Pharmaceuticals #7

Abstract

Suppresses discoloration of halogenated isoquinoline derivative-containing aqueous compositions during high-temperature storage. To provide technology. [Solution] The following general formula (1) TIFF2026116450000013.tif45170 [In the formula, X represents a halogen atom.] An aqueous composition containing a compound represented by or a salt thereof, or a solvate thereof, is polio A pharmaceutical preparation housed in a container made of refin resin.

Description

Technical Field

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[0001] The present invention relates to pharmaceutical preparations and the like.

Background Art

[0002] The following structural formula:

[0003]

Chem.

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

[0005]

Chem.

[0006] represents 4-bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl sulfonyl]isoquinoline and other halogenated isoquinoline derivatives have pharmacological actions such as Rho kinase inhibitory effects (for example, Patent Documents 1 and 2), and are known to be useful for the prevention and treatment of eye diseases Specifically, for example, the prevention or treatment of glaucoma and other ocular hypertension (for example , Patent Document 3), or the prevention or treatment of fundus diseases such as age-related macular degeneration (for example, Patent Document 4) has been reported to be useful.

[0007] Therefore, establishing a technique for formulating these halogenated isoquinoline derivatives stably as, for example, ophthalmic agents and the like is extremely useful.

Prior Art Documents

Patent Documents

[0008] ​ [Patent Document 1] Patent No. 4212149 [Patent Document 2] International Publication No. 2006 / 115244 Pamphlet [Patent Document 3] International Publication No. 2006 / 068208 Brochure [Patent Document 4] Patent No. 5557408 [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] Ophthalmic preparations and the like are usually compositions containing water (aqueous compositions), and the contents may dissipate or be exposed to the outside air. To prevent contamination by impurities, etc., it is necessary to contain it in a container. Therefore, the inventors of this invention When formulating lipasudil, a halogenated isoquinoline derivative, as an ophthalmic agent, etc. The material of the container for containing the aqueous composition was examined. However, the material of a particular container When an aqueous composition containing lipasudil is contained in it, the aqueous composition will deteriorate due to long-term storage at high temperatures. It was discovered that this could cause discoloration of the material. Therefore, the present invention relates to the changes in an aqueous composition containing a halogenated isoquinoline derivative during high-temperature storage. The objective is to provide a technology for suppressing color. [Means for solving the problem]

[0010] Therefore, the inventors diligently investigated the matter in order to solve the above problem and found that halo such as lipasudil When housing an aqueous composition containing a genated isoquinoline derivative in a container, the material of the container is When made from polyolefin resin, discoloration can be specifically suppressed even after long-term storage at high temperatures. We discovered this and completed the present invention.

[0011] That is, the present invention provides a pharmaceutical preparation comprising an aqueous composition containing a compound represented by the following general formula (1), a salt thereof, or a solvate thereof, which is contained in a container made of a polyolefin resin.

[0012]

Chemical formula

[0013] [In the formula, X represents a halogen atom.] An aqueous composition containing a compound represented by or a salt thereof or a solvate thereof is provided as a pharmaceutical preparation, which is contained in a container made of a polyolefin resin. The present invention also provides a method for suppressing discoloration of an aqueous composition, which comprises a step of containing an aqueous composition containing a compound represented by the general formula (1), a salt thereof, or a solvate thereof in a container made of a polyolefin resin.

Advantages of the Invention

[0014] According to the present invention, discoloration of an aqueous composition containing a halogenated isoquinoline derivative such as repasodil during high-temperature storage can be suppressed.

Modes for Carrying Out the Invention

[0015] This specification discloses inventions in the following aspects, although not limited thereto. [1] A pharmaceutical preparation comprising an aqueous composition containing a compound represented by the following general formula (1), a salt thereof, or a solvate thereof, which is contained in a container made of a polyolefin resin.

[0016]

Chemical formula

[0017] [In the formula, X represents a halogen atom.] An aqueous composition containing a compound represented by or a salt thereof or a solvate thereof is provided as a pharmaceutical preparation, which is contained in a container made of a polyolefin resin. [2] The pharmaceutical preparation according to [1], wherein the compound represented by the general formula (1) is repasodil. . [3] The polyolefin resin is polyethylene or polypropylene, [1] or [2] is a pharmaceutical preparation. [4] The polyolefin resin container is a container for eye drops, one of [1] to [3] Any of the listed pharmaceutical preparations. [5] Contains the compound represented by the general formula (1) above, a salt thereof, or a solvate thereof. Discoloration of the aqueous composition, including the step of housing the aqueous composition in a polyolefin resin container. Methods for suppressing it. [6] The method according to [5], wherein the compound represented by the general formula (1) is lipasudil. [7] The polyolefin resin is polyethylene or polypropylene, [5] or The method described in [6]. [8] The polyolefin resin container is a container for eye drops, one of [5] to [7] Please describe the method.

[0018] [9] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, and a carbonate Dehydration enzyme inhibitors, prostaglandin F2α derivatives, sympathetic agonists, parasympathetic agonists It contains one or more selected from the group consisting of calcium channel blockers and cholinesterase inhibitors. A pharmaceutical preparation having any of the following characteristics: [1] to [4].

[10] The aqueous composition further contains latanoprost, nipradilol, dorzolamide, b Contains one or more selected from the group consisting of linzolamide, timolol, and salts thereof. A pharmaceutical preparation described in any of [1] to [4].

[11] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, and a carbon Acid anhydrase inhibitors, prostaglandin F2α derivatives, sympathetic agonists, parasympathetic agonists One or more drugs selected from the group consisting of drugs, calcium channel blockers, and cholinesterase inhibitors. The method described in any of [5] to [8], which includes the inclusion of the substance.

[12] The aqueous composition further contains latanoprost, nipradilol, dorzolamide, b Contains one or more selected from the group consisting of linzolamide, timolol, and salts thereof. The method described in any of [5] to [8].

[0019] In the general formula (1) above, the halogen atoms are fluorine, chlorine, and bromine atoms. Examples include the following. In the above general formula (1), the halogen atoms are fluorine and bromine. Atoms are preferred, and fluorine atoms are particularly preferred. Furthermore, in the general formula (1) above, the carbon constituting the homopiperazine ring substituted with a methyl group The primary atom is a chiral carbon. Therefore, stereoisomerism occurs, but the compound is represented by general formula (1). A substance can contain any stereoisomer, or it may have only one stereoisomer, or it may have various stereoisomers. A mixture of any proportion is also acceptable. The compound represented by the general formula (1) is one in which the absolute configuration is S A compound with a specific configuration is preferred.

[0020] The salt of the compound represented by the general formula (1) is not limited to any pharmaceutically acceptable salt. It is not specified, and specifically, for example, hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide Inorganic salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, etc. Hacitate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluene Examples include organic salts such as sulfonates, naphthalene sulfonates, and camphor sulfonates. Hydrochloride salts are preferred. Furthermore, the compound represented by the general formula (1) or its salt is a hydrate or an alcoholic, etc. It may be a solvate, but a hydrate is preferred.

[0021] The compound represented by the general formula (1) above, or a salt thereof, or a solvate thereof, is: Physically, for example, Lipasdil (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepa [I-1-yl]sulfonyl]isoquinoline) or its salts or solvates thereof; 4-Bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl Isoquinoline or its salts or solvates thereof; These are some examples.

[0022] The compounds represented by the general formula (1) above, their salts, or their solvates include: Pasudil or its salts or their solvates, 4-bromo-5-[[(2S)-2-methyl [Tyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline or its salt or These solvates are preferred, and lipasudil or its salts or their solvates are more preferred. Furthermore, lipasudil or its hydrochloride or hydrate thereof is more preferable, and the following structure formula:

[0023] [ka]

[0024] Lipasdil hydrochloride hydrate (lipasdil 1-hydrochloride dihydrate) represented by [formula] is particularly preferred.

[0025] Compounds represented by the general formula (1) above, salts thereof, or solvates thereof are known. It can be manufactured by known methods. Specifically, for example, lipasudil or its salts or the These solvates are described in International Publication No. 1999 / 020620, International Publication No. 200 It can be manufactured using the methods described in the 6 / 057397 pamphlet. Also, 4- Bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl] Soquinoline or its salts or solvates thereof, International Publication No. 2006 / 115244 It can be manufactured using the methods described in the pamphlet.

[0026] Compounds represented by the general formula (1) or salts thereof in aqueous compositions or solvations thereof The amount of substance contained is not particularly limited and should be considered as appropriate depending on the applicable disease, the patient's gender, age, symptoms, etc. It is fine to decide by doing so, but from the viewpoint of obtaining excellent pharmacological effects, the amount of the aqueous composition relative to the total volume is generally It is preferable to contain 0.01 to 10 w / v% of the compound represented by formula (1) in terms of its free form. It is preferable to contain 0.02-8 w / v%, and more preferably 0.04-6 w / v%. It is particularly preferable to use lipasudil as the compound represented by general formula (1). In some cases, from the viewpoint of obtaining excellent pharmacological effects, lipasdi is added to the total volume of the aqueous composition. Contains 0.05-5 w / v% of the free form of 170 It is preferable to have it, more preferably to contain 0.1-3 w / v%, and 0.1-2 w / v It is particularly preferable to contain %.

[0027] In this specification, “aqueous composition” means a composition containing at least water, and The properties include liquid (solution or suspension) and semi-solid (ointment). For the water inside, for example, purified water, water for injection, or sterile purified water can be used. The water content in the aqueous composition is not particularly limited, but is preferably 5% by mass or more. 0% by mass or more is more preferable, 50% by mass or more is even more preferable, and 90% by mass or more is even more preferable. More preferably, and particularly preferably 90 to 99.8% by mass.

[0028] Aqueous compositions are prepared, for example, according to known methods described in the General Provisions for Preparations of the Sixteenth Edition of the Japanese Pharmacopoeia, etc. It can be made into various dosage forms. These dosage forms are those that can be contained in the containers described later. There are no particular limitations as long as it is used, but for example, injectable preparations, inhaled solutions, eye drops, eye ointments, ear drops, ointments, etc. Examples include nasal solutions, enemas, topical solutions, sprays, ointments, gels, oral solutions, and syrups. It can be used. In terms of dosage form, it is advantageous to utilize the pharmacological effects of the compound represented by general formula (1). From this perspective, eye disease agents, specifically eye drops and eye ointments, are preferred, and eye drops are particularly preferred. It's nice.

[0029] In addition to those mentioned above, aqueous compositions may be used as additives in pharmaceuticals, quasi-drugs, etc., depending on the dosage form. It may contain additives. Examples of such additives include inorganic salts, isotonic agents, and ki Raters, stabilizers, pH adjusters, preservatives, antioxidants, viscosity enhancers, surfactants, solubilizers Examples include suspending agents, cooling agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, etc. It can be done. Examples of such additives include, for instance, ascorbic acid and potassium aspartate. Sodium bisulfite, alginic acid, sodium benzoate, benzyl benzoate, ip Silon-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, Ruboxyvinyl polymer, anhydrous sodium sulfite, anhydrous sodium carbonate, d-camphor, dl-camphor, xylitol, citric acid hydrate, sodium citrate hydrate, glycerin Gluconic acid, L-glutamic acid, L-sodium glutamate, creatinine, chloroglycerides Guhexidine gluconate solution, chlorobutanol, sodium dihydrogen crystalline phosphate, gerani All, chondroitin sulfate sodium, acetic acid, potassium acetate, sodium acetate hydrate, Titanium dioxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzoyl bromide Decinium tartaric acid, sodium hydroxide, polyoxyl 45 stearate, purified lanolin D-sorbitol, sorbitol solution, sorbic acid, potassium sorbate, taurine, charcoal Sodium hydrogen oxyphosphate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, Tyroxapol, sodium dehydroacetate, trometamol, concentrated glycerin, concentrated mixed Copherol, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride solution 50, Ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, Methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin, hydroxyethyl Hypodium cellulose, hydroxypropylcellulose, hypromellose, glacial acetic acid, pyrosulfite Sodium, phenylethyl alcohol, glucose, propylene glycol, bergamot Oil, benzalkonium chloride, benzalkonium chloride solution, benzyl alcohol, benz Zethonium chloride, benzethonium chloride solution, borax, boric acid, povidone, polyoxyen Tylene (200) polyoxypropylene glycol (70), sodium polystyrene sulfonate Thorium, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl aluminum Kohl (partially hydrolyzed), d-borneol, macrogol 4000, macrogol 60 00, D-mannitol, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous dihydrate phosphate Sodium phosphate, methanesulfonic acid, methylcellulose, l-menthol, monoethanol Amine, aluminum monostearate, polyethylene glycol monostearate, yu Potassium oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, bonito flakes, Phosphate, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate Examples include sodium dihydrogen phosphate monohydrate, malic acid, and petrolatum.

[0030] Examples of additives include potassium chloride, calcium chloride hydrate, sodium chloride, and salt. Magnesium chloride, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, water Sodium oxide, sodium bicarbonate, sodium carbonate hydrate, concentrated glycerin, hydrochloride Cethylcellulose, hydroxypropylcellulose, hypromellose, borax, boric acid Povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, monostearate Polyethylene glycol, polyvinyl alcohol (partially saponified), macrogol 400 0, Macrogol 6000, Anhydrous Citric Acid, Anhydrous Sodium Monohydrogen Phosphate, Anhydrous Dihydrogen Phosphate Sodium hydrogen, methylcellulose, monoethanolamine, phosphoric acid, sodium hydrogen phosphate Potassium dihydrogen hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate Monohydrate, sodium hyaluronate, glucose, l-menthol, etc. are preferred.

[0031] The aqueous composition may also contain other active ingredients depending on the disease or other condition being treated, in addition to those mentioned above. It is acceptable to have it. Examples of such medicinal ingredients include bunazosin hydrochloride and other bunazosin compounds. α1 receptor blockers containing salts thereof or solvates thereof; brimonidine tartrate, etc. Any brimonidine or its salts or their solvates, apraclonidine or its α2 receptor agonists containing salts or solvates thereof; such as carteolol hydrochloride Roll or its salts or solvates thereof, nipradilol or its salts or the Solvates of timolol, timolol maleate, timolol or its salts, or their solvents Betaxol or its salts, such as betaxolol hydrochloride, or their solvates. levovunol or its salts, such as levovunol hydrochloride, or their solvates, Funolol or its salts or solvates thereof, methypranolol or its salts or Beta-blockers containing those solvates; dorzolamide hydrochloride or similar dorzolamide or its Salts or solvates thereof, brinzolamide or its salts or solvates thereof, aceta Zolamide or its salts or their solvates, dichlorphenamide or its salts or Carbonic anhydrase containing those solvates, metazolamide or its salts, or those solvates Isopropyl unoprostone or its salts or their solvates, taflup Rost or its salts or their solvates, travoprost or its salts or their solvates of bimatoprost or its salts or their solvates, latanoprost or or its salt or solvates, cloprostenol or its salt or its solvent Prostaglands containing fluprostenol, its salts, or their solvates Dipivefrin F2α derivatives; dipivefrin hydrochloride, or dipivefrin or its salts or their solutions Epinephrine, including antiparasitic agents, epinephrine, epinephrine borate, and epinephrine hydrochloride. Sympathomimetic agents containing the salt thereof or solvates thereof; distigmine bromide or These include salts thereof or their solvates, pilocarpine, pilocarpine hydrochloride, and pilocarpine nitrate. Pyrocarpine salts or their salts or solvates thereof, carbachol or similar Parasympathetic drugs containing salts or solvates thereof; lomerizine hydrochloride and other lomerizine-containing drugs Calcium channel blockers containing their salts or solvates; demepotassium or its Salts or solvates thereof, ecothiophates or salts thereof or solvates thereof, phi Cholinesterase inhibitors containing zostigmine or its salts or solvates thereof, etc. These include, and one or more of these can be combined. Other active ingredients include latanoprost, nipradilol, dorzolamide, and brinzola. Preferably, one or more selected from the group consisting of mido, timolol, and salts thereof.

[0032] The pH of the aqueous composition is not particularly limited, but is preferably 4 to 9, and more preferably 4.5 to 8. A value of 5 to 7 is particularly preferred. Furthermore, the osmotic pressure ratio to physiological saline is not particularly limited, A value of 0.6 to 3 is preferred, and a value of 0.6 to 2 is particularly preferred.

[0033] In this specification, "container" means a package that directly contains the aqueous composition. The container is a "sealed container," "airtight container," or "closed container" as defined in the General Rules of the Sixteenth Revised Japanese Pharmacopoeia. This concept encompasses all aspects of "sealed containers."

[0034] The form of the container is not particularly limited, as long as it is capable of containing the aqueous composition. The appropriate selection and setting should be made according to the dosage form, the intended use of the pharmaceutical preparation, etc. Specifically, examples include containers for injections, containers for inhalants, containers for sprays, and bottle-shaped containers. Examples include containers, tube-shaped containers, eye drop containers, nasal drop containers, ear drop containers, and bag containers. It can be done.

[0035] In this specification, "polyolefin resin container" means a container that has at least an aqueous component This refers to a container in which the part that comes into contact with the product is made of "polyolefin resin". Therefore, for example A polyolefin layer is provided in the inner layer that comes into contact with the aqueous composition, and a resin of another material is provided on the outside thereof. Containers made by laminating or other similar methods also fall under the category of "polyolefin resin containers." Here, polio The refin resin is not particularly limited and is a polymer (homopolymer) of a single monomer. It may also be a copolymer of multiple types of monomers. In such cases, the polymerization mode is not particularly limited, and can be random polymerization or block polymerization. Good. Furthermore, its three-dimensional regularity (tacticity) is not particularly limited. Examples of such polyolefin resins include, specifically, polyethylene (more details For example, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene Polyethylene (including medium-density polyethylene), polypropylene, cyclic polyolefin, poly(4-methyl) Tylpentene, polytetrafluoroethylene, ethylene-propylene copolymer, ethylene α-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid Examples include copolymers, ethylene-vinyl acetate copolymers, and ethylene-ethyl acrylate copolymers. These can be used in combination of one or more types. Polyolefin resins are also available. Therefore, from the standpoint of suppressing discoloration, polyethylene, polypropylene, and cyclic polyolefins are used. Polyethylene is preferred, polypropylene is more preferred, and polypropylene is particularly preferred. stomach. In this specification, "made of polyolefin resin" means at least a part of its material. This means that it contains polyolefin resin, for example, polyolefin resin and other A mixture of two or more resins (polymer alloy) with the resin is also classified as "made from polyolefin resin". It is included.

[0036] Polyolefin resin containers also contain UV absorbers and UV scatterers to counteract ultraviolet light. It is preferable to incorporate a substance that inhibits permeation. This prevents the compound represented by general formula (1) from permeating. The stability of these materials to light is improved. Specifically, such materials include, for example, ultraviolet radiation Examples of disruptors include titanium dioxide and zinc oxide. Also, examples of UV absorbers include 2 -(2H-benzotriazol-2-yl)-p-cresol (e.g., Tinuvin P:B ASF Corporation, 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl -1-phenylethyl)phenol (e.g., Tinuvin 234: BASF), 2-(3, 5-di-t-butyl-2-hydroxyphenyl)benzotriazole (e.g., Tinuvin3 20: BASF, 2-[5-chloro(2H)-benzotriazol-2-yl]-4- Methyl-6-(tert-butyl)phenol (e.g., 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 (e.g., Tinuvin PA328: BASF), 2- (2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl) )Phenol (e.g., Tinuvin 329: BASF), 2,2'-methyllenbis[6-( 2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl) Phenol (e.g., Tinuvin 360: BASF), methyl 3-(3-(2H-benzo Riazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionate The reaction product of polyethylene glycol 300 (e.g., Tinuvin 213: BASF), 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol For example, Tinuvin 571 (BASF), 2-(2'-hydroxy-3',5'-di-t-amine) (ruphenyl)benzotriazole, 2-[2'-hydroxy-3'-(3'',4'',5'', 6''-Tetrahydrophthalimidomethyl)-5'-methylphenyl]benzotriazole ,2,2'-methylenebis[4-(1,1,3,3-tetramethylbutyl)-6-(2H Benzotriazole-based UV absorbers such as [benzotriazole-2-yl)phenol] ;2,2-bis{[2-cyano-3,3-diphenylacryloyloxy]methyl}pro Pan-1,3-diyl=bis(2-cyano-3,3-diphenylacrylate) (for example) Uvinul 3030 FF (BASF), 2-cyano-3,3-diphenylacrylate ethyl ( For example, Uvinul 3035 (BASF), 2-cyano-3,3-diphenylacrylic acid 2- Cyanoacrylate-based ultraviolet light such as ethylhexyl (e.g., Uvinul 3039: BASF). Absorbent; 2-(4,6-diphenyl-1,3,5-triazine-2-yl)-5-[(he Triadioxyphenol (e.g., Tinuvin 1577 ED: BASF) UV absorbers; octabenzone (e.g., Chimassorb 81: BASF), 2,2'- Dihydroxy-4,4'-dimethoxybenzophenone (e.g., Uvinul 3049: BASF) ), 2,2'-4,4'-tetrahydrobenzophenone (e.g., Uvinul 3050:BASF Oxybenzone, hydroxymethoxybenzophenone sulfonic acid, hydroxymeth Sodium xybenzophenone sulfonate, dihydroxydimethoxybenzophenone, di Sodium hydroxydimethoxybenzophenone disulfonate, dihydroxybenzophen Benzophenone-based UV absorbers such as tetrahydroxybenzophenone; diisopropyl alcohol Methyl pyrucinate, cinoxate, mono-2-ethylhexane diparamethoxycinnamate Glyceryl acid, isopropyl paramethoxycinnamate / diisopropyl cinnamate ester blend Cinnamic acid-based UV filters such as compound, 2-ethylhexyl paramethoxycinnamate, and benzyl cinnamate. Radiation absorbent; para-aminobenzoic acid, ethyl para-aminobenzoate, glyceryl para-aminobenzoate Lyl, amyl p-dimethylaminobenzoate, 2-ethylhexyl p-dimethylaminobenzoate Benzoates such as ethyl 4-[N,N-di(2-hydroxypropyl)amino]benzoate Acid ester-based UV absorbers; ethylene glycol salicylate, octyl salicylate, salicylate Dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, salicy Salicylic acid-based UV absorbers such as methyl methylate; guaiazulene; dimethoxybenzylidene 2-ethylhexyl oxoimidazolidinepropionate; 2,4,6-tris[4-(2 -Ethylhexyloxycarbonyl)anilino]1,3,5-triazine;parahydrox Cyanisole; 4-tert-butyl-4'-methoxydibenzoylmethane; phenylbenzyl Imidazole sulfonic acid; 2-(4-diethylamino-2-hydroxybenzoyl)-benzoyl Examples include hexyl furoseate.

[0037] Furthermore, when incorporating a substance that inhibits the transmission of ultraviolet light into the container, the proportion of that substance should be... This varies depending on the type, but for example, the container contains 0.001 to 50% by mass, preferably 0. The amount should be approximately 0.02 to 25% by mass, and particularly preferably 0.01 to 10% by mass.

[0038] The container should preferably allow the inside to be visible (observable) to the naked eye. Therefore, it becomes possible to inspect for the presence or absence of foreign matter contamination in the manufacturing process of pharmaceutical products. This offers advantages such as allowing the user to check the remaining amount of the contents (aqueous composition). Recognition only needs to be ensured on at least a portion of the container surface (for example, eye drops) Even if the sides of the container are obscured by shrink film or the like, the bottom can still be seen. If it is visible, then it can be said to be visible. If the inside is visible from a part of the container surface, then This makes it possible to confirm the aqueous composition inside the container.

[0039] The means of containing the aqueous composition in the container are not particularly limited and can be filled by conventional methods according to the form of the container, etc. Fill it in.

[0040] The diseases to which the pharmaceutical preparation can be applied are not particularly limited, and the drug contains the compound represented by the general formula (1) above. You should select the appropriate one depending on the physiological effects and other factors. Specifically, for example, the Rho kinase inhibitory effect of the compound represented by general formula (1), and Based on its intraocular pressure-lowering effect, it can be used as a preventive or therapeutic agent for ocular hypertension and glaucoma. Glaucoma can be further categorized into, for example, primary open-angle glaucoma, normal-tension glaucoma, and aqueous humor glaucoma. Hyperglaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed Combined glaucoma, steroid glaucoma, lens capsule glaucoma, pigment glaucoma, amyloid glaucoma, Examples include neovascular glaucoma and malignant glaucoma.

[0041] Furthermore, as disclosed in Japanese Patent Publication No. 5557408, fundus diseases (mainly retinal Lesions that manifest in the membrane and / or choroid. Specifically, for example, fundus changes due to hypertension and arteriosclerosis. This includes conditions such as central retinal artery occlusion, central retinal vein occlusion, and retinal vein occlusion. Retinal vein occlusion such as branch retinal vein occlusion, diabetic retina disease, diabetic macular edema, diabetic maculopathy, Eales disease, Coats disease Retinal vascular congenital anomalies such as isease, von Hippel disease, pulseless disease ess disease), macular disease (central serous chorioretinopathy), Cystoid macular edema, age-related macular degeneration myopic macular degeneration), macular hole, myopic macular degeneration ), retinovitreous interface macular degeneration, drug-toxic macular degeneration, hereditary macular degeneration, etc., (rhegmatogenous Examples include retinal detachment (tractional, exudative, etc.), retinitis pigmentosa, and retinopathy of prematurity. A preventive or therapeutic agent, more preferably for the prevention of diabetic retinopathy, diabetic macular edema, or age-related macular degeneration. It can be used as a therapeutic agent. [Examples]

[0042] Next, the present invention will be further described with reference to examples, but the present invention is not limited in any way to these examples. isn't it. In the following test examples, ripasudil 1-hydrochloride dihydrate is used, for example, in International Publication No. 20 It can be manufactured using the method described in pamphlet No. 06 / 057397.

[0043] [Test Example 1] Preservation Test Part 1 After preparing the aqueous compositions of the formulations shown in Table 1 by conventional methods, polyethylene (PE) and poly Pharmaceutical preparations are manufactured in containers made of propylene (PP) or polyvinyl chloride (PVC). Ta. Each obtained pharmaceutical preparation was stored at 60°C for 3 months, and the color difference (ΔYI) before and after storage was measured. The measurement was performed using a spectrophotometer (CM-700d: Konica Minolta Sensing, Inc.), and Δ We evaluated YI values ​​of 5 or greater as × and values ​​less than 5 as ○. The results are shown in Table 2.

[0044] [Table 1]

[0045] [Table 2]

[0046] As shown in Table 2, the aqueous composition containing lipasudil was made of polyethylene (PE), When stored in polyolefin resin containers such as polypropylene (PP), it may be subjected to high temperatures for extended periods. Even when stored for an extended period, the value of ΔYI was kept low, whereas polyvinyl chloride ( When the container was made of PVC, the value of ΔYI increased.

[0047] [Test Example 2] Preservation Test Part 2 After preparing the aqueous compositions of the formulations shown in Table 3 by conventional methods, polyethylene (PE) or poly The pharmaceutical preparation was manufactured in a container made of polypropylene (PP). Each obtained pharmaceutical preparation was stored at 60°C for 3 months, and the color difference (ΔYI) before and after storage was measured. The measurement was performed using a spectrophotometer (CM-700d: Konica Minolta Sensing, Inc.), and Δ We evaluated YI values ​​of 5 or greater as × and values ​​less than 5 as ○. The results are shown in Table 4.

[0048] [Table 3]

[0049] [Table 4]

[0050] As shown in the results in Table 4, even when the formulation of the aqueous composition is changed, polyethylene ( When contained in a polyolefin resin container such as PE (polyethylene) or polypropylene (PP), Even when stored at high temperatures for extended periods, the value of ΔYI remained low.

[0051] From the results of the above test examples 1 and 2, a compound represented by general formula (1) containing lipasudil, or or an aqueous composition containing a salt thereof or a solvate thereof in a polyolefin resin container When stored, it is relatively resistant to discoloration even when stored at high temperatures for extended periods, demonstrating excellent storage stability. It became clear that this was the case.

[0052] [Manufacturing Examples 1-27] The following ingredients and quantities (amount per 100 mL of aqueous composition (g)) are included in Tables 5 to 7. A aqueous composition is prepared by a conventional method, and this is placed in a polyethylene eye drop container. It is possible to manufacture pharmaceutical formulations as shown in Examples 1 to 27.

[0053] [Table 5]

[0054] [Table 6]

[0055] [Table 7]

[0056] [Manufacturing Examples 28-54] In manufacturing examples 1-27, polypropylene is used instead of polyethylene for the eye drop container. Using this method, pharmaceutical formulations shown in manufacturing examples 28 to 54 can be produced.

[0057] [Manufacturing Examples 55-81] In manufacturing examples 1-27, cyclic polyolefin (COP) was used instead of polyethylene. Using the eye drop container, the pharmaceutical formulations shown in manufacturing examples 55 to 81 can be manufactured.

[0058] [Manufacturing Examples 82-162] In manufacturing examples 1-81, the same amount of 4-bromo- was used instead of lipasudil 1-hydrochloride dihydrate. 5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoli Products using this ingredient can be manufactured by conventional methods as pharmaceutical preparations as described in manufacturing examples 82 to 162. [Industrial applicability]

[0059] According to the present invention, a pharmaceutical formulation with excellent storage stability can be provided, making it suitable for the pharmaceutical industry and the like. It can be used for this purpose.

Claims

[Claim 1] The invention described in the application.

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