Pharmaceuticals

Abstract

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. The present invention relates to 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 of either or both, and a lower aliphatic carboxylic acid, and which is contained in a polyethylene container.

Description

[Technical field]

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

[0002] The structural formula:

[0003] [ka]

[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 eye diseases. Specifically, it has been reported that it is 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). In addition, "Granatec" (registered trademark) and "GlaAlpha" (registered trademark) have been developed and marketed in several countries including Japan as preventive and therapeutic agents for ocular hypertension and glaucoma, which contain ripasudil hydrochloride hydrate as an active ingredient (Non-Patent Documents 1 and 2). Therefore, it would be extremely useful to establish a technique for stably formulating Ripasudil, for example, as an ophthalmic agent.

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

[0006] [Patent Document 1] Patent No. 4212149 [Patent Document 2] International Publication No. 2006 / 068208 Brochure [Patent Document 3] Patent No. 5557408 [Patent Document 4] Patent No. 6244038 [Non-patent literature]

[0007] [Non-Patent Document 1] Pharmaceutical interview form "Granatec (registered trademark) eye drops 0.4%" Kowa Company, Ltd., September 2023 [Non-Patent Document 2] Pharmaceutical interview form "GlaAlpha (registered trademark) combination eye drops" Kowa Company, Ltd., June 2024 Summary of the Invention [Problem to be solved by the invention]

[0008] Ophthalmic preparations and the like are usually compositions containing water (aqueous compositions). Therefore, the present inventors have studied the storage stability of an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof (hereinafter, sometimes referred to as "Ripasudil-containing aqueous composition"). However, when an investigation was conducted into the case where a Ripasudil-containing aqueous composition was contained in a polyolefin resin container, it was found that while no problems arose when the composition was stored at room temperature (1 to 30°C), a problem arose in that the aqueous composition may freeze over time when stored at temperatures as low as -5°C, and when the amount of dissolved oxygen in the Ripasudil-containing aqueous composition was 8.5 mg / L or more.

[0009] This problem can be solved, for example, by adjusting the amount of dissolved oxygen in the Ripasudil-containing aqueous composition to a low level. In this regard, in order to adjust the amount of dissolved oxygen in the Ripasudil-containing aqueous composition to a low level, for example, methods such as replacing the dissolved oxygen with an inert gas by nitrogen purging or vacuum deaeration can be considered. 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. [Means for solving the problem]

[0010] The inventors have further conducted 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 further contains lower aliphatic carboxylic acids represented by one or more selected from the group consisting of edetic acid and its salts and solvates thereof, and when the aqueous composition is contained in a polyolefin resin container, especially a polyethylene container, and thus completed the present invention.

[0011] That is, the present invention provides a pharmaceutical formulation comprising an aqueous composition containing Ripasudil or a salt thereof, or a solvate of either, and a lower aliphatic carboxylic acid, and having a dissolved oxygen content of 8.5 mg / L or more, 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 lower aliphatic carboxylic acids to an aqueous composition which contains Ripasudil or a salt thereof, or a solvate thereof and has a dissolved oxygen content of 8.5 mg / L or more, and placing 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 lower aliphatic carboxylic acids to an aqueous composition which contains Ripasudil or a salt thereof, or a solvate of either and has a dissolved oxygen content of 8.5 mg / L or more, and placing the aqueous composition in a polyethylene container. Effect of the Invention

[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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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 or its salt or solvate> 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 pharma- ceutically acceptable salt, and specific examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide; organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate, and the like, and hydrochloride is preferred. Furthermore, Ripasudil or a salt thereof may be a solvate such as a hydrate or an alcohol solvate, and is preferably a hydrate.

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

[0016] [ka]

[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 a known method. 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 its salt or solvate thereof in the aqueous composition is not particularly limited and may be appropriately determined depending on the disease to be treated, the patient's sex, age, symptoms, etc., but from the viewpoint of obtaining an excellent pharmacological effect, it may contain 0.01 w / v% or more, preferably 0.02 w / v% or more, 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 contain 10 w / v% or less, preferably 8 w / v% or less, particularly preferably 6 w / v% or less. Among them, from the viewpoint of obtaining an excellent pharmacological effect, it is preferable to contain Ripasudil or its salt or solvate thereof in an amount of 0.05 to 5 w / v% in terms of the free form, 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% relative to the total volume of the aqueous composition.

[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 in which one or more carbon atoms may be replaced by a nitrogen atom, and salts thereof (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.), and solvates thereof (hydrates, etc.). Here, the number of carbon atoms in the lower aliphatic carboxylic acids is not particularly limited as long as it is about 15 or less, but from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, it is preferably 2 to 12, more preferably 4 to 12, and particularly preferably 6 to 12. Among these carbon atoms, carbon atoms other than those constituting the carboxyl group may be partially replaced with nitrogen atoms, but from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, the number of such nitrogen atom replacements 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 about 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 hydroxyl groups and amino groups. The lower aliphatic carboxylic acids are known compounds, and may be produced by known methods or may be commercially available. The lower aliphatic carboxylic acids may be used in the form of a salt or complex with other components, and the aqueous composition containing the component that forms such a salt or complex is also included 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, and the like. 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, its salts, and solvates thereof; acetic acid, acetic acid At least one 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; at least one selected from the group consisting of tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, and potassium sodium tartrate, and solvates thereof; at least one selected from the group consisting of sorbic acid and its salts, such as sorbic acid and potassium sorbate, 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 malic acid include malic acid, DL-malic acid, DL-sodium malate, and other malic acids and their salts, and solvates thereof, and these may be used alone or in combination of two or more. These lower aliphatic carboxylic acids are all known and may be produced by known methods, or commercially available products may be used.

[0023] As the lower aliphatic carboxylic acid, from the viewpoint of suppressing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, citric acid, acetic acid, sorbic acid, and their salts and solvates are preferred, one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, and their salts and solvates are more preferred, and one or more selected from the group consisting of edetic acid, its salts, and solvates are particularly preferred. By using one or more selected from the group consisting of edetic acid, its salts, and solvates 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 contained in an amount of 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 contained in an amount of 5 w / v% or less, preferably 3.5 w / v% or less, and particularly preferably 1 w / v%. In particular, when one or more types selected from the group consisting of epsilon-aminocaproic acid and 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 0.003 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. In particular, when one or more types selected from the group consisting of edetic acid and 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 0.0003 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. In particular, when one or more types selected from the group consisting of citric acid and 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 0.006 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. In particular, when one or more types selected from the group consisting of acetic acid and 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 0.003 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. In particular, when one or more types selected from the group consisting of sorbic acid and 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] In addition, the mass ratio of Ripasudil or a salt thereof, or a solvate thereof, and 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 part by mass or more, preferably 0.01 part by mass or more, more preferably 0.3 part by mass or more, more preferably 0.6 part by mass or more, and even more preferably 0.8 part by mass or more of lower aliphatic carboxylic acids per part by mass of Ripasudil, calculated as the free form, and may contain 8 parts by mass or less, preferably 4 parts by mass or less, and particularly preferably 3 parts by mass or less. In particular, when one or more types selected from the group consisting of epsilon-aminocaproic acid and 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 0.05 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 and its salts and solvates thereof per 1 part by mass of Ripasudil converted into its free form. 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 1 part by mass of Ripasudil converted into its free form. In particular, when one or more types selected from the group consisting of citric acid and 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 and its salts and solvates thereof per 1 part by mass of Ripasudil converted into its free form. In particular, when one or more types selected from the group consisting of acetic acid and 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 0.03 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 and its salts and solvates thereof per 1 part by mass of Ripasudil converted into its free form. 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, it is preferable to contain 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 1 part by mass of Ripasudil converted into its free form.

[0026] <Dissolved oxygen content> In the present invention, the amount of dissolved oxygen in the Ripasudil-containing aqueous composition must be 8.5 mg / L or more. As shown in the test examples described later, when the amount of dissolved oxygen in the Ripasudil-containing aqueous composition is 8.5 mg / L or more, freezing over time during low-temperature storage can occur, but by further adding lower aliphatic carboxylic acids to the Ripasudil-containing aqueous composition and storing 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 in order to reduce and maintain the amount of dissolved oxygen, 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 in which a Ripasudil-containing aqueous composition having good storage stability and which is inhibited from freezing over time when stored at low temperatures is contained in a container.

[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 to 9.5 mg / L). It is preferable that the concentration is 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), and it is particularly preferable that the concentration is 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 amount of dissolved oxygen refers to a value measured by a membrane electrode method, particularly a polarographic method (a membrane polarographic method). Examples of the dissolved oxygen meter used to measure the amount of dissolved oxygen by such a method include a portable waterproof dissolved oxygen meter, model number AS720 (manufactured by AS ONE Corporation). In the present invention, the amount of dissolved oxygen is measured when the pharmaceutical preparation is continuously stored under the specified storage conditions (storage method). That is, for example, for a pharmaceutical preparation whose storage method is specified as "room temperature storage", the amount of dissolved oxygen in the Ripasudil-containing aqueous composition for the pharmaceutical preparation stored at any temperature in the range of 1 to 30°C may be measured according to the meaning of "room temperature" (1 to 30°C) specified in the Japanese Pharmacopoeia, 18th Edition. If the amount of dissolved oxygen is 9 mg / L or more under the normally expected storage conditions, freezing can be advantageously suppressed even when exposed to a low-temperature environment due to some accident during distribution or storage.

[0029] No special process is required to make the dissolved oxygen content of the Ripasudil-containing aqueous composition 8.5 mg / L or more. For example, a person skilled in the art can appropriately make the dissolved oxygen content 8.5 mg / L or more by simple ingenuity in the manufacturing process usually assumed for Ripasudil-containing aqueous compositions, such as adjusting the stirring speed or stirring blades so as to incorporate air when mixing the aqueous composition. Therefore, according to the present invention, the labor and cost are significantly less than actively and forcibly adjusting and maintaining the dissolved oxygen content at a low value. In addition, a means such as blowing in oxygen gas may be adopted within a range that does not impose an excessive burden in terms of labor and cost. In this specification, "an aqueous composition having a dissolved oxygen content of 8.5 mg / L or more" is not limited to an aqueous composition in which the dissolved oxygen content has been intentionally "adjusted" to 8.5 mg / L or more, but also includes an aqueous composition in which the dissolved oxygen content naturally fluctuates to that range after production. Such interpretation guidelines are also applicable to cases 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). The water in the composition may be, for example, purified water, water for injection, sterilized purified water, etc. The water content 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 described in, for example, the 18th revised Japanese Pharmacopoeia, General Provisions for Preparations, etc. The dosage form is not particularly limited as long as it can be accommodated in a container described later, and examples thereof include injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal drops, enemas, external solutions, sprays, ointments, creams, gels, oral solutions, syrups, etc. From the viewpoint of advantageously utilizing the pharmacological action of Ripasudil, the dosage form is preferably an agent for eye diseases, specifically eye drops and eye ointments, and more preferably eye drops.

[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 regulators, 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, and crystalline phosphoric acid. Sodium dihydrogen, geraniol, sodium chondroitin sulfate, titanium dioxide, gellan gum, dibutyl hydroxytoluene, potassium bromide, benzododecyl bromide, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution, taurine, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyloxapol, trometamol, concentrated glycerin, concentrated mixed tocopherols, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride solution 50, paraoxybenzoic acid Ethyl, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin, sodium pyrosulfite, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalkonium chloride, benzalkonium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, borax, boric acid, povidone, polyoxyethylene (200), polyoxypropylene glycol (70), sodium polystyrene sulfonate, polysorbate 80, polio Hydrogenated castor oil 60, polyvinyl alcohol (partially saponified), d-borneol, macrogol 4000, macrogol 6000, D-mannitol, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methanesulfonic acid, l-menthol, monoethanolamine, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, ryunou, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate,Examples include Vaseline.

[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 l-menthol.

[0034] The aqueous composition may further contain other medicinal ingredients in addition to the above, depending on the application disease, etc. Examples of such medicinal ingredients include α1 receptor blockers including bunazosin or a salt thereof or a solvate thereof, such as bunazosin hydrochloride; brimonidine or a salt thereof or a solvate thereof, such as brimonidine tartrate; α2 receptor agonists including apraclonidine or a salt thereof or a solvate thereof, such as carteolol hydrochloride, such as nipradilol or a salt thereof or a solvate thereof, timolol or a salt thereof or a solvate thereof, such as timolol maleate, betaxolol or a salt thereof or a solvate thereof, such as betaxolol hydrochloride, levobunolol or a salt thereof or a solvate thereof, such as levobunolol hydrochloride, befunolol or a salt thereof or a solvate thereof, and β-blockers including metipranolol or a salt thereof or a solvate thereof; Rho kinase inhibitors including netarsudil or a salt thereof or a solvate thereof, such as netarsudil mesylate; dorzolamide hydrochloride, etc. carbonic anhydrase inhibitors including azolamide or a salt thereof or a solvate thereof, brinzolamide or a salt thereof or a solvate thereof, acetazolamide or a salt thereof or a solvate thereof, dichlorphenamide or a salt thereof or a solvate thereof, methazolamide or a salt thereof or a solvate thereof; isopropyl unoprostone or a salt thereof or a solvate thereof, tafluprost or a salt thereof or a solvate thereof, travoprost or a salt thereof or a solvate thereof, bimatoprost or a salt thereof or a solvate thereof, prostaglandin F2α derivatives including prost or its salts or solvates thereof, latanoprost or its salts or solvates thereof, cloprostenol or its salts or solvates thereof, and fluprostenol or its salts or solvates thereof; sympathomimetics including dipivefrin or its salts or solvates thereof such as dipivefrin hydrochloride, epinephrine, epinephrine borate, epinephrine hydrochloride, or its salts or solvates thereof;Parasympathomimetics including distigmine bromide or its salts or solvates thereof, pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate or other such pilocarpine or its salts or solvates thereof, carbachol or its salts or solvates thereof; calcium antagonists including lomerizine or its salts or solvates thereof such as lomerizine hydrochloride; cholinesterase inhibitors including demecarium or its salts or solvates thereof, echothiophate or its salts or solvates thereof, physostigmine or its salts or solvates thereof; EP2 receptor agonists including omidenepag isopropyl or other such omidenepag or its salts or solvates thereof, and one or more of these may be combined; The other active ingredient is preferably one or more selected from the group consisting of brimonidine, latanoprost, nipradilol, dorzolamide, brinzolamide, timolol, omidenepagisopropyl, and salts thereof.

[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 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" encompasses any of the terms "sealed container", "airtight container" and "sealed container" 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, bag containers, etc.

[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 in which a polyethylene layer is provided as an inner layer that comes into contact with the aqueous composition and a resin of another material is laminated on the outside also falls under the category of a "polyethylene container". Here, 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 may be used in combination. In this specification, "made of polyethylene" means that at least a part of the material contains polyethylene; for example, a mixture of two or more resins, including polyethylene and a resin other than polyethylene (polymer alloy), is also included in "made of polyethylene."

[0039] It is preferable to further knead a substance that blocks the transmission of ultraviolet light, such as an ultraviolet absorbing agent 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 include zinc oxide. Examples of ultraviolet absorbers include 2-(2H-benzotriazol-2-yl)-p-cresol (e.g., Tinuvin P, manufactured by BASF), 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol (e.g., Tinuvin 234, manufactured by BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)benzotriazole (e.g., Tinuvin 320, manufactured by BASF), 2-[5-chloro(2H)-benzotriazol-2-yl]-4-methyl-6-(tert-butyl)phenol (e.g., Tinuvin 326, manufactured by BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)-5-chlorobenzotriazole (e.g., Tinuvin 327, manufactured by 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 product of methyl 3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionate with polyethylene glycol 300 (e.g., Tinuvin 213: BASF), 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol (e.g., Tinuvin 571: BASF), benzotriazole-based ultraviolet absorbers such as 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole, 2-[2'-hydroxy-3'-(3'',4'',5'',6''-tetrahydrophthalimidomethyl)-5'-methylphenyl]benzotriazole, and 2,2'-methylenebis[4-(1,1,3,3-tetramethylbutyl)-6-(2H-benzotriazol-2-yl)phenol];Cyanoacrylate-based UV 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 UV 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), oxybenzone, hydroxymethoxybenzophenone sulfonic acid, hydroxymethoxybenzophenone sodium sulfonate, dihydroxydimethoxybenzophenone, dihydroxydimethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, tetrahydroxybenzophenone and other benzophenone-based ultraviolet absorbers; methyl diisopropylcinnamate, cinoxate, glyceryl di-p-methoxycinnamate mono-2-ethylhexanoate, isopropyl p-methoxycinnamate / diisopropylcinnamate mixture, 2-ethylhexyl p-methoxycinnamate, benzyl cinnamate cinnamic acid-based UV 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 UV absorbers such as ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, and methyl salicylate; guaiazulene; 2-ethylhexyl dimethoxybenzylidene dioxoimidazolidinepropionate;2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,5-triazine; parahydroxyanisole; 4-tert-butyl-4'-methoxydibenzoylmethane; phenylbenzimidazole sulfonic acid; 2-(4-diethylamino-2-hydroxybenzoyl)-hexyl benzoate;

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

[0041] The inside of the container is preferably visible (observable) with the naked eye. If the inside is visible, there are advantages such as enabling inspection for the presence or absence of foreign matter in the manufacturing process of the pharmaceutical preparation, and enabling users of the pharmaceutical preparation to check the remaining amount of the contents (aqueous composition). Here, visibility is sufficient as long as at least a part 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 to be visible as long as the bottom surface is visible). If the inside is visible from a part of the container surface, this allows the aqueous composition in the container to be confirmed.

[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 indication of the "pharmaceutical preparation" is 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 and glaucoma based on its Rho kinase inhibitory activity and intraocular pressure reducing activity. More specific examples of glaucoma include primary open-angle glaucoma, normal tension glaucoma, aqueous humor hyperproduction 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] As disclosed in Japanese Patent No. 5557408, ocular fundus diseases (lesions mainly occurring in the retina and / or choroid. Specific examples thereof include fundus changes due to hypertension and arteriosclerosis, retinal vein occlusions such as central retinal artery occlusion, central retinal vein occlusion, and branch retinal vein occlusion, congenital retinal vascular anomalies such as diabetic retinopathy, diabetic macular edema, diabetic macular edema, Eales disease, and Coats disease, von Hippel disease, pulseless disease, macular diseases (central serous chorioretinopathy, cystoid macular edema, age-related macular degeneration, macular hole, myopic macular atrophy, etc.), and other diseases. degeneration), vitreoretinal interface macular degeneration, drug-induced macular degeneration, hereditary macular degeneration, etc.), retinal detachment (rhegmatogenous, tractional, exudative, etc.), retinitis pigmentosa, retinopathy of prematurity, etc.), more preferably as an agent for the prevention or treatment of diabetic retinopathy, diabetic macular edema, or age-related macular degeneration. Furthermore, as disclosed in Japanese Patent No. 5657252, it can also be used as an agent for preventing and / or treating corneal endothelial disorders.

[0045] <Significance of other terms> In the present invention, "low-temperature storage" refers to storage at a temperature lower than room temperature (1 to 30°C) that a pharmaceutical preparation may accidentally encounter during distribution or storage after production, and 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 is a concept that also includes the case where only a part of the composition is frozen. In the present invention, "suppression" of freezing means that by taking the technical means disclosed in this specification, "freezing" is suppressed for a relatively longer period of time compared to when such means are not taken, or that by taking the technical means disclosed in this specification, the extent of "freezing" over the same period of time is suppressed (the range / spread of freezing is smaller) compared to when such means are not taken, and does not necessarily mean that the Ripasudil-containing aqueous composition will not freeze at all. For example, if the evaluation target contains edetic acid as a lower aliphatic carboxylic acid, and a comparison target that does not contain edetic acid but has equivalent components, dissolved oxygen content, etc. is prepared and stored under the same low-temperature storage conditions, it means that the evaluation target will be inhibited from "freezing" for a relatively longer period of time than the comparison target, or that the degree of "freezing" will be inhibited at the same time.

[0046] <Method for preventing freezing, and method for producing pharmaceutical preparations> The present invention also relates to a method for preventing freezing of an aqueous composition during low-temperature storage, the method comprising the steps of adding lower aliphatic carboxylic acids to an aqueous composition which contains Ripasudil or a salt thereof, or a solvate thereof and has a dissolved oxygen content of 8.5 mg / L or more, and placing the aqueous composition in a polyethylene container. Furthermore, the present invention also relates to a method for producing a pharmaceutical preparation that is inhibited from freezing during low-temperature storage, the method 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 has a dissolved oxygen content of 8.5 mg / L or more, and placing the aqueous composition in a polyethylene container. In the above method, the order of the step of incorporating Ripasudil into the aqueous composition, the step of incorporating a lower aliphatic carboxylic acid into the aqueous composition, and the step of placing the aqueous composition in a polyethylene container does not matter. In addition, the timing at which the amount of dissolved oxygen in the aqueous composition becomes 8.5 mg / L or more does not matter, and as long as the amount of dissolved oxygen in the aqueous composition becomes 8.5 mg / L or more at any timing, it can be considered as the "method for inhibiting freezing" or the "method for producing a pharmaceutical preparation" disclosed in the present specification. The meanings of other various terms, the amounts of each ingredient, etc. are all the same as those explained for the "pharmaceutical preparation" above.

[0047] The present invention discloses, for example, embodiments of the following aspects, but is in no way limited thereto. [1A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof, or a solvate of either, and a lower aliphatic carboxylic acid, and 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) 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 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) contained in a polyethylene container. [3A] 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 12 mg / L (preferably 8.7 to 12 mg / L, and 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 of either, and a lower aliphatic carboxylic acid, and having a dissolved oxygen content of 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, and particularly preferably 9 to 11 mg / L), which is contained in a polyethylene container. [5A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof or a solvate thereof and a lower aliphatic carboxylic acid, the composition having a dissolved oxygen content of 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, and particularly preferably 9 to 10 mg / L) in a polyethylene container. [6A] The pharmaceutical preparation 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 preparation 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, a salt thereof, and a solvate thereof. [8A] The pharmaceutical formulation according to any one of [1A] to [7A], wherein freezing of the aqueous composition is suppressed after low-temperature storage (preferably storage at -5°C, particularly preferably storage at -5°C for 2 weeks).

[0048] [1B] A method for preventing 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 of either of them 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 which contains Ripasudil or a salt thereof, or a solvate of either, 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. [3B] 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 which contains Ripasudil or a salt thereof, or a solvate of either, 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. [4B] 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 which contains Ripasudil or a salt thereof, or a solvate of either, 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. [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 which contains Ripasudil or a salt thereof, or a solvate of either, and 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. [6B] The method according to any one 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 one of [1B] to [6B], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid, a salt thereof, and a solvate thereof.

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

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

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

[0052] The obtained pharmaceutical preparations were 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 made regarding the appearance. The results are shown in Table 1. The amount of dissolved oxygen was rounded off to one decimal place.

[0053] [Table 1]

[0054] As shown in the results in Table 1, when a Ripasudil-containing aqueous composition having 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 confirmed after storage at -5°C for 2 weeks. On the other hand, when a Ripasudil-containing aqueous composition having 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 confirmed after similar storage. From this, it was revealed that such freezing depends on the amount of dissolved oxygen in the Ripasudil-containing aqueous composition, and is a phenomenon that occurs when the amount of dissolved oxygen is 8.5 mg / L or more. Furthermore, when an aqueous composition not containing Ripasudil and having a dissolved oxygen content of 8.5 mg / L or more was placed in a polyolefin resin container (Examples 7 and 8), and when an aqueous composition containing Ripasudil and having 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 demonstrated that such freezing was due to the aqueous composition containing Ripasudil and being placed in a polyolefin resin container.

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

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

[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 off to one decimal place.

[0058] [Table 2]

[0059] As shown in the results in Table 2, freezing of the entire aqueous composition was confirmed after storage for 2 weeks 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 polyolefin resin container, especially a polyethylene container, 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, its salts, and solvates thereof, a similar effect of inhibiting freezing during low-temperature storage can be confirmed.

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

[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 off to one decimal place.

[0063] [Table 3]

[0064] As shown in the results 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 composition was contained in a polyethylene container, no freezing was observed at all after storage at -5°C for 2 weeks, as was the case with the pharmaceutical preparation of Example 1. [Manufacturing Examples 1 to 5] An aqueous composition containing the ingredients and amounts shown in Table 4 in 100 mL was prepared by a conventional method, and the amount of dissolved oxygen was adjusted to the amount shown in Table 3 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 Manufacturing Examples 1 to 5.

[0065] [Table 4]

[0066] [Manufacturing Examples 6-10] An aqueous composition containing the ingredients and amounts shown in Table 5 in 100 mL was prepared by a conventional method, and the amount of dissolved oxygen was adjusted to the amount shown in Table 4 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 Manufacturing Examples 6 to 10.

[0067] [Table 5]

[0068] [Examples 11 to 15] An aqueous composition containing the ingredients and amounts shown in Table 6 in 100 mL was prepared by a conventional method, and the amount of dissolved oxygen was adjusted to the amount shown in Table 5 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 11 to 15.

[0069] [Table 6]

[0070] [Examples 16-20] An aqueous composition containing the ingredients and amounts shown in Table 7 in 100 mL was prepared by a conventional method, and the amount of dissolved oxygen was adjusted to the amount 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 Manufacturing Examples 16 to 20.

[0071] [Table 7]

[0072] [Examples 21-25] An aqueous composition containing the ingredients and amounts shown in Table 8 in 100 mL was prepared by a conventional method, and the amount of dissolved oxygen was adjusted to the amount shown in Table 7 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 Manufacturing Examples 21 to 25.

[0073] [Table 8]

[0074] [Examples 26-30] An aqueous composition containing the ingredients and amounts shown in Table 9 in 100 mL was prepared by a conventional method, and 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] [Table 9] [Industrial Applicability]

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

Claims

1. A pharmaceutical preparation comprising an aqueous composition containing lipasudil or its salt or a solvate thereof, and one or more selected from the group consisting of edetic acid and its salt and solvates thereof, with a dissolved oxygen content of 8.5 mg / L or more, contained in a polyethylene container.

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

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

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

5. A method for producing a pharmaceutical formulation in which freezing of an aqueous composition is suppressed, comprising the steps of: adding one or more substances selected from the group consisting of edetic acid and its salts and their solvates to an aqueous composition containing lipasudil or a salt thereof or a solvate thereof, and having a dissolved oxygen content of 8.5 mg / L or more; and housing the aqueous composition in a polyethylene container.

6. A method for producing a pharmaceutical formulation in which the freezing of the aqueous composition is suppressed, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 13 mg / L, according to claim 5.

7. A method for producing a pharmaceutical formulation in which the freezing of the aqueous composition is suppressed, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 12 mg / L, according to claim 5.

8. A method for producing a pharmaceutical formulation in which the freezing of the aqueous composition is suppressed, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 11 mg / L, according to claim 5.