JP2021185209A - Aqueous composition (iii) - Google Patents

Abstract

To provide a technique for inhibiting the crystal deposition of a halogenated isoquinoline derivative-containing aqueous composition during low-temperature storage.SOLUTION: The aqueous composition contains a compound represented by the general formula (1) in the figure [where X represents a halogen atom] or a salt thereof or a solvate of them, and methylcellulose.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 are 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, an ophthalmic agent. Ophthalmic preparations are usually water-containing compositions (aqueous compositions), and often have problems such as crystal precipitation over time during low-temperature storage. In this regard, Patent Document 5 describes ripasudil ((S)-(-) -1- (4-fluoro-5-isoquinoline sulfonyl) -2-methyl-1,4-homopiperazine) or a salt thereof. Disclosed are compositions for aqueous eye drops containing 0.5 to 5% by weight of glycerin, phosphoric acid or a salt thereof, and a mixture thereof, in which precipitation of crystals is suppressed.

By the way, in Patent Document 6, Ripasudil ((S)-(-)-1- (4-fluoro-5-isoquinoline sulfonyl) -2-methyl-1,4-homopiperazine) or a salt thereof, water-soluble film formation A film preparation containing an agent and a carboxyvinyl polymer is disclosed. However, in the film preparation disclosed in Patent Document 6, after dissolving and dispersing lipasyl, a film-forming agent and a carboxyvinyl polymer in a volatile solvent such as methanol, the solvent is volatilized by drying to precipitate and film a solid component. It is a non-aqueous preparation obtained by forming.
Therefore, the film formulation disclosed in Patent Document 6 is completely different from the aqueous composition, and since it is a dried solid formulation, crystal precipitation over time does not become a problem.

Japanese Patent No. 4212149 International Publication No. 2006/115244 Pamphlet International Publication No. 2006/068208 Pamphlet Japanese Patent No. 5557408 Japanese Patent No. 4168071 Japanese Unexamined Patent Publication No. 2013-129604 International Publication No. 94/23750 Pamphlet

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

Therefore, the present inventors have diligently studied to solve the above-mentioned problems. By further incorporating a cellulose ether derivative such as methyl cellulose into an aqueous composition containing a halogenated isoquinoline derivative such as ripasudil, the present inventions can be stored at low temperature. The present invention has been completed by finding that the precipitation of crystals can be suppressed.

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

[In the formula, X represents a halogen atom. ]
The present invention provides an aqueous composition containing a compound represented by (1), a salt thereof, a solvate thereof, and a cellulose ether derivative.
Further, the present invention comprises a step of incorporating a cellulose ether derivative into an aqueous composition containing the compound represented by the general formula (1), a salt thereof, or a solvate thereof, and crystal precipitation of the aqueous composition. It provides a method of suppressing the above.

According to the present invention, it is possible to suppress crystal precipitation of an aqueous composition containing a halogenated isoquinoline derivative such as ripasudil during low temperature storage.

The present specification discloses, for example, the invention of the following aspects, without limitation to these.
[1] 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 a cellulose ether derivative.
[2] The aqueous composition according to [1], wherein the compound represented by the general formula (1) is ripasudil.
[3] The cellulose ether derivative is one or more selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, carboxyalkyl cellulose and salts thereof, and carboxyalkyl (alkyl) cellulose and salts thereof. , [1] or [2].
[4] The aqueous composition according to [1] or [2], wherein the cellulose ether derivative is at least one selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and sodium carmellose.
[5] The aqueous composition according to [1] or [2], wherein the cellulose ether derivative is methyl cellulose.
[6] The aqueous composition according to any one of [1] to [5], which is an ophthalmic agent.
[7] The aqueous composition according to [6], which is an eye drop.
[8] The aqueous composition according to any one of [1] to [7], which is a preventive and / or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma and fundus disease.

[9] Further, from α1 receptor blockers, α2 receptor agonists, β blockers, carbon dioxide dehydration enzyme inhibitors, prostaglandins, sympathomimetics, parasympathomimetics, calcium antagonists and cholinesterase inhibitors. The aqueous composition according to any one of [1] to [8], which contains at least one selected from the group.
[10] The aqueous solution according to any one of [1] to [8], further containing at least one selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol and salts thereof, and solvates thereof. Composition.

[11] A method for suppressing crystal precipitation of an aqueous composition, which comprises a step of incorporating a cellulose ether derivative into an aqueous composition containing the compound represented by the general formula (1), a salt thereof, or a solvate thereof. ..
[12] The method according to [11], wherein the compound represented by the general formula (1) is ripasudil.
[13] The cellulose ether derivative is one or more selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, carboxyalkyl cellulose and salts thereof, and carboxyalkyl (alkyl) cellulose and salts thereof. , [11] or [12].
[14] The method according to [11] or [12], wherein the cellulose ether derivative is at least one selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and sodium carmellose.
[15] The method according to [11] or [12], wherein the cellulose ether derivative is methyl cellulose.
[16] The method according to any one of [11] to [15], wherein the aqueous composition is an ophthalmic agent.
[17] The method according to [16], wherein the ophthalmic agent is an eye drop.
[18] The method according to any one of [11] to [17], wherein the aqueous composition is a prophylactic and / or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma and fundus disease.

[19] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, a carbonate dehydration enzyme inhibitor, prostaglandins, a sympathomimetic agent, a parasympathomimetic agent, and a calcium antagonist. The method according to any one of [11] to [18], which comprises one or more selected from the group consisting of a cholineresterase inhibitor and a cholineresterase inhibitor.
[20] The aqueous composition further comprises one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol and salts thereof, and solvates thereof. Any method described.

[21] The compound represented by the general formula (1), which comprises a step of incorporating methyl cellulose into an aqueous composition containing the compound represented by the general formula (1), a salt thereof, or a solvate thereof. Or a method for promoting the transfer of a salt thereof or a solvate thereof to an ocular tissue.
[22] The method according to [21], wherein the compound represented by the general formula (1) is ripasudil.
[23] The method according to [21] or [22], wherein the aqueous composition is an ophthalmic agent.
[24] The method according to [23], wherein the ophthalmic agent is an eye drop.
[25] The method according to any one of [21] to [24], wherein the aqueous composition is a prophylactic and / or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma and fundus disease.

[26] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, a carbonate dehydration enzyme inhibitor, prostaglandins, a sympathomimetic agent, a parasympathomimetic agent, and a calcium antagonist. The method according to any one of [21] to [25], which comprises one or more selected from the group consisting of a cholineresterase inhibitor and a cholineresterase inhibitor.
[27] The aqueous composition further comprises one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol and salts thereof and solvates thereof. Any method described.

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 a single steric isomer may be used, or a mixture of various steric isomers in any proportion may be used. .. 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, a hydrochloride, a sulfate, a nitrate, a hydrofluoride salt, 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 lipasyl 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, lipasyl or a salt thereof or a solvate thereof is more preferable, and lipasyl 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. For 4-bromo-5-{[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl} isoquinoline or a salt thereof or a solvate thereof, see 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, symptoms, 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 preferable, 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.

As used herein, the term "cellulose ether derivative" means a derivative in which all or part of the hydroxy group of cellulose forms an ether bond, and specifically, for example, alkyl cellulose such as methyl cellulose and ethyl cellulose; hydroxyethyl cellulose and hydroxy. Hydroxyalkyl cellulose such as propyl cellulose; Alkali (hydroxyalkyl) cellulose such as hydroxyethylmethyl cellulose and hydroxypropylmethyl cellulose (mixed ether of alkyl and hydroxyalkyl of cellulose); Carboxyalkyl (alkyl) cellulose such as carboxymethyl ethyl cellulose (alkyl of cellulose) And a mixed ether of carboxyalkyl) or a salt thereof (specifically, an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt); a carboxyalkyl cellulose such as sodium carboxymethyl cellulose or a salt thereof. (Specifically, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, etc.) and the like can be mentioned, and one or more of these can be used in combination.
The cellulose ether derivative is known and may be produced by a known method, or a commercially available one may be used.

The etherification rate (%) of the cellulose ether derivative (substitution rate of a substituent forming an ether bond such as an alkyl group or a hydroxyalkyl group) is not particularly limited, but is preferably 10 to 90% from the viewpoint of suppressing crystal precipitation. 20-80% is particularly preferable. The etherification rate (%) is measured for each cellulose ether derivative by the method described in the 16th revised Japanese Pharmacopoeia or a method similar thereto.

The content of the cellulose ether derivative in the aqueous composition is not particularly limited, but is preferably 0.1 to 15 w / v% based on the total volume of the aqueous composition, preferably 0.5, from the viewpoint of suppressing crystal precipitation. It is more preferably contained in an amount of 10 w / v%, and particularly preferably contained in an amount of 1 to 5 w / v%.
Further, the content mass ratio of the compound represented by the general formula (1) or a salt thereof or a solvent mixture thereof to the cellulose ether derivative in the aqueous composition is not particularly limited, but is generally used from the viewpoint of suppressing crystal precipitation. It is preferable that the cellulose ether derivative is contained in an amount of 0.25 to 12 parts by mass, preferably 0.75 to 8 parts by mass, based on 1 part by mass in terms of the free form of the compound represented by the formula (1). It is more preferable, and it is particularly preferable to contain 2 to 5 parts by mass. Above all, when the compound represented by the general formula (1) or a salt thereof or a solvate thereof is ripasudil or a salt thereof or a solvate thereof, a free form of ripasudil is obtained from the viewpoint of suppressing crystal precipitation. It is preferable to contain 0.1 to 20 parts by mass of the cellulose ether derivative, more preferably 0.5 to 15 parts by mass, and 1 to 10 parts by mass with respect to 1 part by mass. Especially preferable.

As the cellulose ether derivative, at least one selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, and carboxyalkyl cellulose and salts thereof is preferable from the viewpoint of suppressing crystal precipitation, and C1-C6 is preferable. More preferably, one or more selected from the group consisting of alkyl cellulose, hydroxy C1-C6 alkyl cellulose, C1-C6 alkyl (hydroxy C1-C6 alkyl) cellulose, and carboxy C1-C6 alkyl cellulose and salts thereof, methyl cellulose, ethyl cellulose, and the like. One or more selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carmellose potassium, carmellose calcium and carmellose sodium is more preferable, and the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose and carmellose sodium. One or more selected from the above is even more preferable, and methyl cellulose is particularly preferable.

From another point of view, methyl cellulose is preferable as the cellulose ether derivative. As specifically disclosed in Test Example 4, when the aqueous composition is administered as an eye drop, the compound represented by the general formula (1) or a salt thereof or a solvate thereof is contained by containing methyl cellulose. It was clarified from the disclosure of Patent Document 7 that unpredictable rapid absorption and improvement of biological utilization rate can be achieved. The compound represented by the general formula (1) has a pharmacological action such as an Rho kinase inhibitory action, and is useful for the prevention and treatment of eye diseases (preferably diseases selected from ocular hypertension, glaucoma and fundus diseases). It is known that there is. Therefore, an aqueous composition containing methyl cellulose as a cellulose ether derivative not only suppresses crystal precipitation during low-temperature storage, but is also an eye compound represented by the general formula (1), which is useful for the prevention and treatment of eye diseases. By promoting the transfer to the tissue, the effect of preventing and treating eye diseases can be achieved more quickly and more, and it is suitable as an ophthalmic agent (preferably an eye drop or an ophthalmic ointment). It has the advantage of being available.

In the present specification, "methyl cellulose" is not particularly limited, and any methyl cellulose having a different methoxy group substitution rate, molecular weight, viscosity, etc. may be used, and these may be used alone or in combination of two or more. .. The substitution rate of the methoxy group of methylcellulose is preferably in the range of 26 to 33%, preferably 27.5, from the viewpoint of the effect of suppressing crystal precipitation and / or the effect of promoting the transfer of the compound represented by the general formula (1) to the ocular tissue. The range of ~ 31.5% is more preferable. The substitution rate of the methoxy group of methyl cellulose is quantified according to the method for quantifying the methoxy group of methyl cellulose described in the 16th revised Japanese Pharmacopoeia. The viscosity of methylcellulose is preferably 1 to 10000 mPa · s, preferably 3 to 6000 mPa · s, from the viewpoint of the action of suppressing crystal precipitation and / or the action of promoting the transfer of the compound represented by the general formula (1) to the ocular tissue. More preferably, 5 to 2000 mPa · s is even more preferable, 7 to 600 mPa · s is even more preferable, and 10 to 150 mPa · s is particularly preferable. The viscosity of methylcellulose is measured according to the method for measuring the viscosity of methylcellulose described in the 16th revised Japanese Pharmacopoeia. Examples of such methyl cellulose as commercially available products include Metrose SM-4, Metrose SM-15, Metrose SM-25, SM-100, SM-400, Metrose SM-1500, SM-4000 (all, Shin-Etsu Chemical Industry Co., Ltd.). (Co., Ltd.), etc., and from the viewpoint of the effect of suppressing crystal precipitation and / or the effect of promoting the transfer of the compound represented by the general formula (1) to the ocular tissue, Metrose SM-15, Metrose SM-25, Metrose SM. -100, Metrose SM-400 are preferable. In addition, these may be used in combination as appropriate.

The content of methyl cellulose in the aqueous composition is not particularly limited, but from the viewpoint of the effect of suppressing crystal precipitation and / or the effect of promoting the transfer of the compound represented by the general formula (1) to the ocular tissue, the total volume of the aqueous composition is increased. On the other hand, it is preferably contained in an amount of 0.75 to 8 w / v%, more preferably 1.5 to 7 w / v%, and particularly preferably 2 to 4 w / v%.
Further, the content mass ratio of the compound represented by the general formula (1) or a salt thereof or a solvent mixture thereof to methyl cellulose in the aqueous composition is not particularly limited, but the crystal precipitation inhibitory action and / or the general formula (1). ) From the viewpoint of promoting the transfer of the compound to the ocular tissue, 0.6 to 14 parts by mass of methylcellulose with respect to 1 part by mass in terms of the free form of the compound represented by the general formula (1). It is preferably contained, more preferably 1.35 to 11 parts by mass, and particularly preferably 2.5 to 7 parts by mass. Above all, when the compound represented by the general formula (1) or a salt thereof or a solvate thereof is ripasudil or a salt thereof or a solvate thereof, a crystal precipitation inhibitory action and / or to the ocular tissue of ripasudil. From the viewpoint of promoting the migration of ribasudil, it is preferable to contain 0.8 to 13 parts by mass of methylcellulose, and more preferably 1.6 to 9 parts by mass, based on 1 part by mass of ribasudil. It is particularly preferable to contain 3 to 6 parts by mass.

As used herein, the term "aqueous composition" means a composition containing at least water, and examples 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, sterile 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 in various dosage forms according to, for example, a known method described in the 16th revised Japanese Pharmacopoeia General Regulations for Formulations and the like. Dosage forms include, for example, injections, inhalants, eye drops, eye ointments, ear drops, nasal drops, enema, external solutions, sprays, ointments, gels, oral solutions, syrups, etc. Can be mentioned. 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, thickening agents, surfactants, solubilizers, suspensions. Examples thereof include a turbidizing agent, a cooling agent, a dispersant, a preservative, an oily base, an emulsion base, and a water-soluble base.
Specific examples of such additives include ascorbic acid, potassium aspartate, sodium hydrogen sulfite, alginic acid, sodium benzoate, benzyl benzoate, epsilon-aminocaproic acid, uikyo 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-kanfur, xylitol, citrate hydrate, sodium citrate hydrate, glycerin, gluconic acid, L-glutamic acid, sodium L-glutamate, creatinine, chlorhexizing luconate solution, chlorobutanol, crystalline sodium dihydrogen phosphate , Geraniol, chondroitin sodium sulfate, acetic acid, potassium acetate, sodium acetate hydrate, titanium oxide, gellan gum, dibutyl hydroxytoluene, potassium bromide, benzododecinium bromide, tartrate acid, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution, sorbic acid, potassium sorbate, taurine, sodium hydrogen carbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyrosapol, sodium dehydroacetate, tromethamol, 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, glacial acetic acid, pyro Sodium sulfite, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalconium chloride, benzalconium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, borosand, boric acid, povidone, polyoxy Ethylene (200) polyoxypropylene glucol (70), sodium polystyrene sulfonate, polysorbate 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 phosphate Sodium dihydrogen, methanesulfonic acid, l-menthol, monoethanolamine, aluminum monostearate, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, Ryunou, phosphoric acid, phosphoric acid Examples thereof include sodium hydrogen hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, phosphoric 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, borosand, boric acid, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified), macrogol 4000, macrogol 6000, citrate anhydrous, phosphorus anhydrous Sodium monohydrogen acid, anhydrous sodium dihydrogen phosphate, monoethanolamine, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, hyalurone Sodium phosphate, glucose, l-menthol and the like are preferred.

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 bunazocin such as bunazosin hydrochloride or a salt thereof or a solvent thereof; brimonidine such as brimonidine tartrate or a salt thereof or a solvent thereof, appla. Α2 receptor agonists including chronidine or salts thereof or solvates thereof; carteolols such as carteolol hydrochloride or salts thereof or solvates thereof, niprazirol or salts thereof or solvates thereof, thymorol maleic acid. Timorol such as a salt or a salt thereof or a solvent thereof, betaxolol such as betaxolol hydrochloride or a salt thereof or a solvent thereof, levobnorol such as levobnorol hydrochloride or a salt thereof or a solvent thereof, befnolol or a salt thereof. Or a β-blocker containing methipranolol or a salt thereof or a salt thereof; a dolzoramide such as dolzolamide hydrochloride or a salt thereof or a solvate thereof, brinzoramide or a salt thereof or a solvate thereof. Carbonated dehydratase inhibitor containing a substance, acetazolamide or a salt thereof or a solvent thereof, dichlorphenamide or a salt thereof or a solvent thereof, metazolamide or a salt thereof or a solvent thereof; isopropyl unoprostone or The salt or its salt, tafluprost or its salt or its salt, travoprost or its salt or its salt, bimatoprost or its salt or its salt, ratanoprost or its salt or their salt. Prostaglandins including solvates; dipibefurin such as dipibefurin hydrochloride or a salt thereof or a solvate thereof, epinephrine such as epinephrine, epinephrineborate, epinephrine hydrochloride or a salt thereof or a salt thereof. A sympathomimetic agent containing a solvent of Parasympathomimetics containing the solvate of; romelysin such as romelysin hydrochloride or a salt thereof or a calcium antagonist containing the solvate thereof; demepotassium or a salt thereof or a solvate thereof, ecothiophate or a salt thereof or Containing their solvates, physostigmine or salts thereof, or their solvates Examples thereof include cholinesterase inhibitors, and one or more of these can be blended.
As the other medicinal ingredient, at least one selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol and salts thereof, and solvates thereof is preferable.

The pH of the aqueous composition is not particularly limited, but is preferably 4-9, more preferably 4.5-8.5, even more preferably 5-8, and particularly preferably 5.5-7.5. 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. 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, bag containers and the like. Further, these containers may be further packaged by a box, a bag or the like.

The material of the container is not particularly limited and may be appropriately selected according to the form of the container. Specific examples thereof include glass, plastic, cellulose, pulp, rubber and metal. 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 resin such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, 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. As the container, a container made of a polyolefin resin is preferable, and a container made of polypropylene is preferable, from the viewpoint of suppressing crystal precipitation.

The disease to which the aqueous composition 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, tufted 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, fundus diseases (lesions that develop mainly in the retina and / or choroid. Specifically, for example, changes in the fundus due to hypertension and arteriosclerosis, central retinal artery occlusion, etc. Retinal vein occlusion such as central retinal vein occlusion and branch retinal vein occlusion, diabetic retinopathy, diabetic luteal edema, diabetic luteal occlusion, Eales disease, Congenital retinal vascular abnormalities such as Coats disease, von Hippel disease, pulseless disease, luteal disease (central serous chorioretinopathy), cystoid macular. edema), age-related macular degeneration, macular hole, myopic macular degeneration, retinal vitreous interface luteal degeneration, drug-toxic luteal degeneration, hereditary luteal lesions Preventive or therapeutic agents for (degeneration, etc.), retinal detachment (such as rhegmatogenous, traction, exudative, etc.), retinal pigment degeneration, premature infant retinopathy, etc.), more preferably diabetic retinopathy, diabetes. It can be used as a prophylactic or therapeutic agent for retinal edema or age-related retinal degeneration.

The aqueous composition is used as a preventive and / or therapeutic agent for eye diseases (preferably diseases selected from ocular hypertension, glaucoma and fundus diseases; particularly preferably diseases selected from ocular hypertension and glaucoma). In this case, it may be administered about 1 to 3 times a day.

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, ripasudil monohydrochloride dihydrate can be produced, for example, by the method described in International Publication No. 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.
Each of the obtained aqueous compositions was stored at −5 ° C. and periodically visually evaluated for the presence or absence of crystal precipitation, and it was confirmed which aqueous composition had crystal precipitation first. Those in which crystal precipitation was not observed first were marked with ◯, and those in which crystal precipitation was observed first were marked with x.
The results are shown in Table 1.

As shown in the results shown in Table 1, it was clarified that when the aqueous composition containing ripasudil was further contained with methyl cellulose, crystal precipitation during low temperature storage was suppressed as compared with the case where it did not contain methyl cellulose.

[Test Example 2] Preservation test 2
The aqueous compositions of Example 2 and Comparative Example 2 containing the components and amounts shown in Table 2 per 100 mL were prepared by a conventional method.
Similar to Test Example 1, each of the obtained aqueous compositions was stored at −5 ° C. and periodically visually evaluated for the presence or absence of crystal precipitation, and which aqueous composition had crystal precipitation first was determined. confirmed. Those in which crystal precipitation was not observed first were evaluated as ◯, and those in which crystal precipitation was observed earlier were evaluated as x.
The results are shown in Table 2.

As shown in the results shown in Table 2, even when the amount of rispasudil is doubled and the amount of glycerin is not added, the same as in Test Example 1, when methylcellulose is contained, the temperature is stored at a lower temperature than when methylcellulose is not contained. It was clarified that the crystal precipitation in the above was suppressed.

[Test Example 3] Preservation test No. 3
The aqueous compositions of Examples 3 to 6 containing the components and amounts shown in Table 3 per 100 mL were prepared by a conventional method.
After storing each of the obtained aqueous compositions at −5 ° C. for 3 months, the presence or absence of crystal precipitation was visually evaluated. The case where crystal precipitation was not observed was evaluated as ◯, and the case where crystal precipitation was observed was evaluated as x.
The results are shown in Table 3.

As shown in the results shown in Table 3, none of the four aqueous compositions having different methyl cellulose contents or types (grades) showed crystal precipitation even after storage at −5 ° C. for 3 months, and were excellent in storage stability. It became clear.

From the results of Test Examples 1 to 3 above, when methyl cellulose is further contained in an aqueous composition containing a compound represented by the general formula (1) represented by ripasudil, a salt thereof, or a solvate thereof. It was clarified that the crystals are relatively difficult to precipitate even when stored at a low temperature, and the storage stability is excellent.

[Test Example 4] Ophthalmic tissue transfer test An aqueous composition is used as an ophthalmic agent (preferably an eye drop; more preferably an eye drop for prevention and / or treatment of a disease selected from ocular hypertension, glaucoma and fundus disease). In order to evaluate its usefulness when used as an ophthalmic composition, the tissue transferability when the aqueous composition was applied to ophthalmic tissue was evaluated.

Specifically, the aqueous compositions of Example 7 and Comparative Example 3 containing the components and amounts shown in Table 4 per 100 mL were prepared by a conventional method. 50 μl of each of the obtained aqueous compositions was instilled into the eyes of white rabbits, and aqueous humor and iris / ciliary body were applied 0.25 hours, 0.5 hours, 1 hour, 2 hours and 4 hours after administration. The sample was collected and the concentration of ripasudil in the aqueous humor or in the iris / ciliary body was measured. The concentration of ripasudil in the tissue was calculated by comparing the peak area with the standard substance having a known concentration using LC-MS / MS.
From the obtained ripasudil concentration in each tissue at each time, AUC (AUC _0-4 ) at 0 to 4 hours of drug administration was calculated. In addition, the time to reach the highest concentration of ripasudil in the tissue was evaluated as Tmax.
The results are shown in Table 4.

As shown in the results shown in Table 4, in both the aqueous humor and the iris / ciliary body tissues, the aqueous composition of Example 7 had a shorter time to reach the maximum concentration in the tissues (Tmax), and the tissue reached the eye tissue. It was confirmed that the transition speed of the (fast absorption) was improved. Further, in both tissues, an increase in AUC was observed in the aqueous composition of Example 7 containing methyl cellulose as compared with the aqueous composition of Comparative Example 3 containing no methyl cellulose.

It is known that eye drops containing methyl cellulose retain the drug on the surface of the eye by gelling at the time of instillation, and increase the bioavailability of the medicinal ingredient (Patent Document 7). It is understood that such an increase in bioavailability due to drug retention is due to an increase in the concentration of the drug on the ocular surface, and although the AUC itself is improved, the time to reach the maximum concentration in the tissue should not change. be. Nevertheless, in this study, a surprising reduction in the time to reach the highest concentration in the tissue was observed.
From this, the improvement in the transfer rate of ripasudil to the ocular tissue (rapid absorption) observed in this test is not simply due to gelation on the ocular surface, but is represented by the general formula (1) such as ripasudil. It was presumed that this was due to the combination of methyl cellulose with the compound or salt thereof or a solvate thereof.

From the above test results, it was clarified that methylcellulose has an action of promoting the transfer of a compound represented by the general formula (1) represented by ripasudil, a salt thereof, or a solvate thereof to an ocular tissue. rice field.

[Manufacturing Examples 1-27]
An aqueous composition containing the components and amounts (amount (g) per 100 mL of the aqueous composition) shown in Tables 5 to 7 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.

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

Claims (4)

The following general formula (1)

[In the formula, X represents a halogen atom. ]
An aqueous composition containing a compound represented by (1), a salt thereof, a solvate thereof, and methyl cellulose. The aqueous composition according to claim 1, wherein the compound represented by the general formula (1) is ripasudil. The aqueous composition according to claim 1 or 2, which is an ophthalmic agent. The aqueous composition according to any one of claims 1 to 3, which is a prophylactic and / or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma and fundus disease.