Pharmaceutical

Abstract

The present invention addresses the problem of providing technology for suppressing the freezing, during low-temperature storage, of a ripasudil-containing aqueous composition that is stored in a polyolefin-based resin container and has a dissolved oxygen amount of 8.5 mg / L or more.　The present invention relates to a pharmaceutical preparation in which an aqueous composition that contains ripasudil or a salt thereof, or a solvate of these, and a lower aliphatic carboxylic acid and has a dissolved oxygen amount of 8.5 mg / L or more is stored in a polyethylene container.

Description

Pharmaceuticals

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

[0002] The following structural formula:

[0003]

[0004] Ripasudil (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline) represented by the formula (I) has pharmacological effects such as Rho kinase inhibitory activity (e.g., Patent Document 1) and is known to be useful for the prevention and treatment of ocular diseases. Specifically, it has been reported to be useful for the prevention or treatment of ocular hypertension, glaucoma, and the like (e.g., Patent Document 2), or for the prevention or treatment of ocular fundus diseases such as age-related macular degeneration (e.g., Patent Document 3). Furthermore, "Glanatec" (registered trademark) and "Glaalpha" (registered trademark), which contain ripasudil hydrochloride hydrate as an active ingredient, have been developed and marketed in several countries, including Japan, as preventive and therapeutic agents for ocular hypertension and glaucoma (Non-Patent Documents 1 and 2). Therefore, it would be extremely useful to establish a technology for stably formulating ripasudil, for example, as an ophthalmic agent.

[0005] It has been reported that discoloration after long-term storage at high temperatures can be suppressed by storing an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof in a container made of a polyolefin resin such as polyethylene or polypropylene (Patent Document 4). Also, both Glanatec and Glaalpha are pharmaceuticals in which an aqueous composition containing Ripasudil hydrochloride hydrate is stored in a polypropylene eye drop container body.

[0006] Japanese Patent No. 4212149 International Publication No. 2006 / 068208 Pamphlet Japanese Patent No. 5557408 Japanese Patent No. 6244038

[0007] Pharmaceutical interview form "Glanatec (registered trademark) eye drops 0.4%" Kowa Company, Ltd., September 2023 Pharmaceutical interview form "Glaalpha (registered trademark) combination eye drops" Kowa Company, Ltd., June 2024

[0008] Ophthalmic agents and the like are usually compositions containing water (aqueous compositions). Therefore, the present inventors investigated the storage stability of aqueous compositions containing Ripasudil, a salt thereof, or a solvate thereof (hereinafter, sometimes referred to as "Ripasudil-containing aqueous compositions"). When Ripasudil-containing aqueous compositions were stored in polyolefin resin containers, they were found to have no problems when stored at room temperature (1 to 30°C), but to have a problem in that the aqueous compositions may freeze over time when stored at temperatures as low as -5°C, especially when the amount of dissolved oxygen in the Ripasudil-containing aqueous composition is 8.5 mg / L or more.

[0009] This problem can be solved, for example, by adjusting the dissolved oxygen content of the Ripasudil-containing aqueous composition to a low level. In this regard, methods such as replacing the dissolved oxygen with an inert gas by nitrogen purging or vacuum degassing can be considered to adjust the dissolved oxygen content of the Ripasudil-containing aqueous composition to a low level. However, implementing these methods requires a great deal of effort and cost. Therefore, an object of the present invention is to provide a technology for preventing freezing of a Ripasudil-containing aqueous composition that is contained in a polyolefin resin container and has a dissolved oxygen content of 8.5 mg / L or more during low-temperature storage.

[0010] The present inventors have conducted further intensive research to solve the above-mentioned problems and have found that freezing during low-temperature storage is specifically suppressed when a Ripasudil-containing aqueous composition having a dissolved oxygen content of 8.5 mg / L or more is further supplemented with lower aliphatic carboxylic acids represented by one or more selected from the group consisting of edetic acid, its salts, and solvates thereof, and the aqueous composition is contained in a polyethylene container, among other polyolefin resin containers, and thus the present invention has been completed.

[0011] That is, the present invention provides a pharmaceutical preparation comprising an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof, and a lower aliphatic carboxylic acid, the aqueous composition having a dissolved oxygen content of 8.5 mg / L or more, and contained in a polyethylene container.The present invention also provides a method for suppressing freezing of an aqueous composition, the method comprising the steps of adding a lower aliphatic carboxylic acid to an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof, and having a dissolved oxygen content of 8.5 mg / L or more, and containing the aqueous composition in a polyethylene container.Furthermore, the present invention provides a method for producing a pharmaceutical preparation in which freezing of the aqueous composition is suppressed, the method comprising the steps of adding a lower aliphatic carboxylic acid to an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof, and having a dissolved oxygen content of 8.5 mg / L or more, and containing the aqueous composition in a polyethylene container.

[0012] According to the present invention, it is possible to prevent freezing of a Ripasudil-containing aqueous composition that is contained in a polyolefin resin container and has a dissolved oxygen content of 8.5 mg / L or more during low-temperature storage.

[0013] As used herein, "w / v %" means mass to volume percentage, specifically, the mass (g) of each component contained per 100 mL of the composition.

[0014] <Ripasudil, its salt, or solvate thereof> In the present invention, Ripasudil (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline) may be a salt. The salt of Ripasudil is not particularly limited as long as it is a pharmaceutically acceptable salt, and specific examples include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide; and organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate; with hydrochloride being preferred. Furthermore, Ripasudil or a salt thereof may be a solvate such as a hydrate or alcoholate, with a hydrate being preferred.

[0015] In the present invention, Ripasudil or its salt or a solvate thereof is more preferably Ripasudil or its hydrochloride or a hydrate thereof, and is represented by the following structural formula:

[0016]

[0017] Ripasudil hydrochloride hydrate (Ripasudil monohydrochloride dihydrate) represented by the following formula is particularly preferred.

[0018] Ripasudil, a salt thereof, or a solvate thereof is known and can be produced by known methods. Specifically, for example, Ripasudil, a salt thereof, or a solvate thereof can be produced by the methods described in WO 1999 / 020620 and WO 2006 / 057397.

[0019] The content of Ripasudil or a salt thereof, or a solvate thereof in the aqueous composition is not particularly limited and may be determined appropriately depending on the disease to be treated, the patient's sex, age, symptoms, etc., but from the viewpoint of obtaining an excellent pharmacological effect, the content may be 0.01 w / v% or more, preferably 0.02 w / v% or more, and more preferably 0.04 w / v% or more, calculated as the free form of Ripasudil, relative to the total volume of the aqueous composition, and may be 10 w / v% or less, preferably 8 w / v% or less, and particularly preferably 6 w / v% or less. Among these, from the viewpoint of obtaining an excellent pharmacological effect, the content of Ripasudil or a salt thereof, or a solvate thereof, calculated as the free form, relative to the total volume of the aqueous composition is preferably 0.05 to 5 w / v%, more preferably 0.1 to 3 w / v%, even more preferably 0.1 to 2 w / v%, and particularly preferably 0.3 to 0.5 w / v%.

[0020] <Lower aliphatic carboxylic acids> In the present invention, the term "lower aliphatic carboxylic acids" refers to one or more selected from the group consisting of lower aliphatic carboxylic acids and their salts (e.g., alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts, etc.), in which one or more carbon atoms may be replaced by a nitrogen atom, and solvates (hydrates, etc.) thereof. The number of carbon atoms in the lower aliphatic carboxylic acids is not particularly limited as long as it is approximately 15 or less. However, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, 2 to 12 carbon atoms are preferred, 4 to 12 carbon atoms are more preferred, and 6 to 12 carbon atoms are particularly preferred. Of these carbon atoms, some of the carbon atoms other than those constituting the carboxyl group may be replaced by nitrogen atoms. However, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, the number of nitrogen atoms substituted is preferably 1 to 2. Furthermore, the carbon chain may be linear or branched, and may be saturated or unsaturated.

[0021] The number of carboxyl groups in the lower aliphatic carboxylic acids is not limited, but is preferably 1 to 4 from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition. Furthermore, the lower aliphatic carboxylic acids may further have approximately 1 to 3 hydrophilic substituents other than carboxyl groups from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition. Specific examples of such hydrophilic substituents include a hydroxyl group and an amino group. The lower aliphatic carboxylic acids are known compounds, and may be produced by known methods or commercially available products may be used. The lower aliphatic carboxylic acids may form salts or complexes with other components, and aqueous compositions containing components that form such salts or complexes are also encompassed in the "aqueous composition containing a lower aliphatic carboxylic acid."

[0022] Specific examples of such lower aliphatic carboxylic acids include adipic acid; one or more selected from the group consisting of aspartic acid, salts thereof such as aspartic acid, sodium L-aspartate, and magnesium L-aspartate, and solvates thereof; one or more selected from the group consisting of epsilon-aminocaproic acid, salts thereof, and solvates thereof; edetic acid, calcium sodium edetate hydrate, sodium edetate hydrate, tetrasodium edetate hydrate, anhydrous disodium edetate, etc. one or more selected from the group consisting of edetic acid, its salts, and solvates thereof; one or more selected from the group consisting of citric acid, calcium citrate, citric acid hydrate, sodium citrate hydrate, sodium dihydrogen citrate, disodium citrate, anhydrous citric acid, anhydrous sodium citrate, and its salts, and solvates thereof; one or more selected from the group consisting of succinic acid, monosodium succinate, disodium succinate hexahydrate, and other succinic acid, salts, and solvates thereof; acetic acid, one or more selected from the group consisting of acetic acid and its salts, such as ammonium, potassium acetate, calcium acetate, sodium acetate hydrate, glacial acetic acid, and anhydrous sodium acetate, and solvates thereof; one or more selected from the group consisting of tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, and potassium sodium tartrate, and its salts, and solvates thereof; one or more selected from the group consisting of sorbic acid, such as sorbic acid and potassium sorbate, and its salts, and solvates thereof; lactic acid, sodium lactate one or more selected from the group consisting of lactic acid, its salts such as propionic acid, sodium propionate, and solvates thereof, and solvates thereof; one or more selected from the group consisting of fumaric acid, its salts, and solvates thereof; one or more selected from the group consisting of maleic acid, its salts, and solvates thereof; one or more selected from the group consisting of malonic acid, its salts, and solvates thereof;Examples of the lower aliphatic carboxylic acids include one or more selected from the group consisting of malic acid, DL-malic acid, sodium DL-malate, and other malic acids and their salts, as well as solvates thereof, and these can be used alone or in combination of two or more. All of these lower aliphatic carboxylic acids are known and may be produced by known methods, or commercially available products may be used.

[0023] From the viewpoint of suppressing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, the lower aliphatic carboxylic acid is preferably one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, citric acid, acetic acid, sorbic acid, and salts thereof and solvates thereof, more preferably one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, and salts thereof and solvates thereof, and particularly preferably one or more selected from the group consisting of edetic acid, its salts, and solvates thereof. By using one or more selected from the group consisting of edetic acid, its salts, and solvates thereof as the lower aliphatic carboxylic acid, freezing of the Ripasudil-containing aqueous composition during low-temperature storage is significantly suppressed compared to other lower aliphatic carboxylic acids.

[0024] The content of lower aliphatic carboxylic acids in the aqueous composition is not particularly limited, but from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, it may be 0.001 w / v or more, preferably 0.01 w / v% or more, more preferably 0.05 w / v% or more, and particularly preferably 0.1 w / v% or more, relative to the total volume of the aqueous composition, and may be 5 w / v% or less, preferably 3.5 w / v% or less, and particularly preferably 1 w / v%. In particular, when one or more lower aliphatic carboxylic acids selected from the group consisting of epsilon-aminocaproic acid, salts thereof, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, it is preferably contained in an amount of 0.003 to 3 w / v%, more preferably 0.07 to 1 w / v%, and particularly preferably 0.2 to 0.5 w / v%, relative to the total volume of the aqueous composition. Furthermore, when one or more lower aliphatic carboxylic acids selected from the group consisting of edetic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, the content is preferably 0.0003 to 0.3 w / v%, more preferably 0.007 to 0.2 w / v%, and particularly preferably 0.02 to 0.1 w / v%, relative to the total volume of the aqueous composition, from the viewpoint of suppressing freezing during low-temperature storage of the Ripasudil-containing aqueous composition. Furthermore, when one or more lower aliphatic carboxylic acids selected from the group consisting of citric acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, the content is preferably 0.006 to 2 w / v%, more preferably 0.04 to 0.4 w / v%, and particularly preferably 0.07 to 0.2 w / v%, relative to the total volume of the aqueous composition, from the viewpoint of suppressing freezing during low-temperature storage of the Ripasudil-containing aqueous composition. Furthermore, in particular, when one or more types selected from the group consisting of acetic acid, salts thereof, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, the content is preferably 0.003 to 2 w / v%, more preferably 0.03 to 0.3 w / v%, and particularly preferably 0.07 to 0.2 w / v%, relative to the total volume of the aqueous composition.Furthermore, in particular, when one or more types selected from the group consisting of sorbic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, the content is preferably 0.02 to 0.8 w / v%, more preferably 0.09 to 0.4 w / v%, and particularly preferably 0.07 to 0.2 w / v%, relative to the total volume of the aqueous composition.

[0025] Furthermore, the mass ratio of Ripasudil or its salt or solvate thereof to lower aliphatic carboxylic acids in the aqueous composition is not particularly limited, but from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, the composition may contain 0.001 mass parts or more, preferably 0.01 mass parts or more, more preferably 0.3 mass parts or more, more preferably 0.6 mass parts or more, and even more preferably 0.8 mass parts or more of lower aliphatic carboxylic acids per mass part of Ripasudil converted to its free form, and may contain 8 mass parts or less, preferably 4 mass parts or less, and particularly preferably 3 mass parts or less. In particular, when one or more types selected from the group consisting of epsilon-aminocaproic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, the composition preferably contains 0.05 to 2.5 parts by mass, more preferably 0.2 to 2 parts by mass, and particularly preferably 0.5 to 1.5 parts by mass of one or more types selected from the group consisting of epsilon-aminocaproic acid, its salts, and solvates thereof per part by mass of Ripasudil converted to its free form. Furthermore, in particular, when one or more types selected from the group consisting of edetic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, it is preferable to contain 0.003 to 2 parts by mass, more preferably 0.01 to 1 part by mass, and particularly preferably 0.02 to 0.5 parts by mass of one or more types selected from the group consisting of edetic acid, its salts, and solvates thereof per part by mass of Ripasudil converted to its free form. Furthermore, in particular, when one or more types selected from the group consisting of citric acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, it is preferable to contain 0.003 to 5 parts by mass, more preferably 0.03 to 2 parts by mass, and particularly preferably 0.07 to 7 parts by mass, of one or more types selected from the group consisting of citric acid, its salts, and solvates thereof per 1 part by mass, calculated as the free form of Ripasudil.Furthermore, when one or more types selected from the group consisting of acetic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, the composition preferably contains 0.003 to 2 parts by mass, more preferably 0.03 to 1 part by mass, and particularly preferably 0.02 to 0.8 parts by mass of one or more types selected from the group consisting of acetic acid, its salts, and solvates thereof per part by mass, calculated as the free form of Ripasudil. Furthermore, when one or more types selected from the group consisting of sorbic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, the composition preferably contains 0.04 to 3 parts by mass, more preferably 0.03 to 1.5 parts by mass, and particularly preferably 0.3 to 0.7 parts by mass of one or more types selected from the group consisting of sorbic acid, its salts, and solvates thereof per part by mass, calculated as the free form of Ripasudil.

[0026] <Dissolved oxygen content> In the present invention, the dissolved oxygen content of the Ripasudil-containing aqueous composition must be 8.5 mg / L or more. As shown in the test examples described below, when the dissolved oxygen content of the Ripasudil-containing aqueous composition is 8.5 mg / L or more, freezing over time during low-temperature storage may occur. However, by further adding a lower aliphatic carboxylic acid to the Ripasudil-containing aqueous composition and housing the aqueous composition in a polyethylene container, such freezing over time during low-temperature storage can be suppressed. Therefore, according to the means for solving the problems of the present invention, it is not necessary to incur significant effort or cost for reducing and maintaining the dissolved oxygen content, for example, by replacing the dissolved oxygen with an inert gas by nitrogen purging or by vacuum degassing, and it is possible to inexpensively and easily obtain a pharmaceutical preparation containing a Ripasudil-containing aqueous composition in a container that has good storage stability and is suppressed from freezing over time during low-temperature storage.

[0027] In the present invention, the amount of dissolved oxygen in the Ripasudil-containing aqueous composition must be 8.5 mg / L or more (more preferably 8.5 to 13 mg / L, even more preferably 8.5 to 12 mg / L, even more preferably 8.5 to 11 mg / L, even more preferably 8.5 to 10 mg / L, and particularly preferably 8.5 to 9.5 mg / L), but is preferably 8.7 mg / L or more (more preferably 8.7 to 13 mg / L, even more preferably 8.7 Preferably, the concentration is 8.7 to 12 mg / L, even more preferably 8.7 to 11 mg / L, even more preferably 8.7 to 10 mg / L, and particularly preferably 8.7 to 9.5 mg / L), and particularly preferably 9 mg / L or more (more preferably 9 to 13 mg / L, even more preferably 9 to 12 mg / L, even more preferably 9 to 11 mg / L, even more preferably 9 to 10 mg / L, and particularly preferably 9 to 9.5 mg / L).

[0028] In the present invention, the dissolved oxygen content refers to a value measured by a diaphragm electrode method, particularly a polarographic method (diaphragm polarographic method). Examples of dissolved oxygen meters used to measure the dissolved oxygen content by such methods include the portable waterproof dissolved oxygen meter model AS720 (manufactured by AS ONE Corporation). In the present invention, the dissolved oxygen content is measured when a pharmaceutical formulation is continuously stored under specified storage conditions (storage method). That is, for example, for a pharmaceutical formulation specified as being stored at "room temperature," the dissolved oxygen content of a Ripasudil-containing aqueous composition for the pharmaceutical formulation stored at any temperature in the range of 1 to 30°C may be measured in accordance with the definition of "room temperature" (1 to 30°C) defined in the 18th Revised Japanese Pharmacopoeia. If the dissolved oxygen content is 9 mg / L or more under normally expected storage conditions, freezing can be advantageously suppressed even when the pharmaceutical formulation is exposed to a low-temperature environment due to some accident during distribution or storage.

[0029] No special process is required to achieve a dissolved oxygen content of 8.5 mg / L or more in a Ripasudil-containing aqueous composition. For example, by simply adjusting the stirring speed or stirring blades to incorporate air during mixing of the aqueous composition, a person skilled in the art can appropriately achieve a dissolved oxygen content of 8.5 mg / L or more through simple modifications to the manufacturing process typically expected for Ripasudil-containing aqueous compositions. Therefore, the present invention requires significantly less labor and cost than actively and forcibly adjusting and maintaining the dissolved oxygen content at a low value. Furthermore, measures such as injecting oxygen gas may be employed as long as they do not result in excessive labor or cost burdens. In this specification, the term "aqueous composition having a dissolved oxygen content of 8.5 mg / L or more" is not limited to aqueous compositions in which the dissolved oxygen content has been intentionally "adjusted" to 8.5 mg / L or more, but also includes aqueous compositions in which the dissolved oxygen content naturally fluctuates within that range after production. These interpretation guidelines also apply to aqueous compositions in which the dissolved oxygen content is in other numerical ranges.

[0030] <Aqueous Composition> In the present invention, the term "aqueous composition" refers to a composition containing at least water, and its properties include liquid (solution or suspension) and semi-solid (ointment). Examples of water that can be used in the composition include purified water, water for injection, and sterile purified water. The content of water contained in the aqueous composition is not particularly limited, but is preferably 5 w / v% or more, more preferably 20 w / v% or more, even more preferably 50 w / v% or more, even more preferably 90 w / v% or more, and particularly preferably 90 to 99.8 w / v%.

[0031] The aqueous composition can be made into various dosage forms according to known methods, for example, as described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition, etc. The dosage form is not particularly limited as long as it can be contained in a container described below, and examples include injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal drops, enemas, topical solutions, sprays, ointments, creams, gels, oral solutions, and syrups. From the viewpoint of advantageously utilizing the pharmacological action of Ripasudil, the dosage form is preferably an agent for ophthalmic diseases, specifically eye drops and eye ointments, with eye drops being particularly preferred.

[0032] In addition to the above, the aqueous composition may contain additives used in pharmaceuticals, quasi-drugs, etc. Examples of such additives include inorganic salts, isotonicity agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, thickening agents, surfactants, solubilizers, suspending agents, refreshing agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, etc. Specific examples of such additives include ascorbic acid, sodium bisulfite, alginic acid, sodium benzoate, benzyl benzoate, fennel oil, ethanol, ethylene-vinyl acetate copolymer, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride solution, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, xylitol, glycerin, gluconic acid, creatinine, chlorhexidine, chlorobutanol, crystalline sodium dihydrogen phosphate, geraniol, sodium chondroitin sulfate, titanium oxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzododecinium bromide, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution, taurine, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, and thimerosal. ethanol, tyloxapol, trometamol, concentrated glycerin, concentrated mixed tocopherols, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride solution 50, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin, sodium metabisulfite, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalkonium chloride, benzal Benzethonium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, borax, boric acid, povidone, polyoxyethylene (200) polyoxypropylene glycol (70), sodium polystyrene sulfonate, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl alcohol (partially saponified), d-borneol, macrogol 4000, macrogol 6000, D-mannitol, anhydrous sodium monohydrogen phosphate,Examples include anhydrous sodium dihydrogen phosphate, methanesulfonic acid, 1-menthol, monoethanolamine, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, ryuuno, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, and petrolatum.

[0033] Preferred examples of additives include potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, glycerin, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, concentrated glycerin, borax, boric acid, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (partially saponified), macrogol 4000, macrogol 6000, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, monoethanolamine, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium hyaluronate, glucose, and 1-menthol.

[0034] The aqueous composition may further contain other medicinal ingredients in addition to Ripasudil depending on the disease to be treated and the like. Examples of such medicinal ingredients include α1 receptor blockers including bunazosin such as bunazosin hydrochloride or a salt thereof or a solvate thereof; α2 receptor agonists including brimonidine such as brimonidine tartrate or a salt thereof or a solvate thereof, and apraclonidine or a salt thereof or a solvate thereof; β-blockers including carteolol such as carteolol hydrochloride or a salt thereof or a solvate thereof, nipradilol or a salt thereof or a solvate thereof, timolol such as timolol maleate or a salt thereof or a solvate thereof, betaxolol such as betaxolol hydrochloride or a salt thereof or a solvate thereof, levobunolol such as levobunolol hydrochloride or a salt thereof or a solvate thereof, befunolol or a salt thereof or a solvate thereof, and metipranolol or a salt thereof or a solvate thereof; Rho kinase inhibitors including netarsudil such as netarsudil mesylate or a salt thereof or a solvate thereof; dorzolamide hydrochloride and other β-blockers including dorzolamide hydrochloride and other β-blockers. carbonic anhydrase inhibitors including acetazolamide or its salt or solvate thereof, brinzolamide or its salt or solvate thereof, acetazolamide or its salt or solvate thereof, dichlorphenamide or its salt or solvate thereof, methazolamide or its salt or solvate thereof; isopropyl unoprostone or its salt or solvate thereof, tafluprost or its salt or solvate thereof, travoprost or its salt or solvate thereof, bimatoprost prostaglandin F2α derivatives including prost 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, and fluprostenol or a salt thereof or a solvate thereof; sympathomimetics including dipivefrin such as dipivefrin hydrochloride or a salt thereof or a solvate thereof, epinephrine, epinephrine borate, epinephrine hydrochloride or another epinephrine or a salt thereof or a solvate thereof;Parasympathomimetics including distigmine bromide or a salt thereof or a solvate thereof, pilocarpine or a salt thereof or a solvate thereof (e.g., pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate), such as pilocarpine nitrate, such as pilocarpine nitrate, such as pilocarpine hydrochloride ...

[0035] 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 relative to physiological saline is not particularly limited, but is preferably 0.6 to 3, and particularly preferably 0.6 to 2.

[0036] <Container> In the present invention, the term "container" refers to a package that directly contains the aqueous composition. The term "container" is a concept that encompasses any of "sealed containers," "airtight containers," and "sealed containers" as defined in the General Rules of the Japanese Pharmacopoeia, 18th Edition.

[0037] The shape of the container is not particularly limited as long as it can accommodate the aqueous composition, and may be appropriately selected and set depending on the dosage form, the use of the pharmaceutical preparation, etc. Specific examples of such container shapes include containers for injections, containers for inhalants, containers for sprays, bottle-shaped containers, tube-shaped containers, containers for eye drops, containers for nasal drops, containers for ear drops, and bag-shaped containers.

[0038] In the present invention, a "polyethylene container" refers to a container in which at least the portion of the container that comes into contact with the aqueous composition is made of polyethylene. Therefore, for example, a container having a polyethylene layer as the inner layer that comes into contact with the aqueous composition and another resin or the like laminated on the outer surface also falls under the category of a "polyethylene container." The polyethylene is not particularly limited, and examples thereof include low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, and medium-density polyethylene, and one or more of these can be used in combination. In this specification, "made of polyethylene" means that at least a portion of the material contains polyethylene. For example, a mixture (polymer alloy) of two or more resins, including polyethylene and a resin other than polyethylene, is also included in the term "made of polyethylene."

[0039] It is preferable to further incorporate a substance that blocks the transmission of ultraviolet light, such as an ultraviolet absorber or an ultraviolet scattering agent, into the polyethylene container. This improves the stability of Ripasudil against light. Specific examples of such substances include titanium oxide as an ultraviolet scattering agent;Examples of the ultraviolet absorber include 2-(2H-benzotriazol-2-yl)-p-cresol (for example, Tinuvin P, manufactured by BASF), 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol (for example, Tinuvin 234, manufactured by BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)benzotriazole (for example, Tinuvin 320, manufactured by 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 (e.g., Tinuvin 327: 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′-methylenebis[6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol] (e.g., Tinuvin 360: BASF), reaction products of methyl 3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionate and polyethylene glycol 300 (e.g., Tinuvin 213: BASF), 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol (e.g., 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 the like;Cyanoacrylate-based ultraviolet absorbers such as 2,2-bis{[2-cyano-3,3-diphenylacryloyloxy]methyl}propane-1,3-diyl=bis(2-cyano-3,3-diphenylacrylate) (e.g., Uvinul 3030 FF: BASF), ethyl 2-cyano-3,3-diphenylacrylate (e.g., Uvinul 3035: BASF), and 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (e.g., Uvinul 3039: BASF); triazine-based ultraviolet absorbers such as 2-(4,6-diphenyl-1,3,5-triazin-2-yl)-5-[(hexyl)oxy]-phenol (e.g., Tinuvin 1577 ED: BASF); 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), benzophenone-based ultraviolet absorbers such as oxybenzone, hydroxymethoxybenzophenone sulfonic acid, hydroxymethoxybenzophenone sodium sulfonate, dihydroxydimethoxybenzophenone, dihydroxydimethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, and tetrahydroxybenzophenone; methyl diisopropylcinnamate, cinoxate, glyceryl di-p-methoxycinnamate mono-2-ethylhexanoate, isopropyl para-methoxycinnamate / diisopropyl cinnamate mixture, 2-ethylhexyl para-methoxycinnamate, cinnamic acid ester mixture, cinnamic acid-based ultraviolet absorbers such as para-aminobenzoic acid, ethyl para-aminobenzoate, glyceryl para-aminobenzoate, amyl para-dimethylaminobenzoate, 2-ethylhexyl para-dimethylaminobenzoate, and ethyl 4-[N,N-di(2-hydroxypropyl)amino]benzoate; salicylic acid-based ultraviolet absorbers such as ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, and methyl salicylate; guaiazulene; and 2-ethylhexyl dimethoxybenzylidene dioxoimidazolidinepropionate.Examples include 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,5-triazine; parahydroxyanisole; 4-tert-butyl-4'-methoxydibenzoylmethane; phenylbenzimidazole sulfonic acid; and 2-(4-diethylamino-2-hydroxybenzoyl)-hexyl benzoate.

[0040] When a substance that blocks ultraviolet light transmission is kneaded into the container, the blending ratio varies depending on the type of substance, etc., but may be, for example, about 0.001 to 50% by mass, preferably 0.002 to 25% by mass, and particularly preferably about 0.01 to 10% by mass in the container.

[0041] It is preferable that the interior of the container is visible (observable) with the naked eye. If the interior is visible, it is possible to inspect for the presence or absence of foreign matter during the manufacturing process of the pharmaceutical preparation, and it is possible for the user of the pharmaceutical preparation to check the remaining amount of the contents (aqueous composition). Here, visibility is sufficient as long as at least a portion of the container surface is ensured (for example, even if the side of an eye drop container is obscured by a shrink film or the like, it can be said that visibility is possible as long as the bottom surface is visible). If the interior is visible from a portion of the container surface, this makes it possible to check the aqueous composition in the container.

[0042] The means for storing the aqueous composition in the container is not particularly limited, and the aqueous composition may be filled in a conventional manner according to the shape of the container.

[0043] <Pharmaceutical Preparations> In the present invention, the indications for the "pharmaceutical preparation" are not particularly limited, and may be appropriately selected depending on the pharmacological action, etc., of ripasudil. Specifically, for example, ripasudil can be used as a preventive or therapeutic agent for ocular hypertension or glaucoma, based on its Rho kinase inhibitory action and intraocular pressure-reducing action. More specific examples of glaucoma include primary open-angle glaucoma, normal-tension glaucoma, excessive aqueous humor production glaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma, steroid-induced glaucoma, lenticular capsular glaucoma, pigmentary glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma.

[0044] Furthermore, as disclosed in Japanese Patent No. 5557408, fundus diseases (lesions that mainly occur in the retina and / or choroid. Specific examples include fundus changes due to high blood pressure and arteriosclerosis, retinal vein occlusions such as central retinal artery occlusion, central retinal vein occlusion, and branch retinal vein occlusion, diabetic retinopathy, diabetic macular edema, diabetic maculopathy, congenital retinal vascular abnormalities such as Eales disease and Coats disease, von Hippel disease, pulseless disease, macular diseases (central chorioretinopathy), and the like. The present invention can be used as a preventive or therapeutic agent for various conditions, including retinal and ocular diseases such as chorioretinopathy, cystoid macular edema, age-related macular degeneration, macular hole, myopic macular degeneration, vitreoretinal interface macular degeneration, drug-toxic macular degeneration, hereditary macular degeneration, retinal detachment (rhegmatogenous, tractional, exudative, etc.), retinitis pigmentosa, retinopathy of prematurity, etc., more preferably as a preventive or therapeutic agent for diabetic retinopathy, diabetic macular edema, or age-related macular degeneration. Furthermore, as disclosed in Japanese Patent No. 5657252, the present invention can also be used as a preventive and / or therapeutic agent for corneal endothelial damage.

[0045] <Meaning of Other Terms> In the present invention, "low-temperature storage" means storage at a temperature lower than room temperature (1 to 30°C) that a pharmaceutical preparation may accidentally encounter after production, during distribution, or during storage; specifically, for example, storage at -5°C is envisaged. In the present invention, "freezing" is not necessarily limited to the case where the entire Ripasudil-containing aqueous composition is frozen, but also includes the case where only a portion of the composition is frozen. In the present invention, "suppression" of freezing means that, by taking the technical means disclosed herein, "freezing" is suppressed for a relatively long period of time compared to when the means is not taken, or that, by taking the technical means disclosed herein, the degree of "freezing" over the same period is suppressed compared to when the means is not taken (the range or extent of freezing is small), and does not necessarily mean that the Ripasudil-containing aqueous composition will never freeze. For example, if the evaluation object contains edetic acid as a lower aliphatic carboxylic acid, and a comparison object that does not contain edetic acid but has equivalent ingredients, dissolved oxygen content, etc. is prepared and stored under the same low-temperature storage conditions, this means that the evaluation object will be inhibited from "freezing" for a relatively longer period of time than the comparison object, or that the degree of "freezing" will be inhibited at the same time.

[0046] <Method for suppressing freezing, method for producing pharmaceutical preparations> The present invention also relates to a method for suppressing freezing of an aqueous composition during low-temperature storage, comprising the steps of: adding a lower aliphatic carboxylic acid to an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 mg / L or more; and placing the aqueous composition in a polyethylene container. The present invention also relates to a method for producing a pharmaceutical preparation that is suppressed from freezing during low-temperature storage, comprising the steps of: adding a lower aliphatic carboxylic acid to an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 mg / L or more; and placing the aqueous composition in a polyethylene container. In the above methods, the order of the steps of adding Ripasudil to the aqueous composition, adding a lower aliphatic carboxylic acid to the aqueous composition, and placing the aqueous composition in a polyethylene container does not matter. Furthermore, the timing at which the dissolved oxygen content of the aqueous composition reaches 8.5 mg / L or more is not particularly important, and as long as the dissolved oxygen content of the aqueous composition reaches 8.5 mg / L or more at any timing, it can be considered a "method for inhibiting freezing" or a "method for producing a pharmaceutical preparation" disclosed in this specification. The meanings of other various terms, the amounts of each component, etc. are all the same as those explained for the "pharmaceutical preparation" above.

[0047] The present invention discloses, for example, the following embodiments, but is not limited thereto: [1A] A pharmaceutical preparation comprising an aqueous composition containing Ripasudil or a salt thereof or a solvate thereof and a lower aliphatic carboxylic acid, the aqueous composition having a dissolved oxygen content of 8.5 mg / L or more (preferably 8.7 mg / L or more, and particularly preferably 9 mg / L or more), which is contained in a polyethylene container. [2A] A pharmaceutical preparation comprising an aqueous composition containing Ripasudil or a salt thereof or a solvate thereof and a lower aliphatic carboxylic acid, the aqueous composition having a dissolved oxygen content of 8.5 to 13 mg / L (preferably 8.7 to 13 mg / L, and particularly preferably 9 to 13 mg / L), which is contained in a polyethylene container. [3A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof or a solvate thereof and lower aliphatic carboxylic acids, the composition having a dissolved oxygen content of 8.5 to 12 mg / L (preferably 8.7 to 12 mg / L, particularly preferably 9 to 12 mg / L), contained in a polyethylene container. [4A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof or a solvate thereof and lower aliphatic carboxylic acids, the composition having a dissolved oxygen content of 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, particularly preferably 9 to 11 mg / L), contained in a polyethylene container. [5A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof or a solvate thereof and lower aliphatic carboxylic acids, the composition having a dissolved oxygen content of 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, particularly preferably 9 to 10 mg / L), contained in a polyethylene container. [6A] The pharmaceutical formulation according to any one of [1A] to [5A], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, citric acid, acetic acid, sorbic acid, salts thereof, and solvates thereof. [7A] The pharmaceutical formulation according to any one of [1A] to [5A], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid, salts thereof, and solvates thereof. [8A] The pharmaceutical formulation according to any one of [1A] to [7A], wherein freezing of the aqueous composition is inhibited after low-temperature storage (preferably at -5°C, particularly preferably at -5°C for 2 weeks).

[0048] [1B] A method for suppressing freezing of an aqueous composition during low-temperature storage, comprising the steps of: adding lower aliphatic carboxylic acids to an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 mg / L or more (preferably about 8.7 mg / L or more, particularly preferably 9 mg / L or more), and placing the aqueous composition in a polyethylene container. [2B] A method for suppressing freezing of an aqueous composition during low-temperature storage, comprising the steps of: adding lower aliphatic carboxylic acids to an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 to 13 mg / L (preferably 8.7 to 13 mg / L, particularly preferably 9 to 13 mg / L), and placing the aqueous composition in a polyethylene container. [3B] A method for suppressing freezing of an aqueous composition during low-temperature storage, comprising the steps of: adding a lower aliphatic carboxylic acid to an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 to 12 mg / L (preferably 8.7 to 12 mg / L, particularly preferably 9 to 12 mg / L), and placing the aqueous composition in a polyethylene container. [4B] A method for suppressing freezing of an aqueous composition during low-temperature storage, comprising the steps of: adding a lower aliphatic carboxylic acid to an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, particularly preferably 9 to 11 mg / L), and placing the aqueous composition in a polyethylene container. [5B] A method for suppressing freezing of an aqueous composition during low-temperature storage, comprising the steps of adding lower aliphatic carboxylic acids to an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, particularly preferably 9 to 10 mg / L), and placing the aqueous composition in a polyethylene container. [6B] The method according to any of [1B] to [5B], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, citric acid, acetic acid, sorbic acid, salts thereof, and solvates thereof. [7B] The method according to any of [1B] to [6B], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid, salts thereof, and solvates thereof.

[0049] [1C] A method for producing a pharmaceutical preparation that is inhibited from freezing during low-temperature storage, comprising the steps of: adding lower aliphatic carboxylic acids to an aqueous composition that contains ripasudil, a salt thereof, or a solvate thereof and has a dissolved oxygen content of 8.5 mg / L or more (preferably 8.7 mg / L or more, particularly preferably 9 mg / L or more), and placing the aqueous composition in a polyethylene container. [2C] A method for producing a pharmaceutical preparation that is inhibited from freezing during low-temperature storage, comprising the steps of: adding lower aliphatic carboxylic acids to an aqueous composition that contains ripasudil, a salt thereof, or a solvate thereof and has a dissolved oxygen content of 8.5 to 13 mg / L (preferably 8.7 to 13 mg / L, particularly preferably 9 to 13 mg / L), and placing the aqueous composition in a polyethylene container. [3C] A method for producing a pharmaceutical preparation that is inhibited from freezing during low-temperature storage, comprising the steps of: adding a lower aliphatic carboxylic acid to an aqueous composition that contains ripasudil, a salt thereof, or a solvate thereof and has a dissolved oxygen content of 8.5 to 12 mg / L (preferably 8.7 to 12 mg / L, particularly preferably 9 to 12 mg / L), and placing the aqueous composition in a polyethylene container. [4C] A method for producing a pharmaceutical preparation that is inhibited from freezing during low-temperature storage, comprising the steps of: adding a lower aliphatic carboxylic acid to an aqueous composition that contains ripasudil, a salt thereof, or a solvate thereof and has a dissolved oxygen content of 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, particularly preferably 9 to 11 mg / L), and placing the aqueous composition in a polyethylene container. [5C] A method for producing a pharmaceutical preparation that is inhibited from freezing during low-temperature storage, comprising the steps of: adding lower aliphatic carboxylic acids to an aqueous composition that contains ripasudil or a salt thereof, or a solvate of either, and that has a dissolved oxygen content of 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, particularly preferably 9 to 10 mg / L); and placing the aqueous composition in a polyethylene container.

[0050] The present invention will now be further described with reference to examples, but is not limited to these examples. In the following test examples, ripasudil monohydrochloride dihydrate can be produced, for example, by the method described in WO 2006 / 057397.

[0051] Test Example 1 Storage Test 1 An aqueous composition containing the ingredients and amounts shown in Table 1 per 100 mL was prepared by a conventional method, and then the dissolved oxygen content was adjusted as shown in Table 1 by blowing in nitrogen gas, oxygen gas, or air while measuring and monitoring the dissolved oxygen content. The aqueous composition with the adjusted dissolved oxygen content was placed in a polyethylene (PE), polypropylene (PP), or glass eye drop container to prepare a pharmaceutical preparation. The dissolved oxygen content was measured using a dissolved oxygen meter (portable waterproof dissolved oxygen meter model AS720, manufactured by AS ONE Corporation) at an ambient temperature of 25°C.

[0052] Each of the obtained pharmaceutical preparations was stored at -5°C for 2 weeks, and the presence or absence of freezing of the aqueous composition in the container after storage was visually evaluated. Cases where no freezing occurred were evaluated as ◯, and cases where freezing occurred were evaluated as ×. Furthermore, in cases where freezing occurred, a comment was added regarding the appearance. The results are shown in Table 1. The amount of dissolved oxygen was rounded to one decimal place.

[0053]

[0054] As shown in Table 1, when a Ripasudil-containing aqueous composition with a dissolved oxygen content of 8.5 mg / L or more, specifically 9 mg / L, was placed in a polyolefin resin container (Examples 1 and 2), freezing of the entire aqueous composition was observed after storage at -5°C for 2 weeks. On the other hand, when a Ripasudil-containing aqueous composition with a dissolved oxygen content of less than 8.5 mg / L (3 or 6 mg / L) was placed in a polyolefin resin container (Examples 3 to 6), no freezing was observed after similar storage. This demonstrates that such freezing depends on the amount of dissolved oxygen in the Ripasudil-containing aqueous composition and is a phenomenon that occurs when the dissolved oxygen content is 8.5 mg / L or more. Furthermore, when an aqueous composition not containing Ripasudil and with a dissolved oxygen content of 8.5 mg / L or more was placed in a polyolefin resin container (Examples 7 and 8), or when a Ripasudil-containing aqueous composition with a dissolved oxygen content of 8.5 mg / L or more was placed in a glass container (Example 9), no freezing was observed after low-temperature storage. This indicates that the freezing is caused by the aqueous composition containing Ripassil and being contained in a polyolefin resin container.

[0055] From the above, it was found that when the dissolved oxygen content of a Ripasudil-containing aqueous composition stored in a polyolefin resin container is a high value of 8.5 mg / L or more, the phenomenon of freezing specifically occurs when stored at low temperatures.

[0056] Test Example 2 Storage Test 2 An aqueous composition containing the ingredients and amounts shown in Table 2 per 100 mL was prepared by a conventional method, and then the dissolved oxygen content was adjusted as shown in Table 2 by blowing in nitrogen gas, oxygen gas, or air while measuring and monitoring the dissolved oxygen content. The aqueous composition with the adjusted dissolved oxygen content was placed in a polyethylene (PE) or polypropylene (PP) eye drop container to prepare a pharmaceutical preparation. The dissolved oxygen content was measured using a dissolved oxygen meter (portable waterproof dissolved oxygen meter, model AS720, manufactured by AS ONE Corporation) at an ambient temperature of 25°C.

[0057] Each of the obtained pharmaceutical preparations was stored at −5° C. for 2 weeks, and the presence or absence of freezing of the aqueous composition in the container after storage was evaluated in the same manner as in Test Example 1. The results are shown in Table 2. The amount of dissolved oxygen was rounded to one decimal place.

[0058]

[0059] As shown in Table 2, freezing of the entire aqueous composition was confirmed after 2 weeks of storage at −5° C. in both the pharmaceutical preparation of Comparative Example 1, in which a Ripasudil-containing aqueous composition having a dissolved oxygen content of 8.5 mg / L or more, specifically 9 mg / L, was contained in a polyethylene container, and the pharmaceutical preparation of Comparative Example 2, in which a Ripasudil-containing aqueous composition having a dissolved oxygen content of 8.5 mg / L or more further contained sodium edetate hydrate and the aqueous composition was contained in a polypropylene container. On the other hand, no freezing was confirmed after similar storage in the pharmaceutical preparation of Example 1, in which a Ripasudil-containing aqueous composition having a dissolved oxygen content of 8.5 mg / L or more further contained sodium edetate hydrate and the aqueous composition was contained in a polyethylene container. From the above, it has become clear that when a Ripasudil-containing aqueous composition having a dissolved oxygen content of 8.5 mg / L or more is made to contain lower aliphatic carboxylic acids represented by one or more selected from the group consisting of edetic acid and its salts and solvates thereof, and the aqueous composition is contained in a polyethylene container, among other polyolefin resin containers, freezing during low-temperature storage can be relatively suppressed compared to cases where the requirements are not met.

[0060] In addition, when one or more types selected from the group consisting of epsilon-aminocaproic acid, citric acid, acetic acid, sorbic acid, salts thereof, and solvates thereof are used as the lower aliphatic carboxylic acids instead of one or more types selected from the group consisting of edetic acid, salts thereof, and solvates thereof, a similar inhibitory effect on freezing during low-temperature storage can be confirmed.

[0061] Test Example 3 Storage Test 3 An aqueous composition containing the ingredients and amounts shown in Table 3 per 100 mL was prepared by a conventional method, and then the dissolved oxygen content was adjusted as shown in Table 3 by blowing in nitrogen gas, oxygen gas, or air while measuring and monitoring the dissolved oxygen content. The aqueous composition with the adjusted dissolved oxygen content was placed in a polyethylene (PE) eye drop container to prepare a pharmaceutical preparation. The dissolved oxygen content was measured using a dissolved oxygen meter (portable waterproof dissolved oxygen meter model AS720, manufactured by AS ONE Corporation) at an ambient temperature of 25°C.

[0062] Each of the obtained pharmaceutical preparations was stored at −5° C. for 2 weeks, and the presence or absence of freezing of the aqueous composition in the container after storage was evaluated in the same manner as in Test Example 1. The results are shown in Table 3. The amount of dissolved oxygen was rounded to one decimal place.

[0063]

[0064] As shown in Table 3, in the pharmaceutical preparations of Examples 2 and 3, in which sodium edetate hydrate was added to a Ripasudil-containing aqueous composition having a dissolved oxygen content of 11.0 mg / L or 13.0 mg / L, respectively, and the aqueous compositions were contained in polyethylene containers, no freezing was observed after 2 weeks of storage at -5°C, as with the pharmaceutical preparation of Example 1. [Preparation Examples 1 to 5] Aqueous compositions containing the ingredients and amounts shown in Table 4 per 100 mL were prepared by a conventional method, and then the dissolved oxygen content was adjusted to the value shown in Table 3 by bubbling in nitrogen gas, oxygen gas, or air while measuring and monitoring the dissolved oxygen content, and these were then contained in polyethylene containers for eye drops, to obtain the pharmaceutical preparations of Preparation Examples 1 to 5.

[0065]

[0066] [Preparation Examples 6 to 10] Aqueous compositions containing the ingredients and amounts shown in Table 5 per 100 mL were prepared by a conventional method, and then the amount of dissolved oxygen was adjusted to the level shown in Table 4 by blowing in nitrogen gas, oxygen gas, or air while measuring and monitoring the amount of dissolved oxygen. These were then placed in polyethylene eye drop containers to obtain pharmaceutical preparations of Preparation Examples 6 to 10.

[0067]

[0068] [Preparation Examples 11 to 15] Aqueous compositions containing the ingredients and amounts shown in Table 6 per 100 mL were prepared by a conventional method, and then the amount of dissolved oxygen was adjusted to the level shown in Table 5 by blowing in nitrogen gas, oxygen gas, or air while measuring and monitoring the amount of dissolved oxygen. These were then placed in polyethylene eye drop containers to obtain pharmaceutical preparations of Preparation Examples 11 to 15.

[0069]

[0070] [Preparation Examples 16 to 20] Aqueous compositions containing the ingredients and amounts shown in Table 7 per 100 mL were prepared by a conventional method, and then the amount of dissolved oxygen was adjusted to the level shown in Table 6 by blowing in nitrogen gas, oxygen gas, or air while measuring and monitoring the amount of dissolved oxygen. This was then placed in a polyethylene eye drop container to obtain the pharmaceutical preparations of Preparation Examples 16 to 20.

[0071]

[0072] [Preparation Examples 21 to 25] Aqueous compositions containing the ingredients and amounts shown in Table 8 per 100 mL were prepared by a conventional method, and then the amount of dissolved oxygen was adjusted to the level shown in Table 7 by blowing in nitrogen gas, oxygen gas, or air while measuring and monitoring the amount of dissolved oxygen. These were then placed in polyethylene eye drop containers to obtain pharmaceutical preparations of Preparation Examples 21 to 25.

[0073]

[0074] [Preparation Examples 26 to 30] Aqueous compositions containing the ingredients and amounts shown in Table 9 per 100 mL were prepared by a conventional method, and then the amount of dissolved oxygen was adjusted to the amount shown in Table 8 by blowing in nitrogen gas, oxygen gas, or air while measuring and monitoring the amount of dissolved oxygen. This was then placed in a polyethylene eye drop container to obtain the pharmaceutical preparations of Preparation Examples 26 to 30.

[0075]

[0076] According to the present invention, a pharmaceutical preparation having excellent storage stability can be provided, and can be suitably used in the pharmaceutical industry and the like.

Claims

1. A pharmaceutical preparation comprising an aqueous composition having a dissolved oxygen content of 8.5 mg / L or more, which contains ripasudil or a salt thereof or a solvate thereof, and one or more members selected from the group consisting of edetic acid and a salt thereof and a solvate thereof, and which is contained in a polyethylene container.

2. The pharmaceutical preparation according to claim 1, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg / L.

3. The pharmaceutical preparation according to claim 1, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg / L.

4. The pharmaceutical preparation according to claim 1, wherein the aqueous composition has a dissolved oxygen content of 8.5 to 11 mg / L.

5. A method for preventing freezing of an aqueous composition, comprising the steps of adding one or more members selected from the group consisting of edetic acid, its salts, and solvates thereof to an aqueous composition containing Ripasudil or its salts, or solvates thereof, and having a dissolved oxygen content of 8.5 mg / L or more, and placing the aqueous composition in a polyethylene container.

6. The method for inhibiting freezing of an aqueous composition according to claim 5, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg / L.

7. The method for inhibiting freezing of an aqueous composition according to claim 5, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg / L.

8. The method for inhibiting freezing of an aqueous composition according to claim 5, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 11 mg / L.

9. A method for producing a pharmaceutical preparation in which freezing of the aqueous composition is inhibited, the method comprising the steps of: adding one or more members selected from the group consisting of edetic acid and its salts and solvates thereof to an aqueous composition containing ripasudil or its salts or solvates and having a dissolved oxygen content of 8.5 mg / L or more; and placing the aqueous composition in a polyethylene container.

10. The method for producing a pharmaceutical preparation in which the aqueous composition is inhibited from freezing according to claim 9, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg / L.

11. The method for producing a pharmaceutical preparation in which the aqueous composition is inhibited from freezing according to claim 9, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg / L.

12. The method for producing a pharmaceutical preparation in which the aqueous composition is inhibited from freezing according to claim 9, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 11 mg / L.

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