Ophthalmic composition 4

Abstract

To provide a technique for promoting the migration of a halogenated isoquinoline derivative into ocular tissues in an ophthalmic composition containing the halogenated isoquinoline derivative.SOLUTION: An ophthalmic 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 one or more lower aliphatic carboxylic acids selected from the group consisting of adipic acid, aspartic acid, edetic acid, succinic acid, acetic acid, tartaric acid, lactic acid, propionic acid, fumaric acid, maleic acid, malonic acid, malic acid, and salts thereof, or solvates of them.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] The structural formula:

[0003] [ka]

[0004] Ripasudil (chemical name: 4-fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline) represented by the following structural formula:

[0005] [ka]

[0006] Halogenated isoquinoline derivatives such as 4-bromo-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline represented by the formula (I) have pharmacological effects such as Rho kinase inhibitory action (e.g., Patent Documents 1 and 2) and are known to be useful for the prevention and treatment of eye diseases. Specifically, it has been reported that they are useful for the prevention or treatment of ocular hypertension, glaucoma, and the like (e.g., Patent Document 3), or for the prevention or treatment of ocular fundus diseases such as age-related macular degeneration (e.g., Patent Document 4).

[0007] In general, when administering a drug effective for eye diseases, it is desirable to administer the drug to the eye as an ophthalmic preparation such as eye drops or eye ointment, from the viewpoint of efficiently transferring the drug to the ocular tissue, which is the diseased site, to exert its medicinal effect, and also reducing the transfer to other tissues to reduce side effects and ensure safety. Therefore, it can be said that it is preferable to use the halogenated isoquinoline derivative by forming it into an ophthalmic composition and administering it to the eye from the viewpoint of efficient use of the drug and safety, and actually several ophthalmic compositions containing such halogenated isoquinoline derivatives have been reported so far (for example, Patent Documents 5, 6, etc.).

[0008] Incidentally, Patent Document 7 discloses a film preparation containing Ripasudil ((S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopiperazine) or a salt thereof, a water-soluble film-forming agent, and an antioxidant such as edetic acid or citric acid. However, Patent Document 7 only describes the antioxidants such as edetic acid and citric acid as ingredients that suppress a decrease in the content of Ripasudil in the preparation and improve storage stability, and does not describe at all the relationship with the transfer of Ripasudil to ocular tissues. In addition, the film preparation disclosed in Patent Document 7 is a non-aqueous preparation obtained by dissolving / dispersing Ripasudil, a film-forming agent, a carboxyvinyl polymer, and an antioxidant in a volatile solvent such as methanol, and then volatilizing the solvent by drying to cause the solid components to precipitate and form a film. Therefore, the film preparation disclosed in Patent Document 7 is a preparation that is completely different from an aqueous composition. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Patent No. 4212149 [Patent Document 2] International Publication No. 2006 / 115244 Brochure [Patent Document 3] International Publication No. 2006 / 068208 Brochure [Patent Document 4] Patent No. 5557408 [Patent Document 5] Patent No. 4099201 [Patent Document 6] Patent No. 4168071 [Patent Document 7] JP 2013-129605 A Summary of the Invention [Problem to be solved by the invention]

[0010] As described above, when administering a drug effective for eye diseases, it is preferable to administer it to the eye as an ophthalmic preparation such as eye drops from the viewpoint of efficient use of the drug and safety, but even so, not all of the administered drug is transferred to the ocular tissue. In particular, the corneal epithelium, which constitutes the outermost surface of the ocular tissue, has a high affinity with lipid-soluble drugs, while the halogenated isoquinoline derivative is a water-soluble drug and its transfer rate to the ocular tissue is not high at all. In general, it is said that a drug that has not transferred to the ocular tissue after application to the eye mixes with tears and flows out of the body, or reaches the nasal mucosa or pharyngeal mucosa from the lacrimal puncta through the nasolacrimal duct, where it is absorbed and enters the systemic circulation. In the ophthalmic composition containing a halogenated isoquinoline derivative, it is strongly desired to develop a technology that promotes the transfer of the halogenated isoquinoline derivative to the ocular tissue when applied to the ocular tissue, from the viewpoint of more efficiently utilizing its medicinal effect and further reducing the risk of side effects that may occur due to entry into the systemic circulation.

[0011] Therefore, an object of the present invention is to provide a technique for promoting the transfer of a halogenated isoquinoline derivative into ocular tissues in an ophthalmic composition containing a halogenated isoquinoline derivative. [Means for solving the problem]

[0012] Therefore, the present inventors conducted intensive research to solve the above-mentioned problems and discovered that by further adding a lower aliphatic carboxylic acid such as sorbic acid, citric acid, edetic acid, etc. to an ophthalmic composition containing a halogenated isoquinoline derivative such as Ripasudil, the transfer of the halogenated isoquinoline derivative into ocular tissues is promoted, and thus the present invention was completed.

[0013] That is, the present invention relates to a compound represented by the following general formula (1):

[0014] [ka]

[0015] [In the formula, X represents a halogen atom.] or a salt thereof, or a solvate thereof, and a lower aliphatic carboxylic acid. The present invention also provides a method for promoting the transfer of the compound represented by the general formula (1) or a salt thereof, or a solvate thereof, into ocular tissue, the method comprising the step of incorporating a lower aliphatic carboxylic acid into an ophthalmic composition containing the compound represented by the general formula (1) or a salt thereof, or a solvate thereof. Effect of the Invention

[0016] According to the present invention, the transfer of a halogenated isoquinoline derivative to ocular tissue is promoted when the ophthalmic composition is applied to ocular tissue, so that the halogenated isoquinoline derivative can be utilized more efficiently and an ophthalmic composition having superior safety can be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present specification discloses, for example, the following aspects of the invention, although the invention is in no way limited thereto. [1] The following general formula (1)

[0018] [ka]

[0019] [In the formula, X represents a halogen atom.] or a salt thereof, or a solvate thereof, and a lower aliphatic carboxylic acid. [2] The ophthalmic composition described in [1], which is an aqueous composition. [3] The ophthalmic composition according to [1] or [2], wherein the compound represented by the general formula (1) is ripasudil. [4] The ophthalmic composition according to any one of [1] to [3], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of linear or branched, saturated or unsaturated aliphatic carboxylic acids having 2 to 12 carbon atoms, in which 1 or 2 carbon atoms may be replaced by nitrogen atoms, salts thereof, and solvates thereof. [5] The ophthalmic composition according to any one of [1] to [4], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of adipic acid, aspartic acid, edetic acid, citric acid, succinic acid, acetic acid, tartaric acid, sorbic acid, lactic acid, propionic acid, fumaric acid, maleic acid, malonic acid, malic acid, salts thereof, and solvates thereof. [6] The ophthalmic composition according to any one of [1] to [4], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid, citric acid, acetic acid, sorbic acid, salts thereof, and solvates thereof. [7] The ophthalmic composition according to any one of [1] to [6], which is an eye drop. [8] The ophthalmic composition according to any one of [1] to [7], which is an agent for preventing and / or treating a disease selected from the group consisting of ocular hypertension, glaucoma and fundus diseases.

[0020] [9] The ophthalmic composition according to any one of [1] to [8], further comprising one or more members selected from the group consisting of alpha 1 receptor blockers, alpha 2 receptor agonists, beta blockers, carbonic anhydrase inhibitors, prostaglandins, sympathomimetics, parasympathomimetics, calcium antagonists and cholinesterase inhibitors.

[10] The ophthalmic composition according to any one of [1] to [8], further comprising one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol, salts thereof, and solvates thereof.

[11] The ophthalmic composition according to any one of [1] to [8], which contains, as an active ingredient, only the compound represented by the general formula (1) or a salt thereof, or a solvate of either.

[0021]

[12] A method for promoting the transfer of the compound represented by the general formula (1) or a salt thereof, or a solvate thereof to ocular tissue, comprising the step of incorporating a lower aliphatic carboxylic acid into an ophthalmic composition containing the compound represented by the general formula (1) or a salt thereof, or a solvate thereof.

[13] The method described in

[12] , wherein the ophthalmic composition is an aqueous composition.

[14] The method according to

[12] or

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

[15] The method according to any one of

[12] to

[14] , wherein the lower aliphatic carboxylic acids are at least one selected from the group consisting of linear or branched, saturated or unsaturated aliphatic carboxylic acids having 2 to 12 carbon atoms, in which 1 or 2 carbon atoms may be replaced by nitrogen atoms, salts thereof, and solvates thereof.

[16] The method according to any one of

[12] to

[14] , wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of adipic acid, aspartic acid, edetic acid, citric acid, succinic acid, acetic acid, tartaric acid, sorbic acid, lactic acid, propionic acid, fumaric acid, maleic acid, malonic acid, malic acid, salts thereof, and solvates thereof.

[17] The method according to any one of

[12] to

[14] , wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid, citric acid, acetic acid, sorbic acid, salts thereof, and solvates thereof.

[18] The method according to any one of

[12] to

[17] , wherein the ophthalmic composition is an eye drop.

[19] The method according to any one of

[12] to

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

[0022]

[20] The method described in any of

[12] to

[19] , wherein the ophthalmic composition further contains one or more selected from the group consisting of alpha 1 receptor blockers, alpha 2 receptor agonists, beta blockers, carbonic anhydrase inhibitors, prostaglandins, sympathomimetics, parasympathomimetics, calcium antagonists and cholinesterase inhibitors.

[21] The method described in any of

[12] to

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

[22] The method according to any one of

[12] to

[19] , wherein the ophthalmic composition contains only the compound represented by the general formula (1) or a salt thereof, or a solvate of either or both as an active ingredient.

[0023] <Compound represented by general formula (1) or a salt thereof, or a solvate thereof> In the general formula (1), examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, etc. In the general formula (1), examples of the halogen atom include a fluorine atom and a bromine atom, and a fluorine atom is particularly preferred. In addition, in the general formula (1), the carbon atom constituting the homopiperazine ring substituted with a methyl group is an asymmetric carbon. Therefore, stereoisomerism occurs, but the compound represented by the general formula (1) includes any stereoisomer, and may be a single stereoisomer or a mixture of various stereoisomers in any ratio. As the compound represented by the general formula (1), a compound having an absolute configuration of S configuration is preferable.

[0024] The salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharma- ceutically acceptable salt, and specific examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide; and organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate, and hydrochloride is preferred. Furthermore, the compound represented by the general formula (1) or a salt thereof may be a solvate such as a hydrate or an alcohol solvate, and is preferably a hydrate.

[0025] Specific examples of the compound represented by the general formula (1) or a salt thereof, or a solvate thereof include Ripasudil (chemical name: 4-fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline) or its salts or solvates; 4-bromo-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline or a salt thereof, or a solvate thereof; etc.

[0026] The compound represented by the general formula (1) or a salt thereof or a solvate thereof is preferably Ripasudil or a salt thereof or a solvate thereof, 4-bromo-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline or a salt thereof or a solvate thereof, more preferably Ripasudil or a salt thereof or a solvate thereof, and even more preferably Ripasudil or its hydrochloride or a hydrate thereof, and has the following structural formula:

[0027] [ka]

[0028] Ripasudil hydrochloride hydrate (Ripasudil monohydrochloride dihydrate) represented by the following formula is particularly preferred.

[0029] The compound represented by the general formula (1) or its salt or solvate thereof is known and can be produced by known methods. Specifically, for example, Ripasudil or its salt or solvate thereof can be produced by the methods described in WO 1999 / 020620 and WO 2006 / 057397. In addition, 4-bromo-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline or its salt or solvate thereof can be produced by the methods described in WO 2006 / 115244.

[0030] The content of the compound represented by the general formula (1) or its salt or solvate thereof in the ophthalmic composition is not particularly limited and may be appropriately determined depending on the disease to be treated, the sex, age, symptoms, etc. of the patient, but from the viewpoint of obtaining an excellent pharmacological action, it is preferably contained in an amount of 0.01 to 10 w / v%, more preferably 0.02 to 8 w / v%, and particularly preferably 0.04 to 6 w / v% of the compound represented by the general formula (1) in terms of the free form relative to the total volume of the ophthalmic composition. Among them, when using Ripasudil as the compound represented by the general formula (1), from the viewpoint of obtaining an 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% of Ripasudil or its salt or solvate thereof in terms of the free form relative to the total volume of the ophthalmic composition.

[0031] <Lower aliphatic carboxylic acids> As used herein, the term "lower aliphatic carboxylic acids" refers to one or more selected from the group consisting of lower aliphatic carboxylic acids in which one or more carbon atoms may be replaced by a nitrogen atom, and salts thereof (e.g., alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts, etc.), and solvates thereof (hydrates, etc.). Here, the number of carbon atoms in the lower aliphatic carboxylic acids is not particularly limited as long as it is about 15 or less, but from the viewpoint of promoting ocular tissue migration, it is preferably 2 to 12, more preferably 4 to 12, and particularly preferably 6 to 10. Among these carbon atoms, carbon atoms other than those constituting the carboxyl group may be partially replaced with nitrogen atoms, but from the viewpoint of promoting ocular tissue migration, the number of such replacements is preferably 1 to 2. Furthermore, the carbon chain may be linear or branched, and may be saturated or unsaturated.

[0032] The number of carboxyl groups in the lower aliphatic carboxylic acids is not limited, but from the viewpoint of promoting ocular tissue migration, it is preferably 1 to 4, more preferably 1 to 3. Furthermore, from the viewpoint of promoting ocular tissue migration, the lower aliphatic carboxylic acids may further have about 1 to 3 hydrophilic substituents other than carboxyl groups. Specific examples of such hydrophilic substituents include hydroxyl groups and amino groups. The lower aliphatic carboxylic acids are known compounds, and may be produced by known methods or may be commercially available. The lower aliphatic carboxylic acids may be used in the form of a salt or complex with other components, and the ophthalmic composition containing the component that forms such a salt or complex is also included in the "ophthalmic composition containing a lower aliphatic carboxylic acid".

[0033] Specific examples of such lower aliphatic carboxylic acids include adipic acid; aspartic acid, aspartic acid salts such as aspartic acid, sodium L-aspartate, and magnesium L-aspartate, or solvates thereof; edetic acid, salts thereof such as calcium disodium edetate, sodium edetate hydrate, and tetrasodium edetate, or solvates thereof; citric acid, salts thereof such as calcium citrate, citric acid hydrate, sodium citrate hydrate, sodium dihydrogen citrate, disodium citrate, anhydrous citric acid, and anhydrous sodium citrate, or solvates thereof; succinic acid, salts thereof such as succinic acid, monosodium succinate, and disodium succinate hexahydrate, or solvates thereof; acetic acid, ammonium acetate, potassium acetate, calcium acetate, sodium acetate hydrate, glacial acetic acid, acetic acid or a salt thereof, or a solvate thereof, such as anhydrous sodium acetate; tartaric acid or a salt thereof, or a solvate thereof, such as tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, and sodium potassium tartrate; sorbic acid or a salt thereof, or a solvate thereof, such as sorbic acid and potassium sorbate; lactic acid or a salt thereof, or a solvate thereof, such as lactic acid, sodium lactate solution, calcium lactate hydrate, and aluminum lactate; propionic acid or a salt thereof, or a solvate thereof, such as propionic acid and sodium propionate; fumaric acid or a salt thereof, or a solvate thereof; maleic acid or a salt thereof, or a solvate thereof; malonic acid or a salt thereof, or a solvate thereof; malic acid, DL-malic acid, and sodium DL-malate, or a salt thereof, or a solvate thereof.

[0034] As the lower aliphatic carboxylic acids, from the viewpoint of the ocular tissue transfer-promoting effect, one or more selected from the group consisting of linear or branched, saturated or unsaturated aliphatic carboxylic acids having 2 to 12 carbon atoms, in which 1 to 2 carbon atoms may be replaced by a nitrogen atom, their salts, and solvates thereof are preferred, one or more selected from the group consisting of edetic acid, citric acid, acetic acid, sorbic acid, their salts, and solvates thereof are more preferred, one or more selected from the group consisting of edetic acid, citric acid, sorbic acid, their salts, and solvates thereof are even more preferred, and one or more selected from the group consisting of citric acid, sorbic acid, their salts, and solvates thereof are particularly preferred.

[0035] The content of lower aliphatic carboxylic acids in the ophthalmic composition is not particularly limited, but from the viewpoint of promoting ocular tissue delivery, it is preferably contained in an amount of 0.01 to 5 w / v%, more preferably 0.05 to 3.5 w / v%, and particularly preferably 0.1 to 1 w / v%, relative to the total volume of the ophthalmic composition. In addition, the mass ratio of the compound represented by the general formula (1) or its salt or solvate thereof to the lower aliphatic carboxylic acids in the ophthalmic composition is not particularly limited, but from the viewpoint of the ocular tissue migration promoting effect, the lower aliphatic carboxylic acids are preferably contained in an amount of 0.3 to 8 parts by mass, more preferably 0.6 to 4 parts by mass, and particularly preferably 0.8 to 3 parts by mass per part by mass of the compound represented by the general formula (1) in terms of its free form. Among them, when the compound represented by the general formula (1) or its salt or its solvate is Ripasudil or its salt or its solvate, from the viewpoint of the ocular tissue migration promoting effect, the lower aliphatic carboxylic acids are preferably contained in an amount of 0.01 to 10 parts by mass, more preferably 0.05 to 5 parts by mass, and particularly preferably 0.1 to 2 parts by mass per part by mass of Ripasudil in terms of its free form.

[0036] <Ophthalmic composition> As used herein, the term "ophthalmic composition" refers to a composition that can be used as an ophthalmic agent (specifically, for example, a preparation to be administered to the eye, such as eye drops or eye ointments), and its form is not particularly limited, and examples of the form include a liquid (solution or suspension), a semi-solid (ointment), and a solid. The ophthalmic composition is preferably a liquid or semi-solid composition, and particularly preferably a composition containing at least water (aqueous composition). A liquid or semi-solid composition is easy to administer to ocular tissue, and in particular, an aqueous composition contains water as a solvent, and therefore has the advantages of being excellent in safety and usability, and is easy to manufacture. However, since the composition is liquid or semi-solid, it has the disadvantage of being easily transferred to other tissues in addition to being contained in ocular tissue when applied. However, according to the present invention, the transfer of the halogenated isoquinoline derivative to ocular tissue is promoted, and therefore, the effect of the invention of ensuring higher safety can be advantageously utilized, particularly in a composition having such properties.

[0037] In this specification, "aqueous composition" means a composition containing at least water, and its properties include liquid (solution or suspension) and semi-solid (ointment), and liquid is preferred. The water in the composition can be, for example, purified water, water for injection, sterilized purified water, etc. The water content in the aqueous composition is not particularly limited, but is preferably 5% by mass or more, more preferably 20% by mass or more, even more preferably 50% by mass or more, even more preferably 90% by mass or more, and particularly preferably 90 to 99.8% by mass.

[0038] The ophthalmic composition can be formulated into an ophthalmic preparation, specifically, an eye drop, an eye ointment, or the like, preferably an eye drop, or the like, according to a known method described in, for example, the General Provisions for Preparations of the 16th Edition of the Japanese Pharmacopoeia, or the like.

[0039] In addition to the above, the ophthalmic composition may contain additives used in pharmaceuticals, quasi-drugs, etc. Examples of such additives include inorganic salts, isotonicity agents, chelating agents, stabilizers, pH regulators, preservatives, antioxidants, thickening agents, surfactants, solubilizers, suspending agents, refreshing agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, etc. Specific examples of such additives include ascorbic acid, sodium hydrogen sulfite, alginic acid, sodium benzoate, benzyl benzoate, fennel oil, ethanol, ethylene-vinyl acetate copolymer, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride solution, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, xylitol, glycerin, gluconic acid, creatinine, chlorhexidine gluconate solution, chlorobutanol, etc. , crystalline sodium dihydrogen phosphate, geraniol, sodium chondroitin sulfate, titanium dioxide, gellan gum, dibutyl hydroxytoluene, potassium bromide, benzododecyl bromide, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution, taurine, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyloxapol, sodium dehydroacetate, trometamol, concentrated glycerin, concentrated mixed tocopherols, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride Benzalkonium chloride solution 50, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin, sodium pyrosulfite, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalkonium chloride, benzalkonium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, borax, boric acid, povidone, polyoxyethylene (200), polyoxypropylene glycol (70), sodium polystyrene sulfonate sodium, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl alcohol (partially saponified), d-borneol, macrogol 4000, macrogol 6000, D-mannitol, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methanesulfonic acid, l-menthol, monoethanolamine, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, ryunou, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate,Examples include sodium dihydrogen phosphate monohydrate, petrolatum, etc.

[0040] Preferred examples of additives include potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, concentrated glycerin, borax, boric acid, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified), macrogol 4000, macrogol 6000, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, monoethanolamine, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium hyaluronate, glucose, and l-menthol.

[0041] The ophthalmic composition may further contain other medicinal ingredients applicable to eye diseases in addition to the above, depending on the type of eye disease, etc. Examples of such medicinal ingredients include α1 receptor blockers including bunazosin, such as bunazosin hydrochloride, or a salt thereof or a solvate thereof; α2 receptor agonists including brimonidine, or a salt thereof or a solvate thereof, apraclonidine, or a salt thereof or a solvate thereof; carteolol, such as carteolol hydrochloride, or a salt thereof or a solvate thereof; nipradilol, or a salt thereof or a solvate thereof; timolol, or a salt thereof or a solvate thereof; betaxolol, such as betaxolol hydrochloride; beta-blockers including benzodiazepine or its salts or solvates, levobunolol or its salts or solvates such as levobunolol hydrochloride, befunolol or its salts or solvates, metipranolol or its salts or solvates; dorzolamide or its salts or solvates such as dorzolamide hydrochloride, brinzolamide or its salts or solvates, acetazolamide or its salts or solvates, dichlorphenamide or its salts or solvates solvates thereof, carbonic anhydrase inhibitors including methazolamide or a salt thereof or a solvate thereof; prostaglandins including isopropyl unoprostone or a salt thereof or a solvate thereof, tafluprost or a salt thereof or a solvate thereof, travoprost or a salt thereof or a solvate thereof, bimatoprost or a salt thereof or a solvate thereof, and latanoprost or a salt thereof or a solvate thereof; dipivefrin or a salt thereof such as dipivefrin hydrochloride or a solvate thereof, e.g. Sympathomimetics including epinephrine or its salts or solvates thereof, such as pinephrine, epinephrine borate, epinephrine hydrochloride; parasympathomimetics including distigmine bromide or its salts or solvates thereof, pilocarpine or its salts or solvates thereof, such as pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, carbachol or its salts or solvates thereof; calcium antagonists including lomerizine or its salts or solvates thereof, such as lomerizine hydrochloride;Cholinesterase inhibitors including demecarium or a salt thereof or a solvate thereof, echothiophate or a salt thereof or a solvate thereof, and physostigmine or a salt thereof or a solvate thereof can be included, and one or more of these can be combined. Other medicinal ingredients applicable to eye diseases are preferably one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol, salts thereof, and solvates thereof. Another embodiment includes an ophthalmic composition that does not contain one or more other medicinal ingredients applicable to the above-mentioned eye diseases, in particular, an ophthalmic composition that contains only the compound represented by the above-mentioned general formula (1) or a salt thereof, or a solvate thereof as an active ingredient.

[0042] The pH (25° C.) of the ophthalmic composition is not particularly limited, but is preferably 4 to 9, more preferably 4.5 to 8.5, even more preferably 5 to 8, and particularly preferably 5.5 to 7.5. The osmotic pressure ratio to physiological saline is not particularly limited, but is preferably 0.6 to 3, and particularly preferably 0.6 to 2.

[0043] From the viewpoints of storage stability, portability, etc., the ophthalmic composition is preferably contained in a container. The shape of the container is not particularly limited as long as it can contain the ophthalmic composition, and may be appropriately selected and set depending on the dosage form, etc. Specific examples of such container shapes include bottle-shaped containers, tube-shaped containers, eye drop containers, bag containers, etc. Furthermore, these containers may be further packaged in boxes, bags, etc.

[0044] The material (material) of the container is not particularly limited, and may be appropriately selected according to the shape of the container. Specific examples include glass, plastic, cellulose, pulp, rubber, metal, etc. From the viewpoint of processability, squeezability, and durability, it is preferable to use plastic. The resin of the plastic container is preferably a thermoplastic resin, and examples thereof include polyolefin-based resins such as low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, polypropylene, and cyclic polyolefin; polyester-based resins such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, and poly(1,4-cyclohexylene dimethylene terenaphthalate); polyphenylene ether-based resins; polycarbonate-based resins; polysulfone-based resins; polyamide-based resins; polyvinyl chloride resins; and styrene-based resins, and may be mixtures (polymer alloys) of these. From the viewpoint of suppressing crystal precipitation, the container is preferably a polyolefin-based resin container, and preferably a polypropylene container.

[0045] There are no particular limitations on the eye disease to which the ophthalmic composition is applied, and it may be appropriately selected depending on the pharmacological action, etc., of the compound represented by the general formula (1). Specifically, for example, the compound represented by formula (1) can be used as a preventive or therapeutic agent for ocular hypertension or glaucoma based on its Rho kinase inhibitory activity and intraocular pressure reducing activity. More specific examples of glaucoma include primary open-angle glaucoma, normal tension glaucoma, aqueous humor hyperproduction glaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma, steroid-induced glaucoma, lenticular capsular glaucoma, pigmentary glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma.

[0046] As disclosed in Japanese Patent No. 5557408, ocular fundus diseases (lesions mainly occurring in the retina and / or choroid. Specific examples thereof include fundus changes due to hypertension and arteriosclerosis, retinal vein occlusions such as central retinal artery occlusion, central retinal vein occlusion, and branch retinal vein occlusion, congenital retinal vascular anomalies such as diabetic retinopathy, diabetic macular edema, diabetic macular edema, Eales disease, and Coats disease, von Hippel disease, pulseless disease, macular diseases (central serous chorioretinopathy, cystoid macular edema, age-related macular degeneration, macular hole, myopic macular atrophy, etc.), and other diseases. degeneration), vitreoretinal interface macular degeneration, drug-induced macular degeneration, hereditary macular degeneration, rhegmatogenous, tractional, exudative retinal detachment, retinitis pigmentosa, retinopathy of prematurity, etc.), more preferably diabetic retinopathy, diabetic macular edema, or age-related macular degeneration. Furthermore, the present invention may be used as a prophylactic or therapeutic agent for postoperative complications of cataract surgery, such as secondary cataract and anterior capsule contraction, or for corneal edema.

[0047] When the ophthalmic composition is used as a preventive and / or therapeutic agent for eye diseases (preferably a disease selected from ocular hypertension, glaucoma, and fundus diseases; particularly preferably a disease selected from ocular hypertension and glaucoma), it may be administered about 1 to 3 times a day. EXAMPLES

[0048] The present invention will now be described in further detail with reference to examples, but the present invention is not limited to these in any way. Ripasudil monohydrochloride dihydrate used in the following test examples can be prepared, for example, by the method described in WO 2006 / 057397.

[0049] [Test Example 1] Ocular tissue transfer test The ocular tissue migration of the compound represented by formula (1) or a salt thereof, or a solvate thereof, when the ophthalmic composition was applied to the ocular tissue, was evaluated by the following method.

[0050] That is, the ophthalmic compositions (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. 50 μL of each of the obtained compositions was instilled into the eyes of white rabbits, and the aqueous humor and the iris and ciliary body were collected 0.25 hours, 0.5 hours, 1 hour, 2 hours, and 4 hours after administration, and the concentration of Ripasudil in the aqueous humor or the iris and ciliary body was measured (in all administration cases and in all tissues, the drug concentration was low, close to 0, 4 hours after drug administration). The concentration of Ripasudil in the tissues was calculated by comparing the peak area with that of a standard substance of known concentration using LC-MS / MS. From the obtained concentrations of Ripasudil in each tissue at each time point, the AUC (AUC 0-4 ) was calculated. The results are shown in Table 1.

[0051] [Table 1]

[0052] As shown in the results in Table 1, in both the aqueous humor and the iris / ciliary body tissues, the ophthalmic composition of Example 1 containing sorbic acid had a higher AUC value than the ophthalmic composition of Comparative Example 1 not containing sorbic acid.

[0053] The ophthalmic composition of Example 1 and the ophthalmic composition of Comparative Example 1 are equivalent in terms of not only the ingredients but also the pH, etc., except for the presence or absence of sorbic acid. From this, it was presumed that the promotion of migration of Ripasudil into ocular tissue observed in this test is not merely due to the influence of the pH environment, but is due to the action of combining a compound represented by general formula (1) such as Ripasudil, or a salt thereof, or a solvate thereof with sorbic acid.

[0054] [Test Example 2] Ocular tissue transfer test Part 2 In order to reconfirm the effect of sorbic acid in promoting the transfer of the compound represented by general formula (1) into ocular tissue, as confirmed in Test Example 1, the following test was carried out. That is, the ophthalmic 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, and the ophthalmic tissue migration of the compound represented by general formula (1) or a salt thereof, or a solvate thereof was evaluated by a method similar to that of Test Example 1. The results are shown in Table 2.

[0055] [Table 2]

[0056] As shown in the results in Table 2, similar to Test Example 1, the ophthalmic composition of Example 2 containing sorbic acid had a higher AUC value in both the aqueous humor and the iris and ciliary body tissues than the ophthalmic composition of Comparative Example 2 not containing sorbic acid.

[0057] From the results of the above test examples 1 and 2, it was revealed that sorbic acid has the effect of promoting the transfer of a compound represented by general formula (1), such as Ripasudil, or a salt thereof, or a solvate thereof, into ocular tissue.

[0058] [Test Example 3] Ocular tissue transfer test Part 3 In order to confirm the effect of lower aliphatic carboxylic acids other than sorbic acid in promoting the transfer of the compound represented by general formula (1) to ocular tissue, the following test was carried out. That is, the ophthalmic compositions of Example 3 and Comparative Example 3 containing the components and amounts shown in Table 3 per 100 mL were prepared by a conventional method, and the ocular tissue migration of the compound represented by general formula (1) or a salt thereof, or a solvate thereof was evaluated by a method similar to that of Test Example 1. The results are shown in Table 3.

[0059] [Table 3]

[0060] As shown in the results in Table 3, in both the aqueous humor and the iris / ciliary body tissues, the ophthalmic composition of Example 3 containing citric acid had a higher AUC value than the ophthalmic composition of Comparative Example 3 not containing citric acid. In addition, since the ophthalmic composition of Example 3 and the ophthalmic composition of Comparative Example 3 have similar pH and other properties, it was presumed that the promotion of migration of Ripasudil into ocular tissues observed in this test was due to the action of combining a compound represented by general formula (1) such as Ripasudil, or a salt thereof, or a solvate thereof with citric acid. From the above test results, it was revealed that citric acid, like sorbic acid, has the effect of promoting the transfer of a compound represented by general formula (1), such as Ripasudil, or its salt, or a solvate thereof, into ocular tissue.

[0061] [Test Example 4] Ocular tissue transfer test Part 4 In Test Example 3, the same ocular tissue delivery promoting effect could be confirmed by incorporating 0.127 g of sodium edetate hydrate per 100 mL instead of the sodium citrate hydrate contained in the ophthalmic preparation of Example 3.

[0062] From the above test results, it was revealed that lower aliphatic carboxylic acids, such as sorbic acid, citric acid, and edetic acid, have the effect of promoting the transfer of the compound represented by general formula (1), such as Ripasudil, or its salt, or their solvates, into ocular tissue. Each of these lower aliphatic carboxylic acids has one or more hydrophilic groups (carboxyl groups) and a hydrophobic portion of a certain size (specifically, a linear or branched aliphatic group having about 11 carbon atoms or less, more specifically, about 5 to 11 carbon atoms).

[0063] [Manufacturing Examples 1-27] Ophthalmic compositions containing the components and amounts (amounts (g) per 100 mL of ophthalmic composition) shown in Tables 4 to 6 can be produced by a conventional method.

[0064] [Table 4]

[0065] [Table 5]

[0066] [Table 6]

[0067] [Examples 28-54] In Preparation Examples 1 to 27, ophthalmic compositions can be prepared by a conventional method by using the same amount of 4-bromo-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline instead of Ripasudil monohydrochloride dihydrate. [Industrial Applicability]

[0068] INDUSTRIAL APPLICABILITY According to the present invention, an ophthalmic composition having excellent efficacy and safety can be provided, and can be suitably used in the pharmaceutical industry and the like.

Claims

1. The following general formula (1) 【Chemistry 1】 [In the formula, X represents a halogen atom.] or a salt thereof, or a solvate thereof, and one or more lower aliphatic carboxylic acids selected from the group consisting of adipic acid, aspartic acid, edetic acid, succinic acid, acetic acid, tartaric acid, lactic acid, propionic acid, fumaric acid, maleic acid, malonic acid, malic acid, salts thereof, and solvates thereof.

2. The ophthalmic composition of claim 1 which is an aqueous composition.

3. The ophthalmic composition according to claim 1 or 2, wherein the compound represented by the general formula (1) is Ripasudil.

4. The ophthalmic composition according to any one of claims 1 to 3, wherein the lower aliphatic carboxylic acids are one or more lower aliphatic carboxylic acids selected from the group consisting of edetic acid, salts thereof, and solvates thereof.

5. The ophthalmic composition according to any one of claims 1 to 4, which is an eye drop.

6. The ophthalmic composition according to any one of claims 1 to 5, which is an agent for preventing and / or treating a disease selected from the group consisting of ocular hypertension, glaucoma and ocular fundus diseases.

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