JP6495379B2 - Aqueous composition - Google Patents

Description

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

  Brimonidine such as brimonidine tartrate (chemical name: 5-Bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine mono- (2R, 3R) -tartrate) is adrenaline α2. It is a kind of receptor agonist, has an aqueous humor production inhibitory action and an aqueous humor outflow promotion action from the uveal sclera outflow tract, and exhibits an excellent intraocular pressure lowering effect. It is used as an active ingredient of ophthalmic agents such as glaucoma therapeutic agents (Non-patent Document 1). An ophthalmic agent is usually a composition containing water (aqueous composition), and various studies have been made on aqueous compositions containing brimonidine (for example, Patent Documents 1 and 2).

  By the way, the following structural formula:

Ripasudil (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 the formula: For example, it has patent documents 3 and 4) and is known to be useful for prevention and treatment of eye diseases. Specifically, for example, it has been reported that it is useful for prevention or treatment of ocular hypertension, glaucoma, etc. (for example, Patent Document 5), and as an ocular hypertension / glaucoma therapeutic agent containing ripaspil as an active ingredient. Granatech (registered trademark) ophthalmic solution 0.4% has been launched in Japan.
However, an aqueous composition containing both brimonidine or a salt thereof or a solvate thereof and a halogenated isoquinoline derivative has not been specifically reported so far.

JP-T-2004-504279 JP 2012-246304 A Japanese Patent No. 4212149 International Publication No. 2006/115244 Pamphlet International Publication No. 2006/068208 Pamphlet

Aifangan (registered trademark) ophthalmic solution 0.1% Pharmaceutical interview form, Senju Pharmaceutical Co., Ltd. May 2013 (4th revised edition)

Aqueous compositions contain water and are gentle to living organisms such as eye tissues and are excellent in safety, and have the merit that they are easy to handle at the time of manufacture and use. Easy to destabilize. Even in an aqueous composition containing brimonidine, it is possible to provide a pharmaceutical or the like having higher quality by improving its stability.
Therefore, an object of the present invention is to provide a technique for improving the stability of brimonidine in an aqueous composition.

  Therefore, the present inventor has intensively studied to solve the above problems, and surprisingly, by adding an aqueous composition containing brimonidine to a halogenated isoquinoline derivative typified by Ripasudil, an aqueous composition can be obtained. It was found that a decrease in the content of brimonidine therein was suppressed, and the present invention was completed.

That is, the present invention includes the following components (A) and (B):
(A) Brimonidine or a salt thereof or a solvate thereof;
(B) General formula (1)

[Wherein X represents a halogen atom. ]
Or a salt thereof or a solvate thereof;
An aqueous composition is provided.

The present invention also provides the following component (A):
(A) Brimonidine or a salt thereof or a solvate thereof;
In the aqueous composition containing the following component (B):
(B) the compound represented by the general formula (1) or a salt thereof or a solvate thereof;
And a method for stabilizing brimonidine or a salt thereof or a solvate thereof in an aqueous composition.

  ADVANTAGE OF THE INVENTION According to this invention, the content fall of the brimonidine in an aqueous composition can be suppressed, and the aqueous composition excellent in stability can be provided.

<Brimonidine or a salt thereof or a solvate thereof>
In this specification, “brimonidine or a salt thereof or a solvate thereof” includes not only brimonidine but also a pharmacologically acceptable salt of brimonidine, brimonidine or a pharmacologically acceptable salt thereof, water, Solvates with alcohols and the like are also included. Although it does not specifically limit as a salt accept | permitted pharmacologically, Specifically, for example, inorganic acid salts, such as hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide; acetate, tartaric acid Salt, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate Organic tartrate such as tartrate is preferable.

Brimonidine or a salt thereof or a solvate thereof includes brimonidine, brimonidine tartrate (brimonidine monotartrate) (chemical name: 5-Bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline -6-amine mono- (2R, 3R) -tartrate) is preferred.
Brimonidine or a salt thereof or a solvate thereof is known and may be produced by a known method, or a commercially available product may be used.

  The content of brimonidine or a salt thereof or a solvate thereof in the aqueous composition is not particularly limited, and may be determined by appropriately examining depending on the disease, patient sex, age, symptoms, etc. From the viewpoint of obtaining a pharmacological action, it is preferably contained in an amount of 0.01 to 10 w / v%, more preferably 0.02 to 1 w / v%, more preferably 0.06 to 0. It is particularly preferable to contain 5 w / v%.

<Compound represented by 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, and a bromine atom. In the general formula (1), the halogen atom is preferably a fluorine atom or a bromine atom, particularly preferably a fluorine atom.
In the general formula (1), the carbon atom constituting the homopiperazine ring substituted with a methyl group is an asymmetric carbon. Therefore, although stereoisomerism occurs, 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 a compound represented by the said General formula (1), the compound whose absolute configuration is S configuration 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. Specifically, for example, hydrochloride, sulfate, nitrate, hydrofluoride, Inorganic acid salts such as hydrobromide; acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate , Organic acid salts such as toluene sulfonate, naphthalene sulfonate, 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 alcohol solvate, and is preferably a hydrate.

As the compound represented by the general formula (1) or a salt thereof or a solvate thereof, specifically, 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;
Etc.

  Examples of the compound represented by the general formula (1) or a salt thereof or a solvate thereof include 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 is preferable, ripaspil or a salt thereof or a solvate thereof is more preferable, and ripaspil or a hydrochloride thereof or a hydrate thereof. Is more preferred and has the following structural formula:

Ripasudil hydrochloride hydrate represented by the formula (Ripazil monohydrochloride dihydrate) is particularly preferred.

  The compound represented by the general formula (1) or 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 a method described in International Publication No. 1999/020620 Pamphlet, International Publication No. 2006/057397 Pamphlet or the like. Further, 4-bromo-5-{[(2S) -2-methyl-1,4-diazepan-1-yl] sulfonyl} isoquinoline or a salt thereof or a solvate thereof is disclosed in International Publication No. 2006/115244 pamphlet. It can be produced 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, but the action of suppressing a decrease in the content of brimonidine or a salt thereof or a solvate thereof is not particularly limited. In view of the above, it is preferable to contain 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, and 0.1 to 8 w / v It is more preferable to contain v%, and it is especially preferable to contain 0.25-6 w / v%. Among these, when using ripaspil as the compound represented by the general formula (1), lipassyl is used with respect to the total volume of the aqueous composition from the viewpoint of suppressing the decrease in the content of brimonidine or a salt thereof or a solvate thereof. Alternatively, the salt or solvate thereof is preferably contained in an amount of 0.05 to 5 w / v% in terms of free form, more preferably 0.1 to 3 w / v%, It is still more preferable to contain 2 w / v%, and it is especially preferable to contain 0.25-1 w / v%.

  The content mass ratio of brimonidine or a salt thereof or a solvate thereof in the aqueous composition to the compound represented by the general formula (1) or a salt thereof or a solvate thereof is not particularly limited, but brimonidine Alternatively, from the viewpoint of the inhibitory effect on the decrease in the content of the salt or solvate thereof, the brimonidine or the salt thereof or the solvate thereof with respect to 1 part by mass converted to the free form of the compound represented by the general formula (1) It is preferable to contain 0.01 to 1.5 parts by mass of the product, more preferably 0.04 to 0.8 parts by mass, and particularly preferably 0.08 to 0.4 parts by mass. In particular, in the case where 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, the content of brimonidine or a salt thereof or a solvate thereof From the viewpoint of the effect of suppressing the decrease, it is preferable to contain 0.02 to 1 part by mass of brimonidine or a salt thereof or a solvate thereof with respect to 1 part by mass in terms of a free form of ripaspil. The content is more preferably 0.5 parts by mass, and particularly preferably 0.1 to 0.3 parts by mass.

In the present specification, the “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. . In addition, as water in a composition, purified water, water for injection, sterilized purified water, etc. can be used, for example.
Although content of the water contained in an aqueous composition is not specifically limited, 5 mass% or more is preferable, 20 mass% or more is more preferable, 50 mass% or more is further more preferable, 90 mass% or more is further more preferable, 90- 99.8% by mass is particularly preferred.

  The aqueous composition can be made into various dosage forms according to a known method described in, for example, the 16th revised Japanese Pharmacopoeia General Rules for Preparations. Examples of the dosage form include injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal solutions, enemas, external liquids, sprays, ointments, gels, oral solutions, syrups, etc. Is mentioned. The dosage form is preferably an ophthalmic agent, specifically an eye drop or eye ointment, particularly an eye drop, from the viewpoint of advantageously utilizing the pharmacological action of brimonidine and the compound represented by the general formula (1). preferable.

Depending on the dosage form, the aqueous composition may contain additives used in pharmaceuticals, quasi drugs, and the like. Such additives include, for example, inorganic salts, isotonic agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, thickeners, surfactants, solubilizers, suspensions. Examples include turbidizers, cooling agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, and the like.
Specific examples of such additives include ascorbic acid, potassium aspartate, sodium bisulfite, alginic acid, sodium benzoate, benzyl benzoate, epsilon-aminocaproic acid, fennel oil, ethanol, ethylene / vinyl acetate copolymer. , Sodium edetate, tetrasodium edetate, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, xylitol, citric acid hydrate, sodium citrate hydrate, glycerin, gluconic acid, L-glutamic acid, sodium L-glutamate, creatinine, chlorhexidine gluconate solution, Lorobutanol, crystalline sodium dihydrogen phosphate, geraniol, sodium chondroitin sulfate, acetic acid, potassium acetate, sodium acetate hydrate, titanium oxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzododecinium bromide, tartaric acid, water Sodium oxide, 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 tocopherol, white petrolatum, mint water, mint oil, concentrated benzalkonium chloride solution 50, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, Palau Methyl benzoate, sodium hyaluronate, human serum albumin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, glacial acetic acid, 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, polysorbate 80, polyoxyethylene curing Castor oil 60, polyvinyl alcohol (partially saponified product), d-borneol, macrogol 4000, macrogol 6000, D-mannitol, anhydrous citrus Acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methanesulfonic acid, methylcellulose, l-menthol, monoethanolamine, aluminum monostearate, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, Oxyquinoline sulfate, liquid paraffin, camphor, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate Products, malic acid, petrolatum and the like.

  Examples of additives include potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate. , Concentrated glycerin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, borax, boric acid, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified product), macrogol 4000, macro Goal 6000, D-mannitol, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methyl cellulose, monoethanolamine, phosphoric acid, sodium hydrogen phosphate hydrate Potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, sodium hyaluronate, glucose, l-menthol is preferable.

In addition to the above, the aqueous composition may further contain other medicinal ingredients depending on the disease to be applied. 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 operation including apraclonidine or a salt thereof or a solvate thereof. Medicine: 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 such as timolol maleate or a solvate thereof, betaxolol hydrochloride Betaxolol or a salt thereof such as a salt or a solvate thereof, Levobunolol or a salt thereof such as levobanolol hydrochloride or a solvate thereof, befnolol or a salt thereof or a solvate thereof, metipranolol or a salt thereof or the like Β-blockers including solvates; Dorzolamide or a salt thereof such as zolamide hydrochloride or a solvate thereof, brinzolamide or a salt thereof or a solvate thereof, acetazolamide or a salt thereof or a solvate thereof, dichlorofenamide or a salt thereof or a solvate thereof , Metazolamide or a salt thereof, or a carbonic anhydrase inhibitor containing the solvate thereof; isopropyl unoprostone or a salt thereof or a solvate thereof, tafluprost or a salt thereof or a solvate or travoprost or a salt thereof Or a solvate thereof, bimatoprost or a salt thereof or a solvate thereof, latanoprost or a salt thereof or a solvate thereof, cloprostenol or a salt thereof or a solvate thereof, fluprostenol or a salt thereof or the like The solvate of Sympathomimetic drugs comprising dipivefrine such as dipivefrine hydrochloride or a salt thereof or a solvate thereof, epinephrine or a salt thereof such as epinephrine borate, epinephrine hydrochloride, or a solvate thereof A parasympathomimetic agent comprising pistincine bromide or a salt thereof or a solvate thereof, pilocarpine such as pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, or a salt thereof, or a solvate thereof, carbachol or a salt thereof or a solvate thereof; Calcium antagonists including romeridine such as romeridine hydrochloride or a salt thereof or a solvate thereof; deme potassium or a salt thereof or a solvate thereof, ecothiofate or a salt thereof or a solvate thereof, physostigmine or Includes cholinesterase inhibitors containing salts or solvates thereof, and one or more of these can be added.
The other medicinal component is preferably at least one selected from the group consisting of latanoprost, timolol, nipradilol, dorzolamide, brinzolamide and salts thereof.

  Although pH (25 degreeC) of an aqueous composition is not specifically limited, 4-8.5 are preferable, 5-8 are more preferable, and 6-7.5 are especially preferable. Moreover, although the osmotic pressure ratio with respect to the physiological saline is not specifically limited, 0.6-3 are preferable and 0.6-2 are more preferable.

  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 the aqueous composition can be accommodated, and may be appropriately selected and set according to the dosage form and the like. Specific examples of such a container include, for example, an injection container, an inhaler container, a spray container, a bottle container, a tube container, an eye drop container, a nasal drop container, Examples include ear container, bag container and the like. Moreover, these containers may be further packaged by boxes, bags or the like.

  The material (material) of a container is not specifically limited, What is necessary is just to select suitably according to the form of a container. Specific examples include glass, plastic, cellulose, pulp, rubber, metal and the like. 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, polyolefin resins such as low density polyethylene (including linear low density polyethylene), high density polyethylene, medium density polyethylene, polypropylene, and cyclic polyolefin. Polyester resins such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, poly (1,4-cyclohexylenedimethylene terephthalate), polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamides Resin, polyvinyl chloride resin, styrene resin and the like, and a mixture thereof (polymer alloy) may be used.

The applicable disease of the aqueous composition is not particularly limited, and may be appropriately selected depending on the pharmacological action of brimonidine and the compound represented by the general formula (1).
Specifically, for example, based on the adrenergic α2 receptor activation action and intraocular pressure lowering action of brimonidine, and based on the Rho kinase inhibitory action and intraocular pressure lowering action of the compound represented by the general formula (1), It can be used as a preventive or therapeutic agent for ocular hypertension and glaucoma. In this case, the intraocular pressure lowering action of brimonidine and the intraocular pressure lowering action of the compound represented by the general formula (1) are excellent, and an excellent ocular hypertension, glaucoma prevention and / or Alternatively, it is preferable because a therapeutic action can be obtained. Here, as glaucoma, more specifically, for example, primary open-angle glaucoma, normal-tension glaucoma, excessive aqueous production glaucoma, acute closed-angle glaucoma, chronic closed-angle glaucoma, plateau iris syndrome, mixed glaucoma Steroid glaucoma, capsular glaucoma, pigment glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma and the like.

  Further, as disclosed in Japanese Patent No. 5557408, a fundus disease (a lesion expressed mainly in the retina and / or choroid. Specifically, based on the action of the compound represented by the general formula (1). For example, fundus changes due to hypertension and arteriosclerosis, central retinal artery occlusion, retinal vein occlusion such as central retinal vein occlusion and branch retinal vein occlusion, diabetic retinopathy , Diabetic macular edema, diabetic macular disease, Eales disease, Coats disease, and other retinal vascular congenital anomalies, Hippel disease (von Hippel disease), pulseless disease, macular disease (centrality) Central serous chorioretinopathy, cystoid macular edema, age-related macular degeneration, macular hole, myopic macular atrophy ( myopic macular degeneration), retinal vitreous macular degeneration, drug-induced macular degeneration, hereditary macular degeneration, etc.), retinal detachment, retinitis pigmentosa, premature infant retina May also be used as a prophylactic or therapeutic agent for diabetic retinopathy, diabetic macular edema or age-related macular degeneration. Further, it may be used as a therapeutic agent for post-cataract complications such as secondary cataract or anterior capsule contraction, or as a preventive or therapeutic agent for corneal edema.

  The aqueous composition is used as a prophylactic 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 use, an appropriate amount (for example, about 1 drop in the case of eye drops) should be administered 1 to 3 times a day, preferably about 1 to 2 times a day, depending on the expected degree of medicinal effect. That's fine.

In addition, although this specification is not limited to these at all, the invention of the following aspects is disclosed, for example.
[1] The following components (A) and (B):
(A) Brimonidine or a salt thereof or a solvate thereof;
(B) General formula (1)

[Wherein X represents a halogen atom. ]
Or a salt thereof or a solvate thereof;
An aqueous composition containing
[2] The aqueous composition according to [1], wherein the compound represented by the general formula (1) is ripaspil.
[3] The aqueous composition according to [1] or [2], wherein the component (A) is brimonidine tartrate.
[4] The aqueous composition according to any one of [1] to [3], wherein the component (B) is ripaspil hydrochloride hydrate (Ripazil monohydrochloride dihydrate).
[5] The content of the component (A) is 0.01 to 10 (preferably 0.02 to 1, particularly preferably 0.06 to 0.5) w / w based on the total volume of the aqueous composition. The aqueous composition according to any one of [1] to [4], which is v%.
[6] The content of component (B) is 0.01 to 10 (preferably 0.1 in terms of the free form of the compound represented by formula (1) with respect to the total volume of the aqueous composition. The aqueous composition according to any one of [1] to [5], which is -8, particularly preferably 0.25-6) w / v%.
[7] The aqueous composition according to any one of [1] to [6], which is an ophthalmic agent.
[8] The aqueous composition according to [7], which is an eye drop.
[9] The aqueous composition according to any one of [1] to [8], which is a preventive and / or therapeutic agent for a disease selected from the group consisting of ocular hypertension and glaucoma.

[10] Further, from α1 receptor blocker, α2 receptor agonist, β blocker, carbonic anhydrase inhibitor, prostaglandins, sympathomimetic, parasympathomimetic, calcium antagonist and cholinesterase inhibitor The aqueous composition according to any one of [1] to [9], which contains one or more selected from the group consisting of:
[11] The aqueous solution according to any one of [1] to [9], further containing at least one member selected from the group consisting of latanoprost, timolol, nipradilol, dorzolamide, brinzolamide and salts thereof, and solvates thereof. Composition.

[12] The following component (A):
(A) Brimonidine or a salt thereof or a solvate thereof;
In the aqueous composition containing the following component (B):
(B) the compound represented by the general formula (1) or a salt thereof or a solvate thereof;
A method for stabilizing brimonidine or a salt thereof or a solvate thereof in an aqueous composition (preferably a method for suppressing a decrease in content).
[13] The method according to [12], wherein the compound represented by the general formula (1) is ripaspil.
[14] The method according to [12] or [13], wherein the component (A) is brimonidine tartrate.
[15] The method according to any one of [12] to [14], wherein the component (B) is ripaspil hydrochloride hydrate (lipasyl monohydrochloride dihydrate).
[16] The content of the component (A) in the aqueous composition is 0.01 to 10 (preferably 0.02 to 1, particularly preferably 0.06 to 0. 0, relative to the total volume of the aqueous composition. 5) The method according to any one of [12] to [15], which is w / v%.
[17] The content of the component (B) in the aqueous composition is 0.01 to 10 (preferably 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 0.1 to 8, particularly preferably 0.25 to 6) w / v%, the method according to any one of [12] to [16].
[18] The method according to any one of [12] to [17], wherein the aqueous composition is an ophthalmic agent.
[19] The method according to [18], wherein the ophthalmic agent is an eye drop.
[20] The method according to any one of [12] to [19], wherein the aqueous composition is a preventive and / or therapeutic agent for a disease selected from the group consisting of ocular hypertension and glaucoma.

[21] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, a carbonic anhydrase inhibitor, a prostaglandin, a sympathomimetic agent, a parasympathomimetic agent, and a calcium antagonist. And a method according to any one of [12] to [20], which comprises one or more selected from the group consisting of a cholinesterase inhibitor.
[22] The aqueous composition further contains at least one selected from the group consisting of latanoprost, timolol, nipradilol, dorzolamide, brinzolamide and salts thereof, and solvates thereof. Any one of the methods.

Next, the present invention will be further described with reference to examples, but the present invention is not limited to these examples.
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] Storage test (stability evaluation of brimonidine)
In order to evaluate the stability of brimonidine in the aqueous composition, 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 obtained aqueous composition was stored at 80 ° C. for 1 day, and the residual rate of brimonidine after storage was measured as follows.
That is, for each of the aqueous compositions before the start of storage and after storage for 1 day, the peak height was measured using an HPLC apparatus, and the residual rate (%) of brimonidine was calculated according to the following formula. It was.

Residual rate of brimonidine (%) = peak height of brimonidine after storage / peak height of brimonidine before storage × 100

  The results are shown in Table 1.

  From the results shown in Table 1, in the aqueous composition containing only brimonidine (Comparative Example 1), when it was stored at 80 ° C. for 1 day, the residual rate of brimonidine was about 96.5%, and the content decreased. On the other hand, in the aqueous composition (Example 1) further containing Ripasudil in addition to brimonidine, no substantial decrease in the content of brimonidine was observed even after storage at 80 ° C. for 1 day.

[Test Example 2] Storage test (Stability evaluation of brimonidine, part 2)
In order to confirm the stability of brimonidine in a system to which additives commonly used in ophthalmic preparations were added, the aqueous compositions of Example 2 and Comparative Example 2 containing the components and amounts shown in Table 2 per 100 mL were used in a conventional manner. It was prepared by.
The obtained various aqueous compositions were stored at 80 ° C. for 1 day, and the residual rate of brimonidine after storage was measured in the same manner as in Test Example 1.
The results are shown in Table 2.

  From the results shown in Table 2, in the system to which additives commonly used in ophthalmic preparations were added, the content of brimonidine was greatly reduced, and in the case of an aqueous composition containing only brimonidine (Comparative Example 2), when stored at 80 ° C. for 1 day, brimonidine As a result, the residual ratio of the product was greatly reduced to 92.3%, resulting in a decrease in the content. On the other hand, in the aqueous composition (Example 2) containing lipazil in addition to brimonidine, the residual rate of brimonidine was as large as 97.3% even after storage at 80 ° C. for 1 day. Suppression of the decrease in the content was confirmed.

  From the results of Test Examples 1 and 2 above, an aqueous composition containing brimonidine or a salt thereof or a solvate thereof, a compound represented by the general formula (1) represented by lipaspil or a salt thereof, or a salt thereof It has been clarified that the decrease in the content of brimonidine can be suppressed by adding the solvate.

[Production Examples 1 to 27]
An aqueous composition containing the components and amounts shown in Tables 3 to 5 (amount (g) per 100 mL of the aqueous composition) can be produced by a conventional method.

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

  ADVANTAGE OF THE INVENTION According to this invention, the aqueous composition excellent in stability can be provided and it can utilize suitably in pharmaceutical industry etc.

Claims (2)

The following components (A) and (B):
(A) Brimonidine or a salt thereof or a solvate thereof;
(B) General formula (1)

[Wherein X represents a halogen atom. ]
Or a salt thereof or a solvate thereof;
In which the content of the component (B) is 0.25 to 5 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. An aqueous composition that is 6 w / v%.   The aqueous composition according to claim 1, wherein the compound represented by the general formula (1) is ripaspil.