JP6704720B2 - Aqueous composition - Google Patents

Description

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

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:

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

Therefore, it is extremely useful to establish a technique for stably formulating these halogenated isoquinoline derivatives as, for example, ophthalmic agents.

Japanese Patent No. 4212149 International Publication 2006/115244 pamphlet International Publication 2006/068208 pamphlet Patent No. 5557408

The ophthalmic agent is usually a composition containing water (aqueous composition). The present inventor, when formulating Ripasudil, a halogenated isoquinoline derivative, as an ophthalmic agent, etc., prepared an aqueous composition containing Ripasudil and confirmed its storage stability. It has been found that the problem that the aqueous composition discolors occurs.
Therefore, an object of the present invention is to provide a technique for suppressing discoloration of a halogenated isoquinoline derivative-containing aqueous composition during storage at high temperature.

Therefore, the present inventor has conducted extensive studies to solve the above problems, and found that the aqueous composition containing a halogenated isoquinoline derivative such as Ripasudil can further suppress discoloration during high temperature storage by containing trometamol. The present invention has been completed.

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

[In the formula, X represents a halogen atom. ]
The present invention provides an aqueous composition containing a compound represented by or a salt thereof or a solvate thereof, and trometamol.
The present invention also provides a method for suppressing discoloration of an aqueous composition, which comprises the step of incorporating trometamol in an aqueous composition containing the compound represented by the general formula (1), a salt thereof, or a solvate thereof. Is provided.

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

This specification discloses the invention of the following aspects, for example, although not limited thereto.
[1] The following general formula (1)

[In the formula, X represents a halogen atom. ]
An aqueous composition containing a compound represented by: or a salt thereof or a solvate thereof, and trometamol.
[2] The aqueous composition according to [1], wherein the compound represented by the general formula (1) is Ripasudil.
[3] The aqueous composition according to [1] or [2], which is an ophthalmic agent.
[4] The aqueous composition according to [3], which is an eye drop.
[5] The aqueous composition according to any one of [1] to [4], which is a preventive and/or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma and fundus disease.

[6] Furthermore, from α1 receptor blockers, α2 receptor agonists, β blockers, carbonic anhydrase inhibitors, prostaglandins, sympathomimetics, parasympathomimetics, calcium antagonists and cholinesterase inhibitors The aqueous composition according to any one of [1] to [5], containing at least one selected from the group consisting of:
[7] The aqueous solution according to any one of [1] to [5], further containing at least one member selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol, salts thereof, and solvates thereof. Composition.

[8] A pharmaceutical preparation, wherein the aqueous composition according to any one of [1] to [7] is contained in a polyolefin resin container.
[9] The pharmaceutical preparation according to [8], wherein the polyolefin resin is polyethylene or polypropylene.
[10] The pharmaceutical preparation according to [8] or [9], wherein the polyolefin-based resin container is a container for eye drops.

[11] A method for suppressing discoloration of an aqueous composition, which comprises the step of incorporating trometamol in the aqueous composition containing the compound represented by the general formula (1), a salt thereof, or a solvate thereof.
[12] The method according to [11], wherein the compound represented by the general formula (1) is Ripasudil.
[13] The method according to [11] or [12], wherein the aqueous composition is an ophthalmic agent.
[14] The method according to [13], wherein the ophthalmic agent is an eye drop.
[15] The method according to any one of [11] to [14], wherein the aqueous composition is a preventive and/or therapeutic agent for a disease selected from the group consisting of ocular hypertension, glaucoma and fundus disease.

[16] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, a carbonic anhydrase inhibitor, a prostaglandin, a sympathomimetic, a parasympathomimetic, a calcium antagonist. And the method according to any one of [11] to [15], which comprises one or more selected from the group consisting of: and a cholinesterase inhibitor.
[17] In [11] to [15], the aqueous composition further contains one or more kinds selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol and salts thereof and solvates thereof. Either method.

[18] The method according to any one of [11] to [17], further including a step of accommodating the aqueous composition in a polyolefin resin container.
[19] The method according to [18], wherein the polyolefin resin is polyethylene or polypropylene.
[20] The method according to [18] or [19], wherein the polyolefin-based resin container is a container for eye drops.

The aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof and trometamol also has an excellent antiseptic effect. The aqueous composition, which contains water as a solvent, has the advantage of being less irritating to living organisms, but has the problem of being easily contaminated by microorganisms. However, as shown in Test Examples 2 and 3 below, it was revealed that the combination of the compound represented by the general formula (1) or a salt thereof or a solvate thereof and trometamol exhibited an excellent antiseptic effect. .. The antiseptic effect of the compound represented by the general formula (1), a salt thereof, or a solvate thereof has not been known so far.
Therefore, the aqueous composition containing the compound represented by the general formula (1) or a salt thereof or a solvate thereof, and trometamol is suppressed in discoloration during storage at high temperature and has an excellent antiseptic effect. Therefore, it has an advantage of excellent storage stability.

The present application also relates to the following antiseptic effect imparting method.
[21] A method for imparting an antiseptic effect to an aqueous composition, which comprises a step of incorporating a compound represented by the general formula (1) or a salt thereof or a solvate thereof and trometamol into the aqueous composition.
[22] The method according to [21], wherein the compound represented by the general formula (1) is Ripasudil.
[23] The method according to [21] or [22], wherein the aqueous composition is an eye drop or an eye ointment.

[24] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, a carbonic anhydrase inhibitor, a prostaglandin, a sympathomimetic, a parasympathomimetic, a calcium antagonist. And a method according to any one of [21] to [23], which comprises one or more selected from the group consisting of: and a cholinesterase inhibitor.
[25] The aqueous composition further contains one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol and salts thereof, and solvates thereof, [21] to [23] Either method.

Here, the "preservative effect imparting method" means a method of imparting an antiseptic effect to the aqueous composition. In the method for imparting antiseptic effect, the antiseptic effect is compared with the case where the antiseptic power to be evaluated is the compound represented by the general formula (1) or a salt thereof, or a solvate thereof and both components of trometamol. If it is excellent, it is judged that there is an effect, and the degree of the effect does not matter.
Specifically, for example, according to the 16th revised Japanese Pharmacopoeia reference information "preservation efficacy test method", bacteria (for example, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli) or In the case of using a fungus (for example, Candida albicans), a compound represented by the general formula (1) or a salt thereof, or a solvate thereof and trometamol are not mixed together (a control (preservative effect is It is judged that there is an antiseptic effect if it can be confirmed that the number of viable bacteria is small in any one or more microbial species at any given number of days compared to purified water that is known not to exist.) In this case, it is confirmed that the preservative effect is given to the aqueous composition. The meaning of the wording in the preservative effect imparting method, the blending amounts of various components, and the like will be described in detail below, "a compound represented by the general formula (1) or a salt thereof or a solvate thereof, and trometamol. The meaning is the same as that of the wording in the invention of the embodiment relating to the “containing aqueous composition”, the content of each component, and the like.

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, and particularly preferably a fluorine atom.
Further, 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 any stereoisomer is included in the compound represented by the general formula (1), and it may be a single stereoisomer or a mixture of various stereoisomers at an arbitrary ratio. .. The compound represented by the general formula (1) is preferably a compound whose absolute configuration is S configuration.

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, Inorganic acid salts such as hydrobromide; acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate Examples thereof include organic acid salts such as toluene sulfonate, naphthalene sulfonate, camphor sulfonate, and the like, and hydrochloride is preferable.
Furthermore, the compound represented by the general formula (1) or a salt thereof may be a solvate such as a hydrate or an alcoholate, and is preferably a hydrate.

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

Particularly preferred is Ripasudil hydrochloride hydrate represented by (Lipasudil monohydrochloride dihydrate).

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 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 WO 2006/115244 pamphlet. It can be produced by the described method.

The content of the compound represented by the general formula (1) or a salt thereof or a solvate thereof in the aqueous composition is not particularly limited, and may be appropriately examined depending on the disease to be applied, sex of the patient, age, symptoms, and the like. From the viewpoint of obtaining an excellent pharmacological action and/or the viewpoint of obtaining an excellent antiseptic effect, a free form of the compound represented by the general formula (1) is added to the total volume of the aqueous composition. The content is preferably 0.01 to 10 w/v% in terms of conversion, more preferably 0.02 to 8 w/v%, and particularly preferably 0.04 to 6 w/v%. Among them, when Ripasudil is used as the compound represented by the general formula (1), Ripasudil or The salt or solvate thereof 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 0.15 to 2 w. /V% is particularly preferable.

In the present specification, “trometamol” is not particularly limited, and trometamol listed in Japanese Pharmacopoeia Standard 2002, Tromethamine listed in US Pharmacopoeia, and the like may be used.
Trometamol is known, and may be produced by a known method, or a commercially available product may be used. Examples of commercially available products include trometamol (Wako Pure Chemical Industries, Ltd.) and the like.

The content of trometamol in the aqueous composition is not particularly limited, but from the viewpoint of a discoloration suppressing effect and/or from the viewpoint of obtaining an excellent antiseptic effect, it is contained in an amount of 0.01 to 30 w/v% with respect to the total volume of the aqueous composition. It is preferable that the content is 0.05 to 25 w/v%, more preferably 0.1 to 20 w/v%.
Further, the content mass ratio of the compound represented by the general formula (1) or a salt thereof or a solvate thereof and trometamol in the aqueous composition is not particularly limited, but the viewpoint of the discoloration suppressing action and/or the excellent antiseptic property From the viewpoint of obtaining the effect, it is preferable that 0.01 to 75 parts by mass of trometamol be contained per 1 part by mass in terms of the free form of the compound represented by the general formula (1), and 0.05 to 65 parts by mass. More preferably, it is contained in an amount of 0.15 to 55 parts by mass. Among them, when the compound represented by the general formula (1) or a salt thereof or a solvate thereof is Ripasudil or a salt thereof or a solvate thereof, a viewpoint of a discoloration suppressing action and/or an excellent antiseptic effect From the viewpoint of obtaining the above, the amount of trometamol is preferably 0.1 to 70 parts by mass, more preferably 0.2 to 60 parts by mass, and more preferably 0. It is particularly preferable to contain 3 to 50 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 semisolid (ointment), and liquid is preferable. .. As the water in the composition, for example, purified water, water for injection, sterilized purified water or the like can be used.
The content of water contained in the aqueous composition is not particularly limited, but is preferably 5 mass% or more, more preferably 20 mass% or more, further preferably 50 mass% or more, further preferably 90 mass% or more, 90- 99.8 mass% is especially preferable.

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 Formulation. The dosage form includes, for example, injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal drops, enema preparations, external solutions, sprays, ointments, gels, oral solutions, syrups, etc. Is mentioned. As a dosage form, an ophthalmic agent, specifically, an eye drop or an eye ointment is preferable, and an eye drop is particularly preferable, from the viewpoint of advantageously utilizing the pharmacological action of the compound represented by the general formula (1).

In addition to the above, the aqueous composition may contain additives used in pharmaceuticals, quasi drugs, and the like, depending on the dosage form. Examples of such additives include inorganic salts, isotonic agents, chelating agents, stabilizers, pH adjusting agents, preservatives, antioxidants, thickening agents, surfactants, solubilizing agents, suspending agents. Examples include turbidity agents, 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 hydrogen sulfite, 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 solution, carboxyvinyl polymer, dried sodium sulfite, dried 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, chlorobutanol, crystalline sodium dihydrogen phosphate. , Geraniol, sodium chondroitin sulfate, acetic acid, potassium acetate, sodium acetate hydrate, titanium oxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzododesinium bromide, tartaric acid, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol liquid, taurine, sodium hydrogen carbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyloxapol, sodium dehydroacetate, concentrated glycerin, concentrated mixed tocopherols, white petrolatum, peppermint water, peppermint oil, Concentrated benzalkonium chloride solution 50, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, sodium hyaluronate, human serum albumin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, glacial acetic acid, pyro Sodium sulfite, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalkonium chloride, benzalkonium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, borax, boric acid, povidone, polyoxy Ethylene (200) polyoxypropylene glycol (70), sodium polystyrene sulfonate, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl alcohol (partially saponified product), d-borneol, Macrogol 4000, Macrogol 6000, D -Mannitol, anhydrous citric acid, anhydrous phosphoric acid Sodium hydrogen, anhydrous sodium dihydrogen phosphate, methanesulfonic acid, methyl cellulose, l-menthol, monoethanolamine, aluminum monostearate, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin , Agate, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, malic acid, vaseline and the like.

Examples of the additive include potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate. , Concentrated glycerin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, borax, boric acid, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified product), macrogol 4000, macro Goal 6000, 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 hyaluronate, glucose, 1-menthol and the like are preferable.

In addition to the above, the aqueous composition may further contain other medicinal components depending on the disease to be applied and the like. Such medicinal components include, for example, α1 receptor blockers containing bunazosin or a salt thereof such as bunazosin hydrochloride or a solvate thereof; brimonidine such as brimonidine tartrate or a salt thereof or a solvate thereof, or an apra Α2 receptor agonists containing clonidine 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 or a solvate thereof, timolol maleic acid Timolol such as salt or salt thereof or solvate thereof, betaxolol such as betaxolol hydrochloride or salt thereof or solvate thereof, levobunolol such as levobunolol hydrochloride or salt thereof or solvate thereof, befnolol or salt thereof. Or a solvate thereof, a β-blocker containing metipranolol or a salt thereof or a solvate thereof; dorzolamide such as dorzolamide hydrochloride or a salt thereof, a solvate thereof, brinzolamide or a salt thereof, or a solvate thereof. , Acetazolamide or a salt thereof or a solvate thereof, dichlorphenamide or a salt thereof or a solvate thereof, metazolamide or a salt thereof, or a carbonic anhydrase inhibitor containing a solvate thereof; isopropyl unoprostone or Salts or solvates thereof, tafluprost or salts thereof or solvates thereof, travoprost or salts thereof or solvates thereof, bimatoprost or salts thereof or solvates thereof, latanoprost or salts thereof or their Prostaglandins including solvates; dipivefrin or salts thereof such as dipivefrin hydrochloride or solvates thereof, epinephrine such as epinephrine, epinephrine borate, epinephrine hydrochloride or salts thereof, or them. Sympathomimetics including solvates; distigmine bromide or salts thereof or solvates thereof, pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate or other salts thereof or solvates thereof, carbachol or salts thereof or Parasympathomimetics containing solvates of; Calcium antagonists containing lomerizine or salts thereof such as lomerizine hydrochloride or solvates thereof; deme potassium or salts thereof or solvates thereof, ecothiophate or salts thereof; Including those solvates, physostigmine or salts thereof, or solvates thereof. Examples thereof include cholinesterase inhibitors, and one or more of these can be blended.
As other medicinal components, one or more selected from the group consisting of latanoprost, nipradilol, dorzolamide, brinzolamide, timolol, salts thereof, and solvates thereof are preferable.

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

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

The form of the container is not particularly limited as long as it can contain the aqueous composition, and may be appropriately selected and set according to the dosage form and the like. Specific examples of the form of such a container include a container for injections, a container for inhalants, a container for sprays, a bottle-shaped container, a tube-shaped container, a container for eye drops, a container for nasal drops, and a dot. Examples include ear drug containers and bag containers. Further, these containers may be further packaged in boxes, bags, or the like.

The material of the container (material) is not particularly limited and may be appropriately selected depending on the form of the 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 for the plastic container is preferably a thermoplastic resin, for example, polyolefin resin such as low density polyethylene (including linear low density polyethylene), high density polyethylene, medium density polyethylene, polypropylene and cyclic polyolefin. Polyester resin such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, poly(1,4-cyclohexylene dimethylene terephthalate); polyphenylene ether resin; polycarbonate resin; polysulfone resin; polyamide Examples of the resin include a polyvinyl chloride resin and a styrene resin, and a mixture of these (polymer alloy) may be used.
The material of the container is not particularly limited, but from the viewpoint of the discoloration suppressing action, a polyolefin resin is preferable, and polypropylene is particularly preferable. As in the test example described later, in the case where the container is a polyolefin resin container, discoloration is significantly suppressed.

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

It is preferable to further knead into the polyolefin resin container a substance such as an ultraviolet absorber or an ultraviolet scatterer which hinders the transmission of ultraviolet rays. This improves the stability of the compound represented by the general formula (1) against light. Specific examples of such a substance include titanium oxide; zinc oxide and the like as an ultraviolet scattering agent. Moreover, as an ultraviolet absorber, 2-(2H-benzotriazol-2-yl)-p-cresol (for example, Tinuvin P: BASF), 2-(2H-benzotriazol-2-yl)-4,6 -Bis(1-methyl-1-phenylethyl)phenol (for example, Tinuvin 234: BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)benzotriazole (for example, Tinuvin320: BASF) ), 2-[5-chloro(2H)-benzotriazol-2-yl]-4-methyl-6-(tert-butyl)phenol (for example, Tinuvin 326: BASF), 2-(3,5-di). -T-butyl-2-hydroxyphenyl)-5-chlorobenzotriazole (for example, Tinuvin327: BASF), 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (for example, , Tinuvin PA328: BASF), 2-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol (for example, Tinuvin 329: BASF), 2,2 '-Methyllenbis[6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol (for example, Tinuvin 360: BASF), methyl 3-(3-( Reaction product of 2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionate and polyethylene glycol 300 (for example, Tinuvin 213: BASF), 2-(2H-benzotriazole-2-). Yl)-6-dodecyl-4-methylphenol (for example, Tinuvin 571: BASF), 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole, 2-[2'. -Hydroxy-3'-(3",4",5",6"-tetrahydrophthalimidomethyl)-5'-methylphenyl]benzotriazole, 2,2'-methylenebis[4-(1,1 ,3,3-Tetramethylbutyl)-6-(2H-benzotriazol-2-yl)phenol] and other benzotriazole-based UV absorbers; 2,2-bis{[2-cyano-3,3-diphenylacryloyl] Oxy]methyl}propane-1,3-diyl=bis(2-cyano-3,3-diphenylacrylate) (for example, Uvinul 3030 FF: BASF), ethyl 2-cyano-3,3-diphenylacrylate (for example, Uvinul 3035: BASF), 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (for example, Uvinul). 3039: cyanoacrylate UV absorbers such as BASF); 2-(4,6-diphenyl-1,3,5-triazin-2-yl)-5-[(hexyl)oxy]-phenol (for example, Tinuvin 1577 ED: BASF) and other triazine-based UV absorbers; octabenzone (for example, Chimassorb 81: BASF), 2,2′-dihydroxy-4,4′-dimethoxybenphenone (for example, Uvinul 3049: BASF), 2,2'-4,4'-tetrahydrobenphenone (for example, Uvinul 3050: BASF), oxybenzone, hydroxymethoxybenzophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonate, dihydroxydimethoxybenzophenone, sodium dihydroxydimethoxybenzophenone disulfonate, dihydroxy Benzophenone-based UV absorbers such as benzophenone and tetrahydroxybenzophenone; methyl diisopropylcinnamate, cinoxate, glyceryl mono-2-ethylhexanoate diparamethoxycinnamate, isopropylparamethoxycinnamate/diisopropylcinnamate mixture, 2-Ethylhexyl paramethoxycinnamate, benzyl cinnamate, and other cinnamic acid UV absorbers; paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, paradimethylaminobenzoic acid 2 Benzoic acid ester-based UV absorbers such as ethylhexyl, ethyl 4-[N,N-di(2-hydroxypropyl)amino]benzoate; ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, Salicylic acid-based UV absorbers such as methyl salicylate; guaiazulene; 2-ethylhexyl dimethoxybenzylidene dioxoimidazolidine propionate; 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,5-triazine Parahydroxyanisole; 4-tert-butyl-4'-methoxydibenzoylmethane; Examples include benzimidazole sulfonic acid; hexyl 2-(4-diethylamino-2-hydroxybenzoyl)-benzoate and the like.

In the case of kneading a substance that blocks the transmission of ultraviolet rays into a container, the mixing ratio varies depending on the type of the substance and the like, but for example, 0.001 to 50% by mass, preferably 0.002 to 25% in the container. The content may be about 0.01% by mass, particularly preferably about 0.01 to 10% by mass.

The inside of the container is preferably visible (observable) with the naked eye. If the inside is visible, there will be advantages such as the possibility of inspecting foreign substances in the manufacturing process of the pharmaceutical preparation and the user of the pharmaceutical preparation being able to check the remaining amount of the content (aqueous composition). .. Here, the visibility may be ensured at least in a part of the container surface (for example, even if the side surface of the eye drop container cannot be seen through due to a shrink film or the like, the bottom surface is visible if visible). It can be said that). If the inside is visible on a part of the container surface, this makes it possible to confirm the aqueous composition in the container.

The means for accommodating the aqueous composition in the container is not particularly limited, and it may be filled in a conventional manner according to the form of the container and the like.

The disease to which the aqueous composition or the pharmaceutical preparation is applied is not particularly limited and may be appropriately selected depending on the pharmacological action and the like of the compound represented by the general formula (1).
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 the glaucoma, more specifically, for example, primary open-angle glaucoma, normal tension glaucoma, aqueous humor overproduction glaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma , Steroid glaucoma, capsular glaucoma of the lens, pigmented glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma and the like.

Further, as disclosed in Japanese Patent No. 5557408, fundus disease (lesion mainly expressed in retina and/or choroid. Specifically, for example, fundus change 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, Congenital abnormalities of retinal blood vessels such as Coats disease, von Hippel disease, pulseless disease, macular disease (central serous chorioretinopathy), cystoid macular edema (cystoid macular edema), age-related macular degeneration, macular hole, myopic macular degeneration, retinal vitreous macular degeneration, drug-induced macular degeneration, inherited macular degeneration Degeneration, etc.), retinal detachment (eg, rhegmatogenous, traction, exudative), retinitis pigmentosa, retinopathy of prematurity, etc.), and more preferably, diabetic retinopathy, diabetes It can be used as a preventive or therapeutic agent for macular edema or age-related macular degeneration.

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

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

[Test Example 1] Storage test Aqueous compositions of Example 1, Example 2 and Comparative Example 1 containing the components and amounts shown in Table 1 per 100 mL were prepared by a conventional method and then housed in a polypropylene container.
Each of the obtained aqueous compositions was stored at 80° C. for 1 week. To measure the degree of discoloration (yellowing) before and after storage, measure the color difference (ΔYI) of the aqueous composition before and after storage using a color difference meter (Spectrocolorimeter CM-700d: Konica Minolta Sensing Co., Ltd.). It was evaluated by.
The results are shown in Table 1.

As shown in the results shown in Table 1, when the aqueous composition containing Ripasudil further contained trometamol, the value of ΔYI was lower than that in the case where trometamol was not contained, and the discoloration after storage at high temperature was suppressed. Became clear. Further, it was revealed that the value of ΔYI becomes a low value in proportion to the increase in the content of trometamol.

From the above test results, when an aqueous composition containing a compound represented by the general formula (1) represented by Ripasudil or a salt thereof or a solvate thereof further contains trometamol, when stored at high temperature However, it was revealed that discoloration (yellowing) was relatively unlikely to occur and the storage stability was excellent.

[Test Example 2] Confirmation of antiseptic effect by the combination of Ripasudil and trometamol In order to confirm the presence or absence of an antiseptic effect associated with the combination of Ripasudil and trometamol, the following test was performed using Candida albicans as a microorganism. ..
That is, Candida albicans was seeded on a Sabouraud-glucose agar medium and cultured at 20 to 25°C for 40 to 48 hours. Then, the cultured bacterial cells were suspended in a peptone salt buffer solution and adjusted so that the bacterial cells were about 10 ⁷ to 10 ⁸ cells per mL to obtain a test bacterial suspension.
After inoculating the test bacterial suspension to various formulation samples prepared by the following method, the suspension was filled in a container and stored at 20 to 25°C under light-shielding conditions for 14 days.
After storage, various formulation samples were serially diluted 10-fold to prepare a dilution series, and cultured at 20 to 25°C for 5 to 7 days according to the agar plate pour method.
After culturing, the number of viable bacteria in 1 mL of each preparation sample was calculated from the number of formed colonies and the dilution factor.
From the obtained viable cell count and inoculated cell count (converted from the viable cell count in the test bacterial suspension at the time of inoculation into the viable cell count in 1 mL of the sample), the viable cell survival rate (% ) Was calculated.

[Equation 1]
Viable cell survival rate (%) = Number of viable cells per 1 mL of various preparation samples after storage for 14 days / Number of inoculated cells x 100

As the formulation samples, three types were used: a formulation sample containing Ripasudil alone, a formulation sample containing Trometamol alone, and a formulation sample containing Ripasudil and trometamol.

<Formulation Sample Containing Ripasudil Alone (Indicated in the Table as “Lipasudil Only”)>
0.4896 g of Ripasudil monohydrochloride dihydrate (0.4 g as a free form of Ripasudil), 0.4 g of anhydrous sodium dihydrogen phosphate, 2.136 g of glycerin, and appropriate amount of sodium hydroxide (pH 6.0) per 100 mL. And an aqueous composition containing sterilized purified water (remainder) were prepared and sterilized with a filter to obtain a preparation sample.

<Preparation sample containing trometamol alone (in the table, referred to as “trometamol only”)>
An aqueous composition containing 1.5 g of trometamol, 0.4 g of anhydrous sodium dihydrogen phosphate, 2.136 g of glycerin, an appropriate amount of sodium hydroxide (pH 6.0) and sterilized purified water (remainder) per 100 mL was prepared and filtered. It was sterilized to obtain a formulation sample.

<Formulation sample containing ripasudil and trometamol (referred to as "ripasudil + trometamol" in the table)>
0.4896 g of Ripasudil monohydrochloride dihydrate (0.4 g as a free form of Ripasudil), 1.5 g of trometamol, 0.4 g of anhydrous sodium dihydrogen phosphate, 2.136 g of glycerin, and appropriate amount of sodium hydroxide per 100 mL ( An aqueous composition containing pH 6.0) and sterilized purified water (remainder) was prepared and sterilized with a filter to obtain a preparation sample.

The results are shown in Table 2.

From the results shown in Table 2, it was confirmed that Ripasudil alone reduced the viable cell count after 14 days of storage, and the antiseptic effect was confirmed to some extent, but it was not sufficient. In addition, trometamol alone showed an increase in viable cell count after storage for 14 days, and no preservative effect was confirmed.
On the other hand, the combination of Ripasudil and trometamol showed a significant decrease in the viable cell count after storage for 14 days, confirming that it has an excellent antiseptic effect.

[Test Example 3] Confirmation of antiseptic effect by combination of Ripasudil and trometamol Part 2
In order to confirm in more detail whether or not the combination of Ripasudil and trometamol has an antiseptic effect on microorganisms (bacteria and fungi), as bacteria, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli ) Was used as a fungus and Candida albicans was used for the following test.

<Confirmation of growth inhibitory activity against bacteria>
Pseudomonas aeruginosa, Staphylococcus aureus, or Escherichia coli was inoculated on a soybean casein digest agar medium and cultured at 30 to 35°C for 18 to 24 hours. Then, the cultured bacterial cells were suspended in a peptone salt buffer and adjusted to about 10 ⁷ to 10 ⁸ bacterial cells per 1 mL to obtain a test bacterial suspension.
A test sample suspension was inoculated into a formulation sample prepared by the following method, filled in a container, and stored at 20 to 25°C under light-shielding conditions for 14 days and 28 days.
After storage, prepare a dilution series by serially diluting the formulation sample 10-fold, and pour it into the lecithin polysorbate 80-added soybean casein digest agar medium according to the agar plate pour method, and then at 30-35°C for 5-7 days. Cultured.
After culturing, the number of viable bacteria in 1 mL of each preparation sample was calculated from the number of formed colonies and the dilution factor.

<Confirmation of growth inhibitory activity against Candida>
The test was carried out in the same manner as in Test Example 2 except that the storage days were 14 days and 28 days.

As the formulation sample, the formulation having the following composition was used.
<Formulation sample containing Ripasudil and trometamol>
0.4896 g of Ripasudil monohydrochloride dihydrate (0.4 g as a free form of Ripasudil), 5 g of trometamol, 0.4 g of anhydrous sodium dihydrogen phosphate, 2.136 g of glycerin, and appropriate amount of sodium hydroxide (pH 6) per 100 mL. 0.0) and sterile purified water (residual) were prepared and sterilized with a filter to obtain a preparation sample.

The results are shown in Table 3. The number of inoculated bacteria was converted from the number of viable bacteria in the suspension of test bacteria at the time of inoculation into the number of viable bacteria in 1 mL of the sample.

From the results shown in Table 3, it was revealed that the combination of Ripasudil and trometamol has an excellent antiseptic effect against bacteria and fungi.

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

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

[Production Examples 55 to 108]
By accommodating the aqueous compositions of Production Examples 1 to 54 in polypropylene eye drop containers, the pharmaceutical compositions of Production Examples 55 to 108 can be produced by a conventional method.

[Production Examples 109 to 162]
By accommodating the aqueous compositions of Production Examples 1 to 54 in polyethylene eye drop containers, the pharmaceutical formulations of Production Examples 109 to 162 can be produced by a conventional method.

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

Claims (4)

An aqueous composition containing Ripasudil or a salt thereof or a solvate thereof, and trometamol. The aqueous composition according to claim 1, wherein the content of trometamol is 0.01 to 30 w/v% with respect to the total volume of the aqueous composition. The aqueous composition according to claim 1 or 2, which contains 0.1 to 70 parts by mass of trometamol with respect to 1 part by mass of Ripasudil or a salt thereof or a solvate thereof as a free form of Ripasudil. .. A pharmaceutical preparation comprising the aqueous composition according to any one of claims 1 to 3 housed in a polyolefin resin container.