JP6886322B2 - Ophthalmic composition - Google Patents

Description

The present invention relates to ophthalmic compositions and the like.

The following structural formula:

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

In general, when administering a drug effective for an eye disease, it is recommended to administer the drug to the eye as an ophthalmic agent such as an eye drop or an eye ointment so that the drug is efficiently transferred to the eye tissue which is the diseased part. It is desirable from the viewpoint of exerting its medicinal effect, reducing the transfer to other tissues, reducing side effects, and ensuring safety. Therefore, it can be said that it is preferable to prepare a halogenated isoquinoline derivative as an ophthalmic composition and administer it to the eye from the viewpoint of efficient use of the drug and safety, and in fact, such a halogenated isoquinoline derivative is used. A plurality of ophthalmic compositions containing the same have been reported so far (for example, Patent Documents 5 and 6 and the like).

By the way, in Patent Document 7, lipasudil ((S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazin) or a salt thereof, water-soluble film formation A film preparation containing an agent and an antioxidant such as edetic acid or citric acid is disclosed. However, in Patent Document 7, antioxidants such as edetic acid and citric acid are only described as components that suppress a decrease in the content of ripasudil in the preparation and improve storage stability. No mention is made of its association with transfer to ocular tissue.
Further, the film preparation disclosed in Patent Document 7 is a solid component obtained by dissolving and dispersing lipasyl, a film-forming agent, a carboxyvinyl polymer and an antioxidant in a volatile solvent such as methanol, and then volatilizing the solvent by drying. It is a non-aqueous preparation obtained by precipitating and forming a film. Therefore, the film formulation disclosed in Patent Document 7 is a formulation completely different from the aqueous composition.

Japanese Patent No. 421149 International Publication No. 2006/115244 Pamphlet International Publication No. 2006/068208 Pamphlet Japanese Patent No. 5557408 Japanese Patent No. 40992201 Japanese Patent No. 4168071 Japanese Unexamined Patent Publication No. 2013-129605

As described above, when administering a drug effective for eye diseases, it is preferable to administer it to the eye as an ophthalmic agent such as an eye drop from the viewpoint of efficient use and safety of the drug. Nevertheless, not all administered drugs are transferred into the eye tissue. In particular, the corneal epithelium and the like constituting the outermost surface of the eye tissue have a high affinity with a fat-soluble drug, whereas the halogenated isoquinoline derivative is a water-soluble drug, and the transfer rate to the eye tissue is not high at all. In general, drugs that do not migrate to the ocular tissue after application to the eye either mix with tear fluid and flow out of the body, or reach the nasal or pharyngeal mucosa from the punctum through the nasolacrimal duct and are absorbed there. It is said to enter the systemic circulation. The ophthalmic composition containing a halogenated isoquinoline derivative was also applied to ophthalmic tissues from the viewpoint of more efficiently utilizing its medicinal effect and further reducing the risk of side effects that may occur due to entering the systemic circulation. It is strongly desired to develop a technique for promoting the transfer of the halogenated isoquinoline derivative to the ophthalmic tissue.

Therefore, it is an object of the present invention to provide a technique for promoting the transfer of a halogenated isoquinoline derivative to an ophthalmic tissue in an ophthalmic composition containing a halogenated isoquinoline derivative.

Therefore, the present inventor diligently studied to solve the above problems, and found that an ophthalmic composition containing a halogenated isoquinoline derivative such as ribasudil was further added to lower aliphatic carboxylic acids such as sorbic acid, citric acid, and edetonic acid. The present invention has been completed by finding that the inclusion of the halogenated isoquinoline derivative promotes the transfer of the halogenated isoquinoline derivative to the ocular tissue.

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

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

According to the present invention, the halogenated isoquinoline derivative is used more efficiently and is safer because the transfer of the halogenated isoquinoline derivative to the ophthalmic tissue is promoted when the ophthalmic composition is applied to the ophthalmic tissue. It is possible to provide an ophthalmic composition having excellent properties.

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 ophthalmic composition containing a compound represented by (1), a salt thereof, a solvate thereof, and lower aliphatic carboxylic acids.
[2] The ophthalmic composition according to [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 lower aliphatic carboxylic acid is a saturated or unsaturated aliphatic carboxylic acid having a linear or branched chain having 2 to 12 carbon atoms, in which 1 to 2 carbon atoms may be replaced with a nitrogen atom. The ophthalmic composition according to any one of [1] to [3], which is one or more selected from the group consisting of an acid, a salt thereof, and a solvate thereof.
[5] The lower aliphatic carboxylic acids include adipic acid, aspartic acid, edetonic acid, citric acid, succinic acid, acetic acid, tartaric acid, sorbic acid, lactic acid, propionic acid, fumaric acid, maleic acid, malonic acid, malic acid and The ophthalmic composition according to any one of [1] to [4], which is one or more selected from the group consisting of salts thereof and solvates thereof.
[6] The lower aliphatic carboxylic acids are at least one selected from the group consisting of edetic acid, citric acid, acetic acid, sorbic acid and salts thereof, and solvates thereof, [1] to [4]. The ophthalmic composition according to any one of.
[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 a preventive and / or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma and fundus disease.

[9] Furthermore, from α1 receptor blockers, α2 receptor blockers, β blockers, carbon dioxide dehydration enzyme inhibitors, prostaglandins, sympathomimetics, parasympathomimetics, calcium channel blockers and cholinesterase inhibitors The ophthalmic composition according to any one of [1] to [8], which contains at least one selected from the group.
[10] The ophthalmology according to any one of [1] to [8], further containing one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol and salts thereof, and solvates thereof. Composition for.
[11] The ophthalmic composition according to any one of [1] to [8], which contains only the compound represented by the general formula (1), a salt thereof, or a solvate thereof as an active ingredient.

[12] The general formula (1), which comprises a step of adding a lower aliphatic carboxylic acid to an ophthalmic composition containing the compound represented by the general formula (1), a salt thereof, or a solvate thereof. A method for promoting the transfer of a compound represented by the above, a salt thereof, or a solvate thereof to an ophthalmic tissue.
[13] The method according to [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 lower aliphatic carboxylic acids are saturated or unsaturated aliphatic carboxylic acids of a linear or branched chain having 2 to 12 carbon atoms, in which 1 to 2 carbon atoms may be replaced with nitrogen atoms. The method according to any one of [12] to [14], which is one or more selected from the group consisting of an acid, a salt thereof, and a solvate thereof.
[16] The lower aliphatic carboxylic acids include adipic acid, aspartic acid, edetonic acid, citric acid, succinic acid, acetic acid, tartaric acid, sorbic acid, lactic acid, propionic acid, fumaric acid, maleic acid, malonic acid, malic acid and The method according to any one of [12] to [14], which is one or more selected from the group consisting of salts thereof and solvates thereof.
[17] The lower aliphatic carboxylic acids are at least one selected from the group consisting of edetic acid, citric acid, acetic acid, sorbic acid and salts thereof, and solvates thereof, [12] to [14]. Any of the methods described.
[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 a prophylactic and / or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma and fundus disease.

[20] The ophthalmic 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 channel blocker. The method according to any one of [12] to [19], which contains at least one selected from the group consisting of an agent and a cholinesterase inhibitor.
[21] The ophthalmic composition further contains one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol and salts thereof, and solvates thereof [12] to [19]. Any of the methods described.
[22] The description according to any one of [12] to [19], wherein the ophthalmic composition contains only the compound represented by the general formula (1), a salt thereof, or a solvate thereof as an active ingredient. Method.

<Compound represented by the 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 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 homopiperazine ring substituted with a methyl group 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 lipasyl 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 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 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 ophthalmic composition is not particularly limited, and is appropriately determined according to the applicable disease, the sex, age, symptom, etc. of the patient. It may be determined by examination, but from the viewpoint of obtaining excellent pharmacological action, 0.01 to 10 w in terms of the free form of the compound represented by the general formula (1) with respect to the total volume of the ophthalmic composition. It is preferably contained in an amount of / v%, more preferably 0.02 to 8 w / v%, and particularly preferably 0.04 to 6 w / v%. 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 ophthalmic composition from the viewpoint of obtaining excellent pharmacological action. , It is preferably contained in an amount of 0.05 to 5 w / v% in terms of a free form, more preferably 0.1 to 3 w / v%, and particularly preferably 0.1 to 2 w / v%. ..

<Lower aliphatic carboxylic acids>
As used herein, the term "lower aliphatic carboxylic acid" means a lower aliphatic carboxylic acid in which one or more carbon atoms may be replaced with a nitrogen atom and an alkali such as a sodium salt or a potassium salt. It means one or more selected from the group consisting of metal salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts, etc.) and their solvates (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, 2 to 12 is preferable, 4 to 12 is more preferable, and 6 10 to 10 are particularly preferable. Of these carbon atoms, some of the carbon atoms other than the carbon atoms constituting the carboxyl group may be replaced with nitrogen atoms, but from the viewpoint of promoting eye tissue migration, such substitutions may be made. The number is preferably 1 to 2. Further, the carbon chain may be linear or branched, and may be saturated or unsaturated.

The number of carboxyl groups in the lower aliphatic carboxylic acids is not limited, but 1 to 4 is preferable, and 1 to 3 is more preferable, from the viewpoint of promoting eye tissue migration. Further, the lower aliphatic carboxylic acids may further have about 1 to 3 hydrophilic substituents other than the carboxyl group from the viewpoint of promoting eye tissue migration. Specific examples of such a hydrophilic substituent include a hydroxyl group and an amino group.
The lower aliphatic carboxylic acids are known compounds and may be produced by a known method or commercially available ones may be used. As the lower aliphatic carboxylic acids, those having a salt or complex formed with other components may be used, and an ophthalmic composition containing such a component forming a salt or complex is also referred to as "lower aliphatic carboxylic acid". Included in "Ophthalmic Compositions Containing Acids".

Specific examples of such lower aliphatic carboxylic acids include malic acid; malic acid such as aspartic acid, sodium L-aspartate, magnesium L-aspartate or a salt thereof, or a solvent product thereof; malic acid. Edetoic acid such as calcium disodium, sodium edetate hydrate, tetrasodium edetate or a salt thereof or a solvent mixture thereof; calcium citrate, citrate hydrate, sodium citrate hydrate, dihydrogen citrate Citrate or salts thereof such as sodium, disodium citrate, anhydrous citric acid, anhydrous sodium citrate or their solvents; succinic acid such as succinic acid, monosodium succinate, disodium succinate hexahydrate or Acetic acid, its salts or their solvents; acetic acid such as acetic acid, ammonium acetate, potassium acetate, calcium acetate, sodium acetate hydrate, glacial acetic acid, anhydrous sodium acetate and its salts or their salts; malic acid, D-malic acid , Malic acid such as potassium hydrogen tartrate, DL-sodium tartrate, potassium tartrate or salts thereof or a solvent thereof; sorbic acid such as sorbic acid or potassium sorbate or a salt thereof or a solvent thereof; lactic acid, sodium lactate Liquid, calcium lactate hydrate, lactic acid such as aluminum lactate or a salt thereof or a solvent thereof; propionic acid such as propionic acid, sodium propionate or a salt thereof or a solvent thereof; fumalic acid or a salt thereof or a mixture thereof Malic acid or a salt thereof or a solvent thereof; malonic acid or a salt thereof or a solvent product thereof; malic acid such as malic acid, DL-malic acid, DL-sodium malate or a salt thereof or Examples thereof include their solvates.

As lower aliphatic carboxylic acids, from the viewpoint of promoting ocular tissue migration, 1 to 2 carbon atoms may be replaced with nitrogen atoms, and the linear or branched chain having 2 to 12 carbon atoms is saturated or branched. One or more selected from the group consisting of unsaturated aliphatic carboxylic acids and salts thereof and their solvents are preferable, and they consist of edetic acid, citric acid, acetic acid, sorbic acid and salts thereof and their solvents. One or more selected from the group is more preferable, and one or more selected from the group consisting of edetic acid, citric acid, sorbic acid and salts thereof and a solvate thereof is further preferable, citric acid, sorbic acid and their salts. One or more selected from the group consisting of salts and solvates thereof is particularly preferable.

The content of the lower aliphatic carboxylic acids in the ophthalmic composition is not particularly limited, but from the viewpoint of promoting the migration of ophthalmic tissues, it is contained in an amount of 0.01 to 5 w / v% based on the total volume of the ophthalmic composition. It is preferably contained in an amount of 0.05 to 3.5 w / v%, more preferably 0.1 to 1 w / v%.
The mass ratio of the compound represented by the general formula (1) or a salt thereof or a solvate thereof to the lower aliphatic carboxylic acid in the composition for ophthalmology is not particularly limited, but has an action of promoting ocular tissue migration. From the viewpoint, it is preferable to contain 0.3 to 8 parts by mass of lower aliphatic carboxylic acids with respect to 1 part by mass in terms of the free form of the compound represented by the general formula (1), and 0.6 to 4 parts by mass. It is more preferably contained in parts by mass, and particularly preferably 0.8 to 3 parts by mass. Above all, when the compound represented by the general formula (1) or a salt thereof or a solvate thereof is lipasyl or a salt thereof or a solvate thereof, lipasyl is free from the viewpoint of promoting eye tissue migration. It is preferable to contain 0.01 to 10 parts by mass of lower aliphatic carboxylic acids, more preferably 0.05 to 5 parts by mass, and 0.1 to 2 parts by mass with respect to 1 part by mass in terms of body. It is particularly preferable to contain a part.

<Ophthalmic composition>
As used herein, the term "ophthalmic composition" means a composition that can be used as an ophthalmic agent (specifically, a preparation to be administered to the eye, such as an eye drop or an eye ointment), and its properties. Is not particularly limited, and examples thereof include liquid (solution or suspension), semi-solid (ointment), and solid.
As the properties of the ophthalmic composition, a liquid or semi-solid composition is preferable, and a composition containing at least water (aqueous composition) is particularly preferable. The liquid or semi-solid composition is easy to administer to the ocular tissue, and in particular, the aqueous composition contains water as a solvent, so that it is excellent in safety and usability, and has the advantages of being easy to manufacture. Since the properties are liquid or semi-solid, there is a demerit that when the composition is applied, it easily migrates not only to the ocular tissue but also to other tissues. However, according to the present invention, the transfer of the halogenated isoquinoline derivative to the ocular tissue is promoted, so that the effect of the invention of ensuring higher safety can be advantageously utilized, especially in the composition having such properties. Is.

In the present specification, the "aqueous composition" means a composition containing at least water, and examples of the properties thereof include a liquid (solution or suspension) and a semi-solid (ointment), and a 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 composition for ophthalmology is prepared, for example, in accordance with a known method described in the 16th revised general rules of pharmaceutical preparations of the Japanese Pharmacy, for ophthalmic agents, specifically, dosage forms such as eye drops and ointments, preferably eye drops. It can be formulated into a dosage form such as.

In addition to the above, the ophthalmic composition may contain additives used in pharmaceuticals, quasi-drugs, and the like. Such additives include, for example, 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, sodium hydrogen sulfite, alginic acid, sodium benzoate, benzyl benzoate, oyster oil, ethanol, ethylene / vinyl acetate copolymer, potassium chloride, and calcium chloride hydrate. , Sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride solution, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camfur, dl-camfur, xylitol, glycerin, gluconic acid, creatinine, chlorhexidine glycol acid solution , Chlorobutanol, Crystalline Monosodium Dihydrogen Phosphate, Geraniol, Sodium Chondroitin Sulfate, Titanium Oxide, Gellan Gum, Dibutyl hydroxytoluene, Potassium Bromide, Benzoddecinium Bromide, Sodium Hydroxide, Polyoxyl 45 Stearate, Purified Lanolin, D-Sorbitol , Sorbitol solution, 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, sodium pyrosulfate, phenylethyl alcohol, glucose, propylene glycol, bergamot Oil, benzalconium chloride solution, benzalconium chloride solution, benzyl alcohol, benzethonium chloride solution, benzethonium chloride solution, borosand, boric acid, povidone, polyoxyethylene (200), polyoxypropylene glycol (70), Sodium polystyrene sulfonate, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl alcohol (partially saponified), d-bornol, macrogol 4000, macrogol 6000, D-mannitol, sodium monohydrogen phosphate anhydrous, phosphoric acid anhydride Sodium dihydrogen, methanesulfonic acid, l-menthol, monoethanolamine, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, rhyuno, phosphoric acid, sodium hydrogen phosphate hydrate , Potassium dihydrogen phosphate, Sodium dihydrogen phosphate, Dihydrate dihydrogen phosphate Examples thereof include elementary sodium monohydrate and petrolatum.

Additives include, for example, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, 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, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, monoethanolamine, phosphorus Acids, 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 ophthalmic composition may further contain other medicinal ingredients applicable to the eye disease, depending on the type of the eye disease and the like. Such medicinal ingredients include an α1 receptor blocker containing bunazosin such as bunazosin hydrochloride or a solvate thereof; brimonidine or a salt thereof or a solvate thereof, apracronidine or a salt thereof or a solvate thereof. Α2 receptor agonists including solvates; carteolols such as carteolol hydrochloride or salts thereof or solvates thereof, nipradilol or salts thereof or solvates thereof, thymorol or salts thereof or solvates thereof. , Betaxolol or a solvate thereof such as betaxolol hydrochloride or a solvate thereof, levobnorol or a salt thereof such as levobnorol hydrochloride or a solvate thereof, befnorol or a salt thereof or a solvate thereof, methipranolol or a salt thereof Or β-blockers containing their solvates; dolzolamide such as dolsolamide hydrochloride or its salts or their solvates, brinzolamin or its salts or their solvates, acetazolamide or its salts or their solvates, Dichlorphenamide or a salt thereof or a solvate thereof, metazolamide or a salt thereof or a carbonate dehydratase inhibitor containing a solvate thereof; isopropylunoprostone or a salt thereof or a solvate thereof, tafluprost or a salt thereof Or solvates thereof, travoprost or salts thereof or solvates thereof, bimatoprost or salts thereof or solvates thereof, ratanoprost or salts thereof or prostaglandins containing solvates thereof; A sympathomimetic drug containing dipibefurin such as furin hydrochloride or a solvate thereof, epinephrine such as epinephrine, epinephrineborate, epinephrine hydrochloride or a solvate thereof or a solvate thereof; Or a parasympathetic agent containing a solvate thereof or a solvate thereof, a pyrocarpine such as pyrocarpine, a pyrocarpine hydrochloride, a pyrocarpine nitrate or a solvate thereof or a solvate thereof, a carbacol or a salt thereof or a solvate thereof; Calcium antagonists containing romelysin such as salt or a solvate thereof or a solvate thereof; demepotassium or a salt thereof or a solvate thereof, ecothiopate or a salt thereof or a solvate thereof, phizostigmine or a salt thereof or a solvate thereof. Examples thereof include choline esterase inhibitors containing solvates, and one or two of these. The above can be blended.
As other medicinal ingredients applicable to eye diseases, one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol and salts thereof, and solvates thereof is preferable.
In addition, as another embodiment, an ophthalmic composition containing no one or more of other medicinal ingredients applicable to the above-mentioned eye diseases, particularly a compound represented by the above general formula (1) or a salt thereof or a salt thereof. Examples thereof include ophthalmic compositions containing only the solvate of the above as an active ingredient.

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. preferable. The osmotic pressure ratio with respect to the physiological saline is not particularly limited, but is preferably 0.6 to 3, particularly preferably 0.6 to 2.

The ophthalmic 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 ophthalmic composition, and may be appropriately selected and set according to the dosage form and the like. Specific examples of such a container include a bottle-shaped container, a tube-shaped container, an eye drop container, a bag container, and the like. 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 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 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. 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 eye disease to which the ophthalmic 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, 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, fundus diseases (lesions mainly occurring in the retina and / or choroid. Specifically, for example, fundus changes 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 chlorosis, 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 interfacial yellow degeneration, drug-toxic macular degeneration, hereditary yellow spot Degeneration, etc.), retinal detachment (such as rhegmatogenous, traction, exudative, etc.), retinal pigment degeneration, premature infant retinopathy, etc.) Prophylactic or therapeutic agents, more preferably diabetic retinopathy, diabetes It can be used as a prophylactic or therapeutic agent for retinal edema or age-related retinal degeneration. Further, it may be used as a preventive or therapeutic agent for postoperative complications of cataract such as late cataract and anterior capsule contraction, or as a preventive or therapeutic agent for corneal edema.

The ophthalmic 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). When using it, 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.
The Ripasudil monohydrochloride dihydrate used in the following test examples can be produced, for example, by the method described in Pamphlet 2006/057397.

[Test Example 1] Ophthalmic Tissue Transfer Test The ophthalmic tissue transferability of the compound represented by the general formula (1), a salt thereof, or a solvate thereof when the ophthalmic composition is applied to the eye tissue is as follows. Evaluated by method.

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 0.25 hours, 0.5 hours, 1 hour, 2 hours, and 4 hours after administration, aqueous humor and iris / hair. The spores were collected and the concentration of ripasudil in the aqueous humor or in the iris / ciliary body was measured (in any administration example and in any tissue, the drug concentration was 0 4 hours after the administration of the drug. It was a nearby low price.) The concentration of ripasudil in the tissue was calculated by comparing the peak area with a standard substance having a known concentration using LC-MS / MS.
_{The AUC (AUC 0-4} ) for 0 to 4 hours of drug administration was calculated from the concentration of ripasudil in each tissue at each time obtained.
The results are shown in Table 1.

As shown in the results shown in Table 1, in both the aqueous humor and the iris / ciliary body tissues, the ophthalmic composition of Example 1 containing sorbic acid is the ophthalmic composition of Comparative Example 1 containing no sorbic acid. AUC was higher than that of the thing.

The ophthalmic composition of Example 1 and the ophthalmic composition of Comparative Example 1 have the same pH and the like as well as the compounding components, except for the presence or absence of sorbic acid. From this, the promotion of the transfer of ripasudil to the ocular tissue observed in this test is different from the influence of the mere pH environment, etc., the compound represented by the general formula (1) such as ripasudil or a salt thereof, or a salt thereof. It was presumed that the action was due to the combination of the solvate and sorbic acid.

[Test Example 2] Eye tissue transfer test Part 2
In order to reconfirm the action of sorbic acid confirmed in Test Example 1 to promote the transfer of the compound represented by the general formula (1) to the ocular tissue, 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 represented by the general formula (1) by the same method as in Test Example 1. The transferability of the compound to be obtained, a salt thereof, or a solvate thereof was evaluated.
The results are shown in Table 2.

As shown in the results shown in Table 2, the ophthalmic composition of Example 2 containing sorbic acid contained sorbic acid in both the aqueous humor and the iris / ciliary body tissues, as in Test Example 1. No AUC was higher than that of the ophthalmic composition of Comparative Example 2.

From the results of Test Examples 1 and 2 above, sorbic acid has an action of promoting the transfer of the compound represented by the general formula (1) represented by ripasudil, a salt thereof, or a solvate thereof to the ocular tissue. It became clear to have.

[Test Example 3] Eye tissue transfer test Part 3
The following tests were conducted to confirm the effect of lower aliphatic carboxylic acids other than sorbic acid on promoting the transfer of the compound represented by the general formula (1) to the ocular tissue.
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 represented by the general formula (1) by the same method as in Test Example 1. The transferability of the compound to be obtained, a salt thereof, or a solvate thereof was evaluated.
The results are shown in Table 3.

As shown in the results shown in Table 3, in both the aqueous humor and the iris / ciliary body tissues, the ophthalmic composition of Example 3 containing citric acid is used for ophthalmology of Comparative Example 3 which does not contain citric acid. The AUC was higher than that of the composition. Further, since the pH and the like of the ophthalmic composition of Example 3 and the ophthalmic composition of Comparative Example 3 are the same, the promotion of the transfer of ripasudil to the ocular tissue observed in this test can be achieved by using ripasudil or the like. It was presumed that the action was due to the combination of the compound represented by the general formula (1), a salt thereof, or a solvate thereof and citric acid.
From the above test results, citric acid, like sorbic acid, has an action of promoting the transfer of the compound represented by the general formula (1) represented by ripasudil, a salt thereof, or a solvate thereof to the ocular tissue. It became clear that it has.

[Test Example 4] Eye tissue transfer test Part 4
Similarly, in Test Example 3, by blending 0.127 g of sodium edetate hydrate per 100 mL instead of the sodium citrate hydrate contained in the ophthalmic agent of Example 3, ophthalmic tissue transfer is also performed. The promoting action can be confirmed.

From the above test results, lower aliphatic carboxylic acids represented by sorbic acid, citric acid, and edetic acid are compounds represented by the general formula (1) represented by ripasudil, salts thereof, or solvates thereof. It has been clarified that it has an action of promoting the transfer of the compound to the ocular tissue.
All of these lower aliphatic carboxylic acids have one or more hydrophilic groups (carboxyl groups) and have a certain size of hydrophobic sites (specifically, carbon atoms of about 11 or less). Specifically, it has a linear or branched aliphatic group having about 5 to 11 carbon atoms).

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

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

According to the present invention, it is possible to provide an ophthalmic composition having excellent efficacy and safety, and it can be suitably used in the pharmaceutical industry and the like.

Claims (5)

The following general formula (1)

[In the formula, X represents a halogen atom. ]
A compound represented by or a salt thereof or a solvate thereof, containing sorbic acid, one or more selected from citric acid and the group consisting of salts thereof as well as their solvates and, ophthalmic compositions. The ophthalmic composition according to claim 1, which is an aqueous composition. The ophthalmic composition according to claim 1 or 2, wherein the compound represented by the general formula (1) is ripasudil. The ophthalmic composition according to any one of claims 1 to 3 , which is an eye drop. The ophthalmic composition according to any one of claims 1 to 4 , which is a prophylactic and / or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma and fundus disease.