconates of biguanides and acetates of biguanides, and acetates of biguanides. One or more selected from the group consisting of these solvates is preferable, and one or more selected from the group consisting of chlorhexidine, chlorhexidine hydrochloride, chlorhexidine gluconate and chlorhexidine acetate, and chlorhexidine acetates are preferable. More preferably, one or more selected from the group consisting of chlorhexidine hydrochloride and chlorhexidine biguanide solution listed in the 17th revised Japanese Pharmacy is more preferable, and chlorhexidine biguanide solution listed in the 17th revised Japanese Pharmacy is more preferable. Is particularly preferable.
These components are known, and may be produced by a known method, or a commercially available product may be used.

The content of one or more selected from the group consisting of biguanide compounds and salts thereof and solvates thereof in the aqueous composition is not particularly limited, but from the viewpoint of discoloration suppressing action, it is relative to the total volume of the aqueous composition. , 0.00001 to 5 w / v% is preferable, 0.0001 to 1 w / v% is more preferable, and 0.001 to 0.1 w / v% is particularly preferable. When chlorhexidine is used as the biguanide compound, it is preferably contained in an amount of 0.00005 to 3 w / v%, preferably 0.0005 to 0.5 w, based on the total volume of the aqueous composition from the viewpoint of suppressing discoloration. It is more preferably contained in / v%, and particularly preferably 0.002 to 0.05 w / v%.
In addition, one or more selected from the group consisting of the compound represented by the general formula (1) or a salt thereof in the aqueous composition or a solvate thereof, a biguanide compound and a salt thereof, and a solvate thereof. The content mass ratio of the compound is not particularly limited, but from the viewpoint of the discoloration suppressing action, the biguanide-based compound, its salt, and their solvates are converted to 1 part by mass in terms of the free form of the compound represented by the general formula (1). It is preferable to contain 0.00001 to 1 part by mass, more preferably 0.0001 to 0.1 part by mass, and 0.001 to 0.01 part by mass of one or more selected from the group consisting of Japanese compounds. It is particularly preferable to contain it. When ripasudil is used as the compound represented by the general formula (1) and chlorhexidine is used as the biguanide compound, chlorhexidine is converted into a free form of ripasudil in terms of a discoloration inhibitory effect. It is preferable to contain 0.00005 to 0.5 parts by mass, and more preferably 0.0005 to 0.05 parts by mass, at least one selected from the group consisting of and salts thereof and a mixture thereof. It is particularly preferably contained in an amount of 0.003 to 0.008 parts by mass.

As used herein, the term "aqueous composition" means a composition containing at least water, and examples of the properties thereof include liquid (solution or suspension) and semi-solid (ointment), and liquid is preferable. .. As the water in the composition, for example, purified water, water for injection, sterilized purified water and the like can be used.
The content of water contained in the aqueous composition is not particularly limited, but is preferably 5% by mass or more, more preferably 20% by mass or more, further preferably 50% by mass or more, still more preferably 90% by mass or more, and 90 to 90% by mass. 99.8% by mass is particularly preferable.

The aqueous composition can be produced, for example, in various dosage forms according to a known method described in the 17th revised Japanese Pharmacopoeia General Rules for Formulations and the like. Dosage forms include, for example, injections, inhalants, eye drops, eye ointments, ear drops, nasal drops, enema, topical solutions, sprays, ointments, creams, gels, oral solutions, etc. Examples include syrups. As the dosage form, an ophthalmic agent, specifically an eye drop or an eye ointment, is preferable, and an eye drop is particularly preferable, from the viewpoint of advantageously utilizing the pharmacological action of the compound represented by the general formula (1).

In addition to the above, the aqueous composition may contain additives used in pharmaceuticals, quasi-drugs, etc., depending on the dosage form. Examples of such additives include inorganic salts, tonicity agents, chelating agents, stabilizers, pH regulators, preservatives, antioxidants, thickeners, surfactants, solubilizers, suspensions. Examples thereof include turbidity agents, cooling agents, dispersants, preservatives, oil-based bases, emulsion-based bases, and water-soluble bases.
Specific examples of such additives include ascorbic acid, potassium aspartate, sodium hydrogen sulfite, alginic acid, sodium benzoate, benzyl benzoate, epsilon-aminocaproic acid, oyster oil, ethanol, and ethylene / vinyl acetate copolymers. , Sodium edetate, tetrasodium edetate, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride solution, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-campul, dl-Camfur, xylitol, citrate hydrate, sodium citrate hydrate, glycerin, gluconic acid, L-glutamic acid, sodium L-glutamate, creatinine, chlorobutanol, crystalline sodium dihydrogen phosphate, geraniol, sodium chondroitin sulfate , Acetic acid, potassium acetate, sodium acetate hydrate, titanium oxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzododecinium bromide, tartaric acid, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution , Taurine, sodium hydrogen carbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyroxalol, sodium dehydroacetate, tromethamole, concentrated glycerin, concentrated mixed tocopherol, white vaseline, peppermint water, peppermint oil, concentrated benzalconium Chloride solution 50, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, sodium hyaluronate, human serum albumin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromerose, glacial acetic acid, sodium pyrosulfate, phenyl Ethyl alcohol, glucose, propylene glycol, bergamot oil, benzalconium chloride, benzalconium chloride solution, benzyl alcohol, benzethonium chloride solution, benzethonium chloride solution, sodium chloride, boric acid, povidone, polyoxyethylene (200) Polyoxypropylene glucol (70), sodium polystyrene sulfonate, polysolvate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl alcohol (partially saponified), d-borneol, macrogol 4000, macrogol 6000, D-mannitol, anhydrous Citrate, anhydrous sodium monohydrogen phosphate, Anhydrous sodium dihydrogen phosphate, methanesulfonic acid, methylcellulose, l-menthol, monoethanolamine, aluminum monostearate, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, Ryunou, Examples thereof include phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, monosodium dihydrogen phosphate monohydrate, malic acid, and vaseline.

Additives include, for example, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate. , Concentrated glycerin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromerose, borosand, boric acid, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified), macrogol 4000, macro Goal 6000, anhydrous citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methyl cellulose, monoethanolamine, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, Monosodium dihydrogen phosphate monohydrate, sodium hyaluronate, glucose, l-menthol and the like are preferable.

In addition to the above, the aqueous composition may further contain other medicinal ingredients depending on the applicable disease and the like. Such medicinal ingredients include, for example, an α1 receptor blocker containing bunazosin such as bunazosin hydrochloride or a solvate thereof; brimonidine such as brimonidine tartrate or a solvate thereof or a solvate thereof, Appla. Α2 receptor agonist containing clonidine or a salt thereof or a solvate thereof; carteolol such as carteolol hydrochloride or a salt thereof or a solvate thereof, nipradirol or a salt thereof or a solvate thereof, timorol maleic acid Timorol such as salt or solvate thereof, solvate thereof, betaxolol such as betaxolol hydrochloride or salt thereof or solvate thereof, levobnorol such as levobnorol hydrochloride or solvate thereof or solvate thereof, befnorol or salt thereof Or solvates thereof, methipranolol or salts thereof, or β-blockers containing solvates thereof; dolzolamide such as dolsolamide hydrochloride or salts thereof or solvates thereof, brinzolamide or salts thereof or solvates thereof. A carbonate dehydratase inhibitor containing a substance, acetazolamide or a salt thereof or a solvate thereof, dichlorophenamide or a salt thereof or a solvate thereof, metazolamide or a salt thereof or a solvate thereof; isopropylunoprostone or Its solvates or their solvates, tafluprost or its salts or their solvates, travoprost or its salts or their solvates, bimatoprost or its solvates or their solvates, ratanoprost or its salts or theirs Prostaglandins containing solvates; omidenepag isopropyl or salts thereof or EP2 receptor agonists containing solvates thereof; dipibefurin such as dipibefurin hydrochloride or salts thereof or their salts Solvates, epinephrines such as epinephrine, epinephrineborate, epinephrine hydrochloride or salts thereof or sympathomimetics containing solvates thereof; dystigmine bromide or salts thereof or solvates thereof, pyrocarpine, pyrocarpine hydrochloride , Pyrocarpine or salts thereof such as pyrocarpine nitrate or solvates thereof, carbacol or salts thereof or parasympathomimetics containing solvates thereof; containing romelysin such as romeridine hydrochloride or salts thereof or solvates thereof Calcium antagonist; demepotassium or a salt thereof or a solvate thereof, ecothiopate Examples thereof include salts thereof or solvates thereof, physostigmine or salts thereof or cholinesterase inhibitors containing solvates thereof, and one or more of these can be blended.
As the other medicinal ingredient, one or more selected from the group consisting of latanoprost, nipradilol, timolol, omidenepagisopropyl and salts thereof and solvates thereof is preferable.

The pH of the aqueous composition at 25 ° C. is not particularly limited, but is preferably 4 to 9, more preferably 4.5 to 8, and particularly preferably 5 to 7. The osmotic pressure ratio with respect to the physiological saline is not particularly limited, but is preferably 0.6 to 3, and particularly preferably 0.6 to 2.

The aqueous composition is preferably contained in a container from the viewpoint of storage stability, portability and the like. As used herein, the term "container" means a package that directly contains the aqueous composition. A container is a concept that includes any of the "sealed container", "airtight container", and "sealed container" defined in the 16th revised Japanese Pharmacopoeia General Rules.

The form of the container is not particularly limited as long as it can accommodate the aqueous composition, and may be appropriately selected and set according to the dosage form and the like. Specific examples of such a container include a container for injection, a container for inhalant, a container for spray, a bottle-shaped container, a tubular container, a container for eye drops, a container for nasal drops, and a dot. Examples include ears containers and bag containers. Further, these containers may be further wrapped in a box, a bag or the like.

The material of the container is not particularly limited, and may be appropriately selected depending on the form of the container. Specific examples thereof include glass, plastic, cellulose, pulp, rubber and metal. Among these, from the viewpoint of workability, squeeze property and durability, it is preferably made of plastic. The resin of the plastic container is preferably a thermoplastic resin, for example, a polyolefin resin such as low density polyethylene (including linear low density polyethylene), high density polyethylene, medium density polyethylene, polypropylene, cyclic polyolefin, and the like. Polyester resins such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, and poly (1,4-cyclohexylene methylene terenaphthalate); polyphenylene ether resin; polycarbonate resin; polysulfone resin; polyamide Examples thereof include a based resin; a polyvinyl chloride resin; a styrene based resin, and a mixture (polymer alloy) thereof may be used.
The material of the container is not particularly limited, but from the viewpoint of suppressing discoloration, a polyolefin resin is preferable, and polypropylene is particularly preferable.

As used herein, the term "polyolefin-based resin container" means a container in which at least a portion of the container in contact with the aqueous composition is "made of polyolefin-based resin". Therefore, for example, a container in which a polyolefin layer is provided in an inner layer in contact with an aqueous composition and a resin or the like of another material is laminated on the outer side thereof also falls under the category of “polyolefin-based resin container”. Here, the polyolefin-based resin is not particularly limited, and may be a polymer of a single type of monomer (homopolymer) or a copolymer of a plurality of types of monomers (copolymer). Further, in the case of a copolymer, the polymerization mode is not particularly limited, and random polymerization or block polymerization may be used. Furthermore, its stereoregularity (tacticity) is not particularly limited.
Specific examples of such polyolefin-based resins include polyethylene (more specifically, for example, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, etc.), polypropylene, and cyclic polyolefin. , Poly (4-methylpentene), polytetrafluoroethylene, ethylene / propylene copolymer, ethylene / α-olefin copolymer, ethylene / acrylic acid copolymer, ethylene / methacrylate copolymer, ethylene / vinyl acetate Examples thereof include a copolymer and an ethylene / ethyl acrylate copolymer, and one or a combination of two or more of these can be used. As the polyolefin-based resin, polyethylene, polypropylene, and cyclic polyolefin are preferable, polyethylene and polypropylene are more preferable, and polypropylene is particularly preferable, from the viewpoint of suppressing discoloration.
In addition, in this specification, "made of polyolefin-based resin" means that at least a part of the material contains a polyolefin-based resin, for example, two or more kinds of resins of a polyolefin-based resin and another resin. (Polymer alloy) is also included in "made of polyolefin resin".

It is preferable to further knead a substance that blocks the transmission of ultraviolet rays, such as an ultraviolet absorber and an ultraviolet scattering agent, into the polyolefin-based resin container. As a result, the stability of the compound represented by the general formula (1) to light is improved. Specific examples of such a substance include titanium oxide; zinc oxide and the like as an ultraviolet scattering agent. Examples of the ultraviolet absorber include 2- (2H-benzotriazole-2-yl) -p-cresol (for example, Tinuvin P: BASF) and 2- (2H-benzotriazol-2-yl) -4,6. -Bis (1-methyl-1-phenylethyl) phenol (eg, Tinuvin 234: BASF), 2- (3,5-di-t-butyl-2-hydroxyphenyl) benzotriazole (eg, Tinuvin320: BASF) ), 2- [5-Chloro (2H) -benzotriazol-2-yl] -4-methyl-6- (tert-butyl) phenol (eg, Tinuvin 326: BASF), 2- (3,5-di -T-Butyl-2-hydroxyphenyl) -5-chlorobenzotriazole (eg, Tinuvin327: BASF), 2- (2H-benzotriazole-2-yl) -4,6-di-tert-pentylphenol (eg, Tinuvin327: BASF) , Tinuvin PA328: BASF), 2- (2H-benzotriazol-2-yl) -4- (1,1,3,3-tetramethylbutyl) phenol (eg, Tinuvin 329: BASF), 2,2 '-Methyllenbis [6- (2H-benzotriazol-2-yl) -4- (1,1,3,3-tetramethylbutyl) phenol (eg, Tinuvin 360: BASF), methyl 3- (3-( Reaction product of 2H-benzotriazole-2-yl) -5-tert-butyl-4-hydroxyphenyl) propionate and polyethylene glycol 300 (eg, Tinuvin 213: BASF), 2- (2H-benzotriazole-2-) Il) -6-dodecyl-4-methylphenol (eg, Tinuvin 571: BASF), 2- (2'-hydroxy-3', 5'-di-t-amylphenyl) benzotriazole, 2- [2' -Hydroxy-3'-(3'', 4'', 5'', 6''-tetrahydrophthalimidemethyl) -5'-methylphenyl] benzotriazole, 2,2'-methylenebis [4- (1,1) , 3,3-Tetramethylbutyl) -6- (2H-benzotriazole-2-yl) phenol] and other benzotriazole-based ultraviolet absorbers; 2,2-bis {[2-cyano-3,3-diphenylacryloyl) Oxy] Methyl} Propane-1,3-diyl-bis (2-cyano-3,3-diphenylacrylate) (eg, Uvinul 3030 FF: BASF), ethyl 2-cyano-3,3-diphenylacrylate (eg Uvinul 3035: BASF), 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (eg Uvinul) 3039: BASF) and other cyanoacrylate-based UV absorbers; 2- (4,6-diphenyl-1,3,5-triazine-2-yl) -5-[(hexyl) oxy] -phenol (eg, Tinuvin) Triazine-based UV absorbers such as 1577 ED: BASF); octabenzophenone (eg, Chimassorb 81: BASF), 2,2'-dihydroxy-4,4'-dimethoxybenzophenone (eg, Uvinul 3049: BASF), 2,2'-4,4'-tetrahydrobenzophenone (eg, Uvinul 3050: BASF), oxybenzophenone, hydroxymethoxybenzophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonate, dihydroxydimethoxybenzophenone, sodium dihydroxydimethoxybenzophenone disulfonate, dihydroxy Benzophenone-based UV absorbers such as benzophenone and tetrahydroxybenzophenone; methyl diisopropylsilicate, synoxate, mono-2-ethylhexanate glyceryl diparamethoxycinnamic acid, isopropyl-diisopropylsilicate ester mixture of paramethoxycinnamic acid, Cinnamic acid-based ultraviolet absorbers such as 2-ethylhexyl paramethoxycinnamate and benzyl silicate; paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, paradimethylaminobenzoic acid 2 -Ethylhexyl, 4- [N, N-di (2-hydroxypropyl) amino] benzoic acid ester-based ultraviolet absorbers such as ethyl benzoate; ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomentyl salicylate, Salicylic acid-based ultraviolet absorbers such as methyl salicylate; guaiazulene; dimethoxybenzophenone dioxoimidazolidine propionate 2-ethylhexyl; 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) anilino] 1,3,5-triazine Parahydroxyanisole; 4-tert-butyl-4'-methoxydibenzoylmethane; phenylbe Nzuimidazole sulfonic acid; 2- (4-diethylamino-2-hydroxybenzoyl) -hexyl benzoate and the like.

When a substance that hinders the transmission of ultraviolet rays is kneaded into a container, the mixing ratio varies depending on the type of the substance and the like, but for example, it is usually 0.001 to 50% by mass, preferably 0.002 to 0.002 in the container. It may be about 25% by mass, particularly preferably about 0.01 to 10% by mass.

It is preferable that the inside of the container is visible (observable) with the naked eye. If the inside is visible, there are merits such as being able to inspect the presence or absence of foreign matter contamination in the manufacturing process of the pharmaceutical product, and allowing the user of the pharmaceutical product to check the remaining amount of the content (aqueous composition). .. Here, the visibility may be ensured at least on a part of the surface of the container (for example, even if the side surface of the container for eye drops cannot be seen due to a shrink film or the like, it is visible if the bottom surface is visible. It can be said.). If the inside is visible on a part of the surface of the container, this makes it possible to confirm the aqueous composition in the container.
In the present specification, the "pharmaceutical preparation" refers to an aqueous composition contained in a container.

The means for accommodating the aqueous composition in the container is not particularly limited, and the aqueous composition may be filled by a conventional method according to the shape of the container or the like.

The disease to which the aqueous composition or the pharmaceutical preparation is applied is not particularly limited, and may be appropriately selected depending on the pharmacological action of the compound represented by the general formula (1) and the like.
Specifically, for example, it can be used as a preventive or therapeutic agent for ocular hypertension and glaucoma based on the Rho-kinase inhibitory action and the intraocular pressure lowering action of the compound represented by the general formula (1). Here, as glaucoma, more specifically, for example, primary open-angle glaucoma, normal-tension glaucoma, atrioventricular hyperproduction glaucoma, acute closed-angle glaucoma, chronic closed-angle glaucoma, plateau iris syndrome, mixed glaucoma. , Steroid glaucoma, cystic glaucoma of the crystalline body, pigmented glaucoma, amyloid glaucoma, angiogenic glaucoma, malignant glaucoma and the like.

Further, as disclosed in Japanese Patent No. 5557408, a lesion that develops in the fundus disease (mainly the retina and / or the choroid) based on the action of the compound represented by the general formula (1). Specifically. For example, fundus changes due to high blood pressure and arteriosclerosis, central retinal artery occlusion, retinal vein occlusion such as central retinal vein occlusion and branch retinal vein occlusion, diabetic retinopathy. , Diabetic macular edema, diabetic macular degeneration, Eales disease, retinal vascular congenital anomalies such as Coats disease, von Hippel disease, pulseless disease, yellow spot disease (central) Central serous chorioretinopathy, cystoid macular edema, age-related macular degeneration, macular hole, myopic macular degeneration, retina Examples thereof include vitreous interfacial macular degeneration, drug-toxic macular degeneration, hereditary macular degeneration, etc.), retinal detachment (such as rhegmatogenous, traction, and exudative), retinal pigment degeneration, and premature infant retinopathy. ), More preferably, it may be used as a prophylactic or therapeutic agent for diabetic retinopathy, diabetic macular edema or age-related macular degeneration.

The aqueous composition or pharmaceutical preparation is used for prevention and / or treatment of eye diseases (preferably diseases selected from ocular hypertension, glaucoma and fundus diseases: particularly preferably diseases selected from ocular hypertension and glaucoma). When used as an agent, it may be administered about 1 to 3 times a day.

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

[In the formula, X represents a halogen atom. ]
An aqueous composition containing a compound represented by (1) or a salt thereof or a solvate thereof, and one or more selected from the group consisting of a biguanide compound and a salt thereof and a solvate thereof.
[2A] The aqueous composition according to [1A], wherein the compound represented by the general formula (1) is ripasudil.
[3A] The biguanide compound has the following general formula (2).

[During the ceremony,
R ¹ represents a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group having 1 to 20 carbon atoms.
R ² represents a substituted or unsubstituted monovalent hydrocarbon group having 1 to 20 carbon atoms.
R ³ represents a substituted or unsubstituted divalent hydrocarbon group having 1 to 20 carbon atoms.
n represents 0 or 1. ]
The compound represented by, and the following general formula (3)

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

[4A] The aqueous composition according to any one of [1A] to [3A], wherein the biguanide compound is chlorhexidine.
[5A] One or more selected from the group consisting of the biguanide compounds and salts thereof and their solvates are chlorhexidine, chlorhexidine hydrochloride, chlorhexidine gluconate and chlorhexidine acetate, and their solvates. The aqueous composition according to any one of [1A] to [4A], which is one or more selected from the group consisting of.
[6A] The aqueous composition according to any one of [1A] to [5A], wherein one or more selected from the group consisting of the biguanide compound, a salt thereof, and a solvate thereof is chlorhexidine gluconate.

[7A] The aqueous composition according to any one of [1A] to [6A], which is an ophthalmic agent.
[8A] The aqueous composition according to [7A], which is an eye drop.
[9A] The aqueous composition according to any one of [1A] to [8A], which is a prophylactic and / or therapeutic agent for diseases selected from ocular hypertension, glaucoma and fundus diseases.

[10A] Furthermore, α1 receptor blockers, α2 receptor agonists, β blockers, carbonate dehydration enzyme inhibitors, prostaglandins, EP2 receptor agonists, sympathomimetics, parasympathomimetics, calcium antagonists. The aqueous composition according to any one of [1A] to [9A], which contains at least one selected from the group consisting of a drug and a cholinesterase inhibitor.
[11A] Further, any one of [1A] to [9A], which contains at least one selected from the group consisting of latanoprost, nipradilol, timolol, omidenepagisopropyl and salts thereof, and solvates thereof. Aqueous composition of.

[12A] A pharmaceutical preparation comprising the aqueous composition according to any one of [1A] to [11A] contained in a polyolefin-based resin container.
[13A] The pharmaceutical preparation according to [12A], wherein the polyolefin-based resin is polyethylene or polypropylene.
[14A] The pharmaceutical preparation according to [12A] or [13A], wherein the polyolefin-based resin container is a container for eye drops.

[1B] An aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof is selected from the group consisting of a biguanide compound, a salt thereof and a solvate thereof 1 A method for suppressing discoloration of an aqueous composition, which comprises a step of incorporating seeds or more.
[2B] The method according to [1B], wherein the compound represented by the general formula (1) is ripasudil.
[3B] The biguanide compound is one or more selected from the group consisting of the compound represented by the general formula (2) and the polymer having a repeating unit represented by the general formula (3). The method according to [1B] or [2B].

[4B] The method according to any one of [1B] to [3B], wherein the biguanide compound is chlorhexidine.
[5B] One or more selected from the group consisting of the biguanide compounds and salts thereof and their solvates are chlorhexidine, chlorhexidine hydrochloride, chlorhexidine gluconate and chlorhexidine acetate, and their solvates. The method according to any one of [1B] to [4B], which is one or more selected from the group consisting of.
[6B] The method according to any one of [1B] to [5B], wherein one or more selected from the group consisting of the biguanide compound, a salt thereof, and a solvate thereof is chlorhexidine gluconate.

[7B] The method according to any one of [1B] to [6B], wherein the aqueous composition is an ophthalmic agent.
[8B] The method according to [7B], wherein the ophthalmic agent is an eye drop.
[9B] The method according to any one of [1B] to [8B], wherein the aqueous composition is a prophylactic and / or therapeutic agent for diseases selected from ocular hypertension, glaucoma and fundus diseases.

[10B] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor antagonist, a β blocker, a carbonate dehydration enzyme inhibitor, prostaglandins, an EP2 receptor agonist, a sympathomimetic agent, and a parasympathetic nerve. The method according to any one of [1B] to [9B], which comprises at least one selected from the group consisting of an agonist, a calcium antagonist and a cholinesterase inhibitor.
[11B] The aqueous composition further contains one or more selected from the group consisting of latanoprost, nipradilol, timolol, omidenepag isopropyl and salts thereof, and solvates thereof, [1B] to [9B]. ] Any of the methods described.

[12B] The method according to any one of [1B] to [11B], further comprising a step of accommodating the aqueous composition in a polyolefin-based resin container.
[13B] The method according to [12B], wherein the polyolefin resin is polyethylene or polypropylene.
[14B] The method according to [12B] or [13B], wherein the polyolefin-based resin container is a container for eye drops.

Next, the present invention will be further described with reference to examples, but the present invention is not limited thereto.
In the following test examples, the ribasudil monohydrochloride dihydrate can be produced, for example, by the method described in Pamphlet 2006/057397.

[Test Example 1] Preservation Test The aqueous compositions of Example 1 and Comparative Example 1 containing the components and amounts shown in Table 1 per 100 mL were prepared by a conventional method and placed in a polypropylene container.
Each of the obtained aqueous compositions was stored at 80 ° C. for 1 week. The degree of discoloration (yellowing) before and after storage is measured by measuring the color difference (ΔYI) of the aqueous composition before and after storage using a color difference meter (spectrophotometer CM-700d: Konica Minolta Sensing Co., Ltd.). Was evaluated by.
The results are shown in Table 1.

As shown in the results shown in Table 1, when chlorhexidine gluconate was further added to the aqueous composition containing ripasudil, the value of ΔYI was significantly lower than that when chlorhexidine was not contained, and discoloration after high temperature storage. Was revealed to be suppressed.

From the above test results, an aqueous composition containing a compound represented by the general formula (1) represented by ripasudil or a salt thereof or a solvate thereof, and a biguanide compound represented by chlorhexidine and a salt thereof are further added. In addition, when one or more selected from the group consisting of these solvates was contained, discoloration (yellowing) was relatively unlikely to occur even when stored at a high temperature, and it was clarified that the storage stability was excellent. ..

[Manufacturing Examples 1-27]
An aqueous composition containing the components and amounts (amount (g) per 100 mL of the aqueous composition) shown in Tables 2 to 4 can be produced by a conventional method.

[Manufacturing Examples 28 to 54]
In Production Examples 1-27, the same amount of 4-bromo-5-[[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl] isoquinoline instead of lipasudil monohydrochloride dihydrate Can be produced by a conventional method as the aqueous composition of Production Examples 28 to 54.

[Production Examples 55 to 108]
By containing the aqueous composition of Production Examples 1 to 54 in a polypropylene container for eye drops, it can be produced as a pharmaceutical preparation of Production Examples 55 to 108 by a conventional method.

[Manufacturing Examples 109 to 162]
By containing the aqueous composition of Production Examples 1 to 54 in a polyethylene container for eye drops, it can be produced as a pharmaceutical preparation of Production Examples 109 to 162 by a conventional method.

According to the present invention, it is possible to provide an aqueous composition and a pharmaceutical preparation having excellent storage stability, which can be suitably used in the pharmaceutical industry and the like.

Claims (10)

The following general formula (1)

[In the formula, X represents a halogen atom. ]
An aqueous composition containing a compound represented by (1) or a salt thereof or a solvate thereof, and one or more selected from the group consisting of a biguanide compound and a salt thereof and a solvate thereof. The aqueous composition according to claim 1, wherein the compound represented by the general formula (1) is ripasudil. The biguanide compound has the following general formula (2).

[During the ceremony,
R ¹ represents a hydrogen atom or a substituted or unsubstituted monovalent hydrocarbon group having 1 to 20 carbon atoms.
R ² represents a substituted or unsubstituted monovalent hydrocarbon group having 1 to 20 carbon atoms.
R ³ represents a substituted or unsubstituted divalent hydrocarbon group having 1 to 20 carbon atoms.
n represents 0 or 1. ]
The compound represented by, and the following general formula (3)

[In the formula, R ⁴ represents a substituted or unsubstituted divalent hydrocarbon group having 1 to 20 carbon atoms. ]
The aqueous composition according to claim 1 or 2, which is one or more selected from the group consisting of polymers having repeating units represented by. The aqueous composition according to any one of claims 1 to 3, wherein the biguanide compound is chlorhexidine. One or more selected from the group consisting of the biguanide compounds and salts thereof and their solvates are chlorhexidine, chlorhexidine hydrochloride, chlorhexidine gluconate and chlorhexidine acetate, and their solvates. The aqueous composition according to any one of claims 1 to 4, which is one or more selected from the above. A pharmaceutical preparation comprising the aqueous composition according to any one of claims 1 to 5 contained in a polyolefin-based resin container. The pharmaceutical preparation according to claim 6, wherein the polyolefin-based resin is polypropylene. The following general formula (1)

[In the formula, X represents a halogen atom. ]
The aqueous composition containing the compound represented by (1) or a salt thereof or a solvate thereof contains one or more selected from the group consisting of a biguanide compound and a salt thereof and a solvate thereof. A method for suppressing discoloration of an aqueous composition. The method according to claim 8, wherein the compound represented by the general formula (1) is ripasudil. One or more selected from the group consisting of the biguanide compounds and salts thereof and their solvates are chlorhexidine, chlorhexidine hydrochloride, chlorhexidine gluconate and chlorhexidine acetate, and their solvates. The method according to claim 8 or 9, wherein the method is one or more selected from.