Pharmaceuticals

Abstract

The object of the present invention is to provide a technology for suppressing 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 containing Ripasudil or a salt thereof, or a solvate of either, and a boric acid, the aqueous composition having a dissolved oxygen content of 8.5 mg / L or more, 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 objective 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 further conducted intensive research to solve the above-mentioned problems and discovered 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 a boric acid such as boric acid and the aqueous composition is contained in a polyethylene container, among other polyolefin resin containers, 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 boric 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 boric acid 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 boric acid to an aqueous composition which contains Ripasudil or a salt thereof, or a solvate of either of them 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] Particularly preferred is Ripasudil hydrochloride hydrate (Ripasudil monohydrochloride dihydrate) represented by the following formula:

[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] <Boric acid> In the present invention, the term "boric acids" means one or more compounds selected from the group consisting of boric acid, salts of boric acid, anhydrides of boric acid, anhydrides of salts of boric acid, solvates of boric acid, and solvates of salts of boric acid. Here, the "salt" of boric acid is not limited in any way so long as it is a pharmacologically acceptable salt, and examples thereof include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, ammonium salt, etc. Furthermore, the "solvates" of boric acid or salts of boric acid are not limited in any way so long as they are pharmacologically acceptable solvates, and examples thereof include hydrates, etc. In the present invention, as the boric acid, one kind of component corresponding to the boric acid can be used alone, or two or more kinds can be used in appropriate combination. These boric acids are all known and may be produced by known methods, or commercially available products may be used.

[0021] Specific examples of the boric acid include boric acid, ammonium borate, borax, etc. In the present invention, the boric acid is preferably one or more selected from the group consisting of boric acid and its salts, and more preferably boric acid, from the viewpoint of suppressing freezing during low-temperature storage of the Ripasudil-containing aqueous composition.

[0022] The content of boric acid 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 6 w / v% or less, preferably 4 w / v% or less, and particularly preferably 2 w / v%. In particular, when boric acid is used as the boric acid compound, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, it is preferably contained at 0.03 to 5 w / v% relative to the total volume of the aqueous composition, more preferably at 0.07 to 3 w / v%, even more preferably at 0.15 to 2.0 w / v%, and particularly preferably at 0.3 to 1.5 w / v%.

[0023] In addition, the mass ratio of Ripasudil or a salt thereof, or a solvate thereof, and boric 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 0.05 part by mass or more, more preferably 0.1 part by mass or more, and even more preferably 0.5 part by mass or more of boric acids per part by mass of Ripasudil in its free form, and may contain 8 parts by mass or less, preferably 6 parts by mass or less, and particularly preferably 4 parts by mass or less. In particular, when boric acid is used as the boric acid compound, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, it is preferable to contain 0.3 to 7 parts by mass of boric acid per 1 part by mass of Ripasudil, calculated as the free form, more preferably 0.7 to 5 parts by mass, even more preferably 1 to 4 parts by mass, and particularly preferably 1 to 3 parts by mass.

[0024] <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 boric acid 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.

[0025] 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 9.5 to 12 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, More preferably, it 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, it 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).

[0026] 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 specified as the storage method to be "stored at room temperature", 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 8.5 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.

[0027] 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.

[0028] <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%.

[0029] 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.

[0030] In addition to the above, the aqueous composition may contain additives used in pharmaceuticals, quasi-drugs, etc. Examples of such additives include lower aliphatic carboxylic acids, 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 adipic acid, ascorbic acid, aspartic acid, sodium L-aspartate, magnesium L-aspartate, sodium bisulfite, alginic acid, sodium benzoate, benzyl benzoate, epsilon-aminocaproic acid, fennel oil, ethanol, ethylene-vinyl acetate copolymer, edetic acid, calcium sodium edetate hydrate, sodium edetate hydrate, tetrasodium edetate hydrate, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyl dihydrochloride, and the like. Aminoethylglycine solution, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, xylitol, citric acid, calcium citrate, citric acid hydrate, sodium citrate hydrate, sodium dihydrogen citrate, disodium citrate, glycerin, gluconic acid, creatinine, chlorhexidine, chlorobutanol, crystalline sodium dihydrogen phosphate, geraniol, succinic acid, monosodium succinate, disodium succinate hexahydrate, sodium chondroitin sulfate, acetic acid, ammonium acetate, potassium acetate Ingredients: Calcium acetate, Sodium acetate hydrate, Titanium dioxide, Gellan gum, Dibutyl hydroxytoluene, Potassium bromide, Benzododecinium bromide, Tartaric acid, D-Tartaric acid, Potassium hydrogen tartrate, Sodium DL-tartrate, Potassium sodium tartrate, Sodium hydroxide, Polyoxyl 45 stearate, Purified lanolin, D-sorbitol, Sorbitol solution, Sorbic acid, Potassium sorbate, Taurine, Sodium bicarbonate, Sodium carbonate hydrate, Sodium thiosulfate hydrate, Thimerosal, Tyloxapol, Trometamol, Lactic acid, Sodium lactate Liquid, calcium lactate hydrate, aluminum lactate, concentrated glycerin, concentrated mixed tocopherols, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride liquid 50, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin, sodium pyrosulfite, glacial acetic acid, phenylethyl alcohol, glucose, propionic acid, sodium propionate, propylene glycol, fumaric acid, bergamot oil, benzalkonium chloride, benzalkonium chloride liquid,Examples of the surfactant include benzyl alcohol, benzethonium chloride, benzethonium chloride solution, 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, maleic acid, malonic acid, D-mannitol, anhydrous edetate disodium, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium acetate, 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, ryuuno, malic acid, DL-malic acid, sodium DL-malate, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, and petrolatum. ,

[0031] Preferred examples of additives include potassium chloride, calcium chloride hydrate, edetic acid, calcium sodium edetate hydrate, sodium edetate hydrate, tetrasodium edetate hydrate, sodium chloride, magnesium chloride, glycerin, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, concentrated glycerin, 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.

[0032] 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.

[0033] 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.

[0034] <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" defined in the General Rules of the Japanese Pharmacopoeia, 18th Edition.

[0035] 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.

[0036] 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 can be used in combination. In the present invention, "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".

[0037] 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;

[0038] 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.

[0039] 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.

[0040] 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.

[0041] <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.

[0042] 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.

[0043] <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. As used herein, "suppression" with respect to freezing means that by taking the technical means of the present invention, "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 of the present invention, the extent of "freezing" over the same period of time is suppressed compared to when such means are not taken (the range / spread of freezing occurring is smaller), and does not necessarily mean that the Ripasudil-containing aqueous composition will not freeze at all. For example, if the subject of evaluation contains boric acid as a boric acid compound, and a comparison subject that does not contain the boric acid but has equivalent components, dissolved oxygen content, etc. is prepared and stored under the same low-temperature storage conditions, it means that the subject of evaluation will be inhibited from "freezing" for a relatively longer period of time than the comparison subject, or that the degree of "freezing" will be inhibited at the same time.

[0044] <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 boric acid 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 boric acid 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 boric 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.

[0045] 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 boric 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) contained in a polyethylene container. [2A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof, or a solvate of either, and a boric 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) contained in a polyethylene container. [3A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof, or a solvate of either, and a boric 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 boric acid, the aqueous composition 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) 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 boric 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) contained in a polyethylene container. [6A] The pharmaceutical preparation according to any one of [1A] to [5A], wherein the boric acid compound is one or more selected from the group consisting of boric acid, a salt thereof, and a solvate thereof. [7A] The pharmaceutical formulation according to any one of [1A] to [5A], wherein the boric acid compound is boric acid. [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).

[0046] [1B] A method for preventing freezing of an aqueous composition during low-temperature storage, comprising the steps of: adding a boric acid 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 (preferably 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 a boric acid 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 a boric acid 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 a boric acid 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 a boric acid 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 boric acids are one or more selected from the group consisting of boric acid, a salt thereof, and a solvate thereof. [7B] The method according to any one of [1B] to [6B], wherein the boric acid compound is boric acid.

[0047] [1C] A method for producing a pharmaceutical preparation that is inhibited from freezing during low-temperature storage, comprising the steps of: adding a boric acid to an aqueous composition that contains ripasudil or a salt thereof, or a solvate of either of them 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 a boric acid to an aqueous composition that contains ripasudil or a salt thereof, or a solvate of either of them 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 boric acid to an aqueous composition that contains ripasudil or a salt thereof, or a solvate of either of them and 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 that is inhibited from freezing during low-temperature storage, comprising the steps of: adding a boric acid to an aqueous composition that contains ripasudil or a salt thereof, or a solvate of either of them 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 a boric acid to an aqueous composition that contains ripasudil or a salt thereof, or a solvate of either of them and has 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); and placing the aqueous composition in a polyethylene container. EXAMPLES

[0048] The present invention will now be described in further detail with reference to examples, but the present invention is not limited to these examples. In the following test examples, Ripasudil monohydrochloride dihydrate can be prepared, for example, by the method described in WO 2006 / 057397.

[0049] [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).

[0050] 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.

[0051] [Table 1]

[0052] 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 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.

[0053] 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.

[0054] [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).

[0055] 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.

[0056] [Table 2]

[0057] 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 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 boric acid 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 boric acid and the aqueous composition was contained in a polyethylene container. From the above, it has become clear that when a borax such as boric acid is added to a Ripasudil-containing aqueous composition having a dissolved oxygen content of 8.5 mg / L or more, 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.

[0058] [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).

[0059] 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.

[0060] [Table 3]

[0061] As shown in the results in Table 3, in the pharmaceutical preparations of Examples 2 and 3, in which boric acid 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.

[0062] [Table 4]

[0063] [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.

[0064] [Table 5]

[0065] [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.

[0066] [Table 6]

[0067] [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.

[0068] [Table 7]

[0069] [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.

[0070] [Table 8]

[0071] [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.

[0072] [Table 9] [Industrial Applicability]

[0073] 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 Ripasudil or a salt thereof or a solvate thereof and boric acids and having a dissolved oxygen content of 8.5 mg / L or more, and the aqueous composition is contained in a polyethylene container.

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

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

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

5. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the boric acid compound is at least one selected from the group consisting of boric acid, a salt thereof, and a solvate thereof.

6. A method for producing a pharmaceutical preparation in which freezing of the aqueous composition is suppressed, the method comprising the steps of: adding boric acid 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.

7. The method for producing a pharmaceutical preparation in which freezing of the aqueous composition is inhibited according to claim 6, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg / L.

8. The method for producing a pharmaceutical preparation in which freezing of the aqueous composition is inhibited according to claim 6, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg / L.

9. The method for producing a pharmaceutical preparation in which freezing of the aqueous composition is inhibited according to claim 6, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 11 mg / L.

10. The method for producing a pharmaceutical formulation in which freezing of the aqueous composition is inhibited according to any one of claims 6 to 9, wherein the boric acid compound is at least one selected from the group consisting of boric acid, a salt thereof, and a solvate thereof.

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