JP2026016274A - Pharmaceuticals - Google Patents

Abstract

[Problem] 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.
[Solution] 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 contained in a polyethylene container.
[Selection diagram] None

Description

The present invention relates to pharmaceutical preparations, etc.

The following structural formula:

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

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

Patent No. 4212149 International Publication No. 2006/068208 Patent No. 5557408 Patent No. 6244038

Pharmaceutical interview form "Glanatec (registered trademark) eye drops 0.4%" Kowa Company, Ltd., September 2023 Pharmaceutical interview form "Gla Alpha (registered trademark) combination eye drops" Kowa Company, Ltd., June 2024

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

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

The present inventors conducted further 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, typified by boric acid, and the aqueous composition is stored in a polyolefin resin container, particularly a polyethylene container, and thus completed the present invention.

That is, the present invention provides 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, 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 acids to an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 mg/L or more, and placing the aqueous composition in a polyethylene container.
Furthermore, the present invention provides a method for producing a pharmaceutical preparation in which freezing of the aqueous composition is inhibited, the method comprising the steps of: adding boric acids to an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 mg/L or more; and placing the aqueous composition in a polyethylene container.

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

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

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

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

Ripasudil hydrochloride hydrate (ripasudil monohydrochloride dihydrate) represented by the formula:

Ripasudil, its salts, or solvates thereof are known and can be produced by known methods. Specifically, for example, Ripasudil, its salts, or solvates thereof can be produced by the methods described in WO 1999/020620 and WO 2006/057397.

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

<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 as 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 as long as they are pharmacologically acceptable solvates, and examples thereof include hydrates, etc.
In the present invention, as the boric acid compound, one kind of component corresponding to the boric acid compound 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.

Specific examples of boric acids include boric acid, ammonium borate, and borax. In the present invention, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, the boric acid is preferably one or more selected from the group consisting of boric acid and its salts, with boric acid being particularly preferred.

The content of 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, it may contain 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 contain 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 in an amount of 0.03 to 5 w/v%, more preferably 0.07 to 3 w/v%, even more preferably 0.15 to 2.0 w/v%, and particularly preferably 0.3 to 1.5 w/v%, relative to the total volume of the aqueous composition.

Furthermore, the mass ratio of Ripasudil or its salt or solvate thereof to 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 mass parts or more, preferably 0.01 mass parts or more, more preferably 0.05 mass parts or more, more preferably 0.1 mass parts or more, and even more preferably 0.5 mass parts or more of boric acids per mass part of Ripasudil in free form, and may contain 8 mass parts or less, preferably 6 mass parts or less, and particularly preferably 4 mass parts 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 in its 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.

<Dissolved oxygen content>
In the present invention, the dissolved oxygen content of the Ripasudil-containing aqueous composition must be 8.5 mg/L or more. As shown in the test examples described below, when the dissolved oxygen content of the Ripasudil-containing aqueous composition is 8.5 mg/L or more, freezing over time during low-temperature storage can occur. However, 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 to reduce and maintain the amount of dissolved oxygen, for example, by replacing dissolved oxygen with an inert gas using 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.

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).

In the present invention, the dissolved oxygen amount refers to a value measured by a membrane electrode method, particularly a polarographic method (a membrane polarographic method). Examples of dissolved oxygen meters used to measure the dissolved oxygen amount by such methods 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 specified storage conditions (storage method). That is, for example, for a pharmaceutical preparation specified as being stored at "room temperature," the dissolved oxygen amount of a Ripasudil-containing aqueous composition for the pharmaceutical preparation stored at any temperature in the range of 1 to 30°C may be measured in accordance with the definition of "room temperature" (1 to 30°C) specified in the Eighteenth Edition of the Japanese Pharmacopoeia. If the dissolved oxygen amount is 8.5 mg/L or more under normally expected storage conditions, freezing can be advantageously suppressed even when the pharmaceutical preparation is exposed to a low-temperature environment due to some accident during distribution or storage.

No special process is required to achieve a dissolved oxygen content of 8.5 mg/L or more in a Ripasudil-containing aqueous composition. For example, by simple ingenuity in the production process typically expected for Ripasudil-containing aqueous compositions, such as adjusting the stirring speed or stirring blades so as to incorporate air during mixing of the aqueous composition, a person skilled in the art can appropriately achieve a dissolved oxygen content of 8.5 mg/L or more. Therefore, according to the present invention, significantly less labor and cost are required than actively and forcibly adjusting and maintaining the dissolved oxygen content at a low value. Furthermore, a means such as blowing in oxygen gas may be employed as long as it does not result in excessive labor or cost burdens.
In this specification, "an aqueous composition having a dissolved oxygen content of 8.5 mg/L or more" is not limited to only aqueous compositions in which the dissolved oxygen content has been intentionally "adjusted" to 8.5 mg/L or more, but also includes aqueous compositions in which the dissolved oxygen content has naturally fluctuated to that range after production. Such interpretation guidelines are also applicable to aqueous compositions in which the dissolved oxygen content is in other numerical ranges.

<Aqueous composition>
In the present invention, the term "aqueous composition" refers to a composition containing at least water, and its form may be liquid (solution or suspension) or semi-solid (ointment). The water in the composition may be, for example, purified water, water for injection, sterilized purified water, etc.
The content of water 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%.

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

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 adjusters, preservatives, antioxidants, thickening agents, surfactants, solubilizers, suspending agents, refreshing agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, etc.
Specific examples of such additives include 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, alkyldiaminoethylglycine hydrochloride solution, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, xylitol, citric acid, calcium citrate, citric acid hydrate, sodium citrate hydrate, and citric acid dihydrate. Sodium 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, calcium acetate, sodium acetate hydrate, titanium dioxide, gellan gum, dibutylhydroxytoluene, 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 Ingredients: tyloxapol, trometamol, lactic acid, sodium lactate solution, calcium lactate hydrate, aluminum lactate, concentrated glycerin, concentrated mixed tocopherols, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride solution 50, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin, sodium metabisulfite, glacial acetic acid, phenylethyl alcohol, glucose, propionic acid, sodium propionate, propylene glycol, fumaric acid, bergamot oil, benzalkonium chloride, benzalkonium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, povidone, polyoxyethylene (200), polyoxypropylene glycol (70), polystyrene sulfone Examples of the surfactant include sodium edetate, 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, 1-menthol, monoethanolamine, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, rhubarb, 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.

Preferred additives include, for example, 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.

The aqueous composition may further contain other medicinal ingredients in addition to Ripasudil depending on the disease to be treated, etc. Examples of such medicinal ingredients include α1 receptor blockers including bunazosin such as bunazosin hydrochloride or a salt thereof or a solvate thereof; brimonidine such as brimonidine tartrate or a salt thereof or a solvate thereof; α2 receptor agonists including apraclonidine or a salt thereof or a solvate thereof; carteolol such as carteolol hydrochloride or a salt thereof or a solvate thereof; nipradilol or a salt thereof or a solvate thereof; timolol such as timolol maleate or a salt thereof or a solvate thereof; betaxolol such as betaxolol hydrochloride or a salt thereof or a solvate thereof; levobunolol such as levobunolol hydrochloride or a salt thereof or a solvate thereof; or a solvate thereof, befunolol or a salt thereof or a solvate thereof, 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; carbonic anhydrase inhibitors including dorzolamide or a salt thereof or a solvate thereof such as dorzolamide hydrochloride, 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. prostaglandin F2α derivatives including 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, latanoprost or a salt thereof or a solvate thereof, cloprostenol or a salt thereof or a solvate thereof, fluprostenol or a salt thereof or a solvate thereof; sympathomimetics including dipivefrin such as dipivefrin hydrochloride or a salt thereof or a solvate thereof, epinephrine, epinephrine borate, epinephrine hydrochloride or a salt thereof or a solvate thereof; distigmine bromide or a salt thereof or a solvate thereof, Parasympathomimetics including pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, or other pilocarpine or its salts, or solvates thereof, carbachol, its salts, or solvates thereof; calcium antagonists including lomerizine, such as lomerizine hydrochloride, or other lomerizine or its salts, or solvates thereof; cholinesterase inhibitors including demecarium, its salts, or solvates thereof, echothiophate, its salts, or solvates thereof, physostigmine, its salts, or solvates thereof; and EP2 receptor agonists including omidenepag, such as omidenepag isopropyl, or its salts, or solvates thereof, and one or more of these can be combined.
The other active ingredient is preferably at least one selected from the group consisting of brimonidine, latanoprost, nipradilol, dorzolamide, brinzolamide, timolol, omidenepagisopropyl, and salts thereof.

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

<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,""airtightcontainers," and "sealed containers" as defined in the General Rules of the Japanese Pharmacopoeia, 18th Edition.

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 and intended use of the pharmaceutical preparation. Specific examples of such container shapes include injection containers, inhalant containers, spray containers, bottle-shaped containers, tube-shaped containers, eye drop containers, nasal drop containers, ear drop containers, and bag-shaped containers.

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 another resin or the like is laminated on the outside also falls under the category of a "polyethylene container." Here, the polyethylene is not particularly limited, and examples include low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, etc., and these may be used alone or in combination of two or more.
In the present invention, "made of polyethylene" means that at least a part of the material contains polyethylene, and for example, a mixture of two or more resins (polymer alloy) consisting of polyethylene and a resin other than polyethylene is also included in "made of polyethylene."

It is preferable to further incorporate into the polyethylene container a substance that blocks the transmission of ultraviolet light, such as an ultraviolet absorber or an ultraviolet scattering agent. This improves Ripasudil's stability against light. Specific examples of such substances include ultraviolet scattering agents such as titanium oxide and zinc oxide. Furthermore, examples of ultraviolet absorbers include 2-(2H-benzotriazol-2-yl)-p-cresol (e.g., Tinuvin P: BASF), 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol (e.g., Tinuvin 234: BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)benzotriazole (e.g., Tinuvin 320: BASF), and 2-[5-chloro(2H)-benzotriazol-2-yl]-4-methyl-6-(tert-butyl)phenol (e.g., Tinuvin 326: BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)-5-chlorobenzotriazole (e.g., Tinuvin 327: BASF), 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (e.g., Tinuvin PA328: BASF), 2-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol (e.g., Tinuvin 329: BASF), 2,2'-methylenebis[6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol] (e.g., Tinuvin 360: BASF), reaction products of methyl 3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionate with polyethylene glycol 300 (for example, Tinuvin 213: BASF), 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol (for example, 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]; 2,2-bis{[2-cyano-3,3-diphenylacryloyloxy]methyl}propane-1,3-diyl bis(2-cyano-3,3-diphenylacrylate) (for example, Uvinul 3030 FF: BASF), ethyl 2-cyano-3,3-diphenylacrylate (for example, Uvinul 3035: BASF), 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (e.g., Uvinul 3039: BASF), and other cyanoacrylate-based ultraviolet absorbers; 2-(4,6-diphenyl-1,3,5-triazin-2-yl)-5-[(hexyl)oxy]phenol (e.g., Tinuvin 1577 ED: BASF), and other triazine-based ultraviolet absorbers; octabenzone (e.g., Chimassorb 81: BASF), 2,2'-dihydroxy-4,4'-dimethoxybenzophenone (e.g., Uvinul 3049: BASF), 2,2'-4,4'-tetrahydrobenzophenone (e.g., Uvinul 3050: BASF), benzophenone-based ultraviolet absorbers such as oxybenzone, hydroxymethoxybenzophenone sulfonic acid, hydroxymethoxybenzophenone sodium sulfonate, dihydroxydimethoxybenzophenone, dihydroxydimethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, and tetrahydroxybenzophenone; cinnamic acid-based ultraviolet absorbers such as methyl diisopropylcinnamate, cinoxate, glyceryl di-paramethoxycinnamate mono-2-ethylhexanoate, a mixture of isopropyl paramethoxycinnamate and diisopropyl cinnamate, 2-ethylhexyl paramethoxycinnamate, and benzyl cinnamate; para-aminobenzoic acid, ethyl para-aminobenzoate, glyceryl para-aminobenzoate, amyl paradimethylaminobenzoate, and para-dimethylaminobenzoate. Benzoate ester-based UV absorbers such as 2-ethylhexyl methylaminobenzoate 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; and hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate.

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

It is preferable that the interior of the container be visible (observable) with the naked eye. If the interior is visible, it has advantages such as making it possible to inspect for the presence of foreign matter during the manufacturing process of the pharmaceutical preparation, and allowing users of the pharmaceutical preparation to check the remaining amount of the contents (aqueous composition). Here, visibility only needs to be ensured on at least a portion of the container surface (for example, even if the sides of an eye drop container are obscured by a shrink film or the like, it can still be said to be visible as long as the bottom is visible). If the interior is visible on a portion of the container surface, this makes it possible to check the aqueous composition inside the container.

There are no particular limitations on the means for storing the aqueous composition in the container, and it can be filled in a conventional manner according to the shape of the container.

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

Furthermore, as disclosed in Japanese Patent No. 5557408, ocular fundus diseases (lesions occurring mainly 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 abnormalities such as diabetic retinopathy, diabetic macular edema, diabetic maculopathy, 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), and other diseases. The present invention can be used as a prophylactic or therapeutic agent for diseases such as retinal detachment (rhegmatogenous, tractional, exudative, etc.), retinitis pigmentosa, and retinopathy of prematurity, more preferably 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 damage.

<Significance of other words>
In the present invention, "low-temperature storage" means storage at a temperature lower than room temperature (1 to 30°C) that a pharmaceutical preparation may accidentally encounter 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 also includes the case where only a portion of the composition is frozen.
In this specification, "suppression" with respect to freezing means that by taking the technical means of the present invention, "freezing" is suppressed for a relatively long period of time compared to when such means are not taken, or that by taking the technical means of the present invention, the degree of "freezing" over the same period of time is suppressed compared to when such means are not taken (the range or extent of freezing occurring is smaller), and does not necessarily mean that the Ripasudil-containing aqueous composition will never freeze.
For example, if the evaluation object contains boric acid as a boric acid compound, and a comparison object that does not contain the boric acid but has the same components, dissolved oxygen content, etc. is prepared and stored under the same low-temperature storage conditions, this means that the evaluation object will be inhibited from "freezing" for a relatively longer period of time than the comparison object, or that the degree of "freezing" will be inhibited at the same time.

<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 acids to an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 mg/L or more, and placing the aqueous composition in a polyethylene container.
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 acids to an aqueous composition that contains Ripasudil, 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. Furthermore, the timing at which the dissolved oxygen content of the aqueous composition reaches 8.5 mg/L or more is also not particularly important, and as long as the dissolved oxygen content of the aqueous composition reaches 8.5 mg/L or more at any timing, the method can be considered as a "method for inhibiting freezing" or a "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.

The present invention discloses, for example, embodiments of the following aspects, but is not limited thereto.
[1A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof or a solvate thereof and boric acids, the aqueous composition having 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 the aqueous composition being contained in a polyethylene container.
[2A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof or a solvate thereof and boric acids, the aqueous composition having a dissolved oxygen content of 8.5 to 13 mg/L (preferably 8.7 to 13 mg/L, particularly preferably 9 to 13 mg/L), and the aqueous composition being contained in a polyethylene container.
[3A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof or a solvate thereof and boric acids, the aqueous composition having a dissolved oxygen content of 8.5 to 12 mg/L (preferably 8.7 to 12 mg/L, particularly preferably 9 to 12 mg/L), and the aqueous composition being contained in a polyethylene container.
[4A] A pharmaceutical preparation comprising an aqueous composition containing ripasudil or a salt thereof or a solvate thereof and boric acids, the aqueous composition having a dissolved oxygen content of 8.5 to 11 mg/L (preferably 8.7 to 11 mg/L, particularly preferably 9 to 11 mg/L), and the aqueous composition being 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 aqueous composition having a dissolved oxygen content of 8.5 to 10 mg/L (preferably 8.7 to 10 mg/L, particularly preferably 9 to 10 mg/L), and the aqueous composition being contained in a polyethylene container.
[6A] The pharmaceutical formulation 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 inhibited after low-temperature storage (preferably storage at -5°C, particularly preferably storage at -5°C for 2 weeks).

[1B] A method for preventing freezing of an aqueous composition during low-temperature storage, comprising the steps of: adding boric acid to an aqueous composition containing ripasudil or a salt thereof, or a solvate thereof and having 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 boric acids to an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 to 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, the method comprising the steps of: adding boric acids to an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 to 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, the method comprising the steps of: adding boric acids to an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 to 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, the method comprising the steps of: adding boric acids to an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 to 10 mg/L (preferably 8.7 to 10 mg/L, particularly preferably 9 to 10 mg/L); and placing the aqueous composition in a polyethylene container.
[6B] The method according to any one of [1B] to [5B], wherein the boric acid is at least one 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.

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

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

[Test Example 1] Storage 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 then the amount of dissolved oxygen was adjusted as 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 placed in 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).

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

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 observed 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 observed after similar storage. This demonstrated that such freezing depends on the amount of dissolved oxygen in the Ripasudil-containing aqueous composition and is a phenomenon that occurs when the dissolved oxygen content is 8.5 mg/L or more.
Furthermore, when an aqueous composition containing no 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 demonstrates that such freezing is due to the aqueous composition containing Ripasudil and being placed in a polyolefin resin container.

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

[Test Example 2] Storage test No. 2
An aqueous composition containing the components and amounts shown in Table 2 in 100 mL was prepared by a conventional method, and then the amount of dissolved oxygen was adjusted as 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 an eye drop container made of polyethylene (PE) or polypropylene (PP) 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).

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

As shown in Table 2, freezing of the entire aqueous composition was confirmed after 2 weeks of storage at −5° C. in both the pharmaceutical preparation of Comparative Example 1, in which a Ripasudil-containing aqueous composition having a dissolved oxygen content of 8.5 mg/L or more 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 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 was contained in a polyethylene container.
From the above, it has become clear that when a boronic acid 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 stored in a polyethylene container, among other polyolefin resin containers, freezing during low-temperature storage can be relatively suppressed compared to when the requirements are not met.

[Test Example 3] Storage test No. 3
An aqueous composition containing the components and amounts shown in Table 3 in 100 mL was prepared by a conventional method, and then the amount of dissolved oxygen was adjusted as 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 the 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).

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

As shown in Table 3, in the pharmaceutical preparations of Examples 2 and 3, in which boric acid was added to a Ripasudil-containing aqueous composition with a dissolved oxygen content of 11.0 mg/L or 13.0 mg/L, respectively, and the aqueous compositions were placed in a polyethylene container, no freezing was observed after storage at -5°C for two weeks, just as with the pharmaceutical preparation of Example 1.

[Production Examples 1 to 5]
Aqueous compositions containing the ingredients and amounts shown in Table 4 per 100 mL were prepared by a conventional method, and then the 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. These were then placed in polyethylene eye drop containers to obtain pharmaceutical preparations of Preparation Examples 1 to 5.

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

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

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

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

[Production Examples 26 to 30]
An aqueous composition containing the ingredients and amounts shown in Table 9 per 100 mL was prepared by a conventional method, and then the amount of dissolved oxygen was adjusted to the level 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.

The present invention provides a pharmaceutical formulation with excellent storage stability, making it suitable for use in the pharmaceutical industry, etc.

Claims (15)

A pharmaceutical preparation comprising an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof, and boric acids, the aqueous composition having a dissolved oxygen content of 8.5 mg/L or more, and the composition being contained in a polyethylene container. The pharmaceutical preparation according to claim 1, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg/L. The pharmaceutical formulation according to claim 1, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg/L. The pharmaceutical preparation according to claim 1, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 11 mg/L. The pharmaceutical formulation according to any one of claims 1 to 4, wherein the boric acid compound is one or more selected from the group consisting of boric acid, its salts, and solvates thereof. A method for inhibiting freezing of an aqueous composition, comprising the steps of: adding boric acid to an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 mg/L or more; and placing the aqueous composition in a polyethylene container. The method for inhibiting freezing of an aqueous composition according to claim 6, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg/L. The method for inhibiting freezing of an aqueous composition according to claim 6, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg/L. The method for inhibiting freezing of an aqueous composition according to claim 6, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 11 mg/L. The method for inhibiting freezing of an aqueous composition according to any one of claims 6 to 9, wherein the boric acid compound is one or more selected from the group consisting of boric acid, salts thereof, and solvates thereof. A method for producing a pharmaceutical preparation in which freezing of the aqueous composition is inhibited, comprising the steps of: adding boric acid to an aqueous composition containing Ripasudil, a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 mg/L or more; and placing the aqueous composition in a polyethylene container. The method for producing a pharmaceutical formulation in which freezing of the aqueous composition is inhibited according to claim 10, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg/L. The method for producing a pharmaceutical formulation in which freezing of the aqueous composition is inhibited according to claim 9, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg/L. The method for producing a pharmaceutical formulation in which freezing of the aqueous composition is inhibited according to claim 9, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 11 mg/L. The method for producing a pharmaceutical formulation in which freezing of the aqueous composition is inhibited according to any one of claims 11 to 14, wherein the boric acid compound is one or more selected from the group consisting of boric acid, its salts, and solvates thereof.