Pharmaceutical preparations

Abstract

An object of the present invention is to provide a technology for suppressing softening of a polypropylene container containing a Ripasudil-containing aqueous composition during storage at high temperatures. The present invention comprises the following components (A) and (B): (A) Ripasudil or a salt thereof, or a solvate thereof; (B) one or more selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids The present invention relates to a pharmaceutical preparation comprising an aqueous composition having a dissolved oxygen content of 8.5 mg / L or more, the composition being contained in a polypropylene 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 investigated the storage stability of an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof (hereinafter, sometimes referred to as "Ripasudil-containing aqueous composition") when the aqueous composition is contained in a polyolefin resin container. However, it has been found that when a polypropylene container is used as a polyolefin resin container, a problem occurs in that the container softens over time when it contains an aqueous composition containing Ripasudil and is stored under high temperature conditions. Therefore, an objective of the present invention is to provide a technology for suppressing softening of a polypropylene container containing a Ripasudil-containing aqueous composition during high-temperature storage. [Means for solving the problem]

[0009] The inventors further conducted intensive research to solve the above-mentioned problems and discovered that softening of the container during high-temperature storage is specifically suppressed when the dissolved oxygen content of the Ripasudil-containing aqueous composition contained in a polypropylene container is 8.5 mg / L or more and the composition contains lower aliphatic carboxylic acids represented by one or more selected from the group consisting of boric acids represented by boric acid, edetic acid and its salts, and solvates thereof, and thus completed the present invention.

[0010] That is, the present invention relates to a composition comprising the following components (A) and (B): (A) Ripasudil or a salt thereof, or a solvate thereof; (B) one or more selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids The present invention provides a pharmaceutical preparation comprising an aqueous composition having a dissolved oxygen content of 8.5 mg / L or more, the composition being contained in a polypropylene container.

[0011] The present invention also relates to an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof, which is contained in a polypropylene container, the composition comprising a step of adjusting the amount of dissolved oxygen in the composition to 8.5 mg / L or more, and a step of adding to the composition one or more components selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids The present invention provides a method for suppressing softening of a polypropylene container, the method comprising the step of incorporating Furthermore, the present invention relates to an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof, which is contained in a polypropylene container, the composition comprising a step of adjusting the amount of dissolved oxygen in the composition to 8.5 mg / L or more, and a step of adding to the composition one or more components selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids The present invention provides a method for producing a pharmaceutical preparation in which softening of a polypropylene container is suppressed, the method comprising the step of incorporating Effect of the Invention

[0012] According to the present invention, softening of a polypropylene container containing a Ripasudil-containing aqueous composition during high-temperature storage can be suppressed. [Brief description of the drawings]

[0013] [Figure 1] FIG. 2 is a schematic diagram of a test for measuring “the amount of force required to dispense one drop of the content liquid from an eye drop container” carried out in Test Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] As used herein, "w / v %" means mass to volume percentage, specifically, the mass (g) of each component contained per 100 mL of the composition.

[0015] <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.

[0016] 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:

[0017] [ka]

[0018] Ripasudil hydrochloride hydrate (Ripasudil monohydrochloride dihydrate) represented by the following formula is particularly preferred.

[0019] 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.

[0020] 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 action, 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, and more preferably 6 w / v% or less. Among them, from the viewpoint of obtaining an excellent pharmacological action, 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%, more preferably 0.1 to 2 w / v%, and even more preferably 0.3 to 0.5 w / v% relative to the total volume of the aqueous composition.

[0021] <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.

[0022] Specific examples of boric acids 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 particularly preferably boric acid, from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage.

[0023] The content of boric acids in the aqueous composition is not particularly limited, but from the viewpoint of suppressing softening during high-temperature storage in a polypropylene container, the content may be 0.001 w / v or more, preferably 0.01 w / v% or more, more preferably 0.05 w / v% or more, and even more preferably 0.1 w / v% or more, relative to the total volume of the aqueous composition, and may be 6 w / v% or less, preferably 4 w / v% or less, and even more preferably 2 w / v%. In particular, when using boric acid as the boric acid compound, from the viewpoint of suppressing softening during high-temperature storage in a polypropylene container, the content is preferably 0.007 to 5 w / v% relative to the total volume of the aqueous composition, more preferably 0.03 to 3 w / v%, and even more preferably 0.08 to 1.5 w / v%. Furthermore, when borax is used as the boric acid, from the viewpoint of preventing softening during high-temperature storage in a polypropylene container, it is preferably contained at 0.003 to 3 w / v% relative to the total volume of the aqueous composition, more preferably at 0.02 to 2 w / v%, and even more preferably at 0.07 to 1 w / v%.

[0024] 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 suppressing softening during high-temperature storage in polypropylene containers, the aqueous 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, even 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 free form, and may contain 8 parts by mass or less, preferably 6 parts by mass or less, and more preferably 4 parts by mass or less. In particular, when boric acid is used as the boric acid compound, from the viewpoint of preventing softening of polypropylene containers during high-temperature storage, it is preferable to contain 0.3 to 7 parts by mass of boric acid per 1 part by mass of Ripasudil, calculated as a free form, more preferably 0.7 to 5 parts by mass, and even more preferably 1 to 4 parts by mass. In particular, when borax is used as the boric acid, from the viewpoint of preventing softening of polypropylene containers during high-temperature storage, it is preferable to contain 0.002 to 2 parts by mass of boric acid per 1 part by mass of Ripasudil, calculated as the free form, more preferably 0.03 to 1.5 parts by mass, and even more preferably 0.08 to 1.3 parts by mass.

[0025] <Lower aliphatic carboxylic acids> In the present invention, the term "lower aliphatic carboxylic acids" refers to one or more selected from the group consisting of lower aliphatic carboxylic acids in which one or more carbon atoms may be replaced by a nitrogen atom, and salts thereof (e.g., alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts, etc.), and solvates thereof (hydrates, etc.). Here, the number of carbon atoms in the lower aliphatic carboxylic acids is not particularly limited as long as it is about 15 or less, but from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage, it is preferably 2 to 12, more preferably 4 to 12, and even more preferably 6 to 12. Among these carbon atoms, carbon atoms other than those constituting the carboxyl group may be partially replaced with nitrogen atoms, but from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage, the number of such nitrogen atom replacements is preferably 1 to 2. Furthermore, the carbon chain may be linear or branched, and may be saturated or unsaturated.

[0026] The number of carboxyl groups in the lower aliphatic carboxylic acids is not limited, but is preferably 1 to 4 from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage. Furthermore, the lower aliphatic carboxylic acids may further have about 1 to 3 hydrophilic substituents other than carboxyl groups from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage. Specific examples of such hydrophilic substituents include hydroxyl groups and amino groups. The lower aliphatic carboxylic acids are known compounds, and may be produced by known methods or may be commercially available. The lower aliphatic carboxylic acids may be used in the form of a salt or complex with other components, and the aqueous composition containing the component that forms such a salt or complex is also included in the "aqueous composition containing a lower aliphatic carboxylic acid".

[0027] Specific examples of such lower aliphatic carboxylic acids include adipic acid; one or more selected from the group consisting of aspartic acid, salts thereof, such as aspartic acid, sodium L-aspartate, and magnesium L-aspartate, and solvates thereof; one or more selected from the group consisting of epsilon-aminocaproic acid, salts thereof, and solvates thereof; edetic acid, calcium sodium edetate hydrate, sodium edetate hydrate, tetrasodium edetate hydrate, anhydrous disodium edetate, and the like. one or more selected from the group consisting of edetic acid, its salts, and solvates thereof; one or more selected from the group consisting of citric acid, calcium citrate, citric acid hydrate, sodium citrate hydrate, sodium dihydrogen citrate, disodium citrate, anhydrous citric acid, anhydrous sodium citrate, and its salts, and solvates thereof; one or more selected from the group consisting of succinic acid, monosodium succinate, disodium succinate hexahydrate, and other succinic acid, its salts, and solvates thereof; acetic acid, acetic acid At least one selected from the group consisting of acetic acid and its salts, such as ammonium, potassium acetate, calcium acetate, sodium acetate hydrate, glacial acetic acid, and anhydrous sodium acetate, and solvates thereof; at least one selected from the group consisting of tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, and potassium sodium tartrate, and solvates thereof; at least one selected from the group consisting of sorbic acid and its salts, such as sorbic acid and potassium sorbate, and solvates thereof; lactic acid, sodium lactate one or more selected from the group consisting of lactic acid, its salts, such as propionic acid, sodium propionate, and solvates thereof, and solvates thereof; one or more selected from the group consisting of fumaric acid, its salts, and solvates thereof; one or more selected from the group consisting of maleic acid, its salts, and solvates thereof; one or more selected from the group consisting of malonic acid, its salts, and solvates thereof;Examples of the malic acid include malic acid, DL-malic acid, DL-sodium malate, and other malic acids and their salts, and solvates thereof, and these may be used alone or in combination of two or more. These lower aliphatic carboxylic acids are all known and may be produced by known methods, or commercially available products may be used.

[0028] As the lower aliphatic carboxylic acid, from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage, one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, citric acid, acetic acid, sorbic acid, and their salts and solvates are preferred, one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, and their salts and solvates are more preferred, and one or more selected from the group consisting of edetic acid, its salts, and solvates are particularly preferred. By using one or more selected from the group consisting of edetic acid, its salts, and solvates as the lower aliphatic carboxylic acid, softening of the polypropylene container during high-temperature storage is significantly suppressed compared to other lower aliphatic carboxylic acids.

[0029] The content of lower aliphatic carboxylic acids in the aqueous composition is not particularly limited, but from the viewpoint of suppressing softening during high-temperature storage in a polypropylene container, the content may be 0.001 w / v or more, preferably 0.01 w / v% or more, more preferably 0.05 w / v% or more, even more preferably 0.1 w / v% or more, relative to the total volume of the aqueous composition, and may be 5 w / v% or less, preferably 3.5 w / v% or less, even more preferably 1 w / v%. In particular, when one or more types selected from the group consisting of epsilon-aminocaproic acid and its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of suppressing softening during high-temperature storage in a polypropylene container, the content is preferably 0.003 to 3 w / v%, more preferably 0.07 to 1 w / v%, and even more preferably 0.2 to 0.5 w / v%, relative to the total volume of the aqueous composition. Furthermore, in particular, when one or more types selected from the group consisting of edetic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of suppressing softening during high-temperature storage in a polypropylene container, the content is preferably 0.0003 to 0.3 w / v%, more preferably 0.007 to 0.2 w / v%, and even more preferably 0.02 to 0.1 w / v%, relative to the total volume of the aqueous composition. Furthermore, in particular, when one or more types selected from the group consisting of citric acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of suppressing softening during high-temperature storage in a polypropylene container, the content is preferably 0.006 to 2 w / v%, more preferably 0.04 to 0.4 w / v%, and even more preferably 0.07 to 0.2 w / v%, relative to the total volume of the aqueous composition. Furthermore, in particular, when one or more types selected from the group consisting of acetic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of suppressing softening during high-temperature storage in a polypropylene container, the content is preferably 0.003 to 2 w / v%, more preferably 0.03 to 0.3 w / v%, and even more preferably 0.07 to 0.2 w / v%, relative to the total volume of the aqueous composition. Furthermore, in particular, when one or more types selected from the group consisting of sorbic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of suppressing softening during high-temperature storage in a polypropylene container, the content is preferably 0.02 to 0.8 w / v%, more preferably 0.09 to 0.4 w / v%, and even more preferably 0.07 to 0.2 w / v%, relative to the total volume of the aqueous composition.

[0030] In addition, the mass ratio of Ripasudil or a salt thereof, or a solvate thereof, and lower aliphatic carboxylic acids in the aqueous composition is not particularly limited, but from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage, the aqueous composition may contain 0.001 part by mass or more of lower aliphatic carboxylic acids per 1 part by mass of Ripasudil, calculated as free form, preferably 0.01 part by mass or more, more preferably 0.3 part by mass or more, more preferably 0.6 part by mass or more, and even more preferably 0.8 part by mass or more, and may contain 8 parts by mass or less, preferably 4 parts by mass or less, and even more preferably 3 parts by mass or less. In particular, when one or more types selected from the group consisting of epsilon-aminocaproic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage, it is preferable to contain 0.05 to 2.5 parts by mass, more preferably 0.2 to 2 parts by mass, and even more preferably 0.5 to 1.5 parts by mass of one or more types selected from the group consisting of epsilon-aminocaproic acid, its salts, and solvates thereof per 1 part by mass of Ripasudil calculated as a free form. In particular, when one or more types selected from the group consisting of edetic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of suppressing softening during high-temperature storage in polypropylene containers, it is preferable to contain 0.003 to 2 parts by mass, more preferably 0.01 to 1 part by mass, and even more preferably 0.02 to 0.5 parts by mass of one or more types selected from the group consisting of edetic acid, its salts, and solvates thereof per 1 part by mass, calculated as the free form of Ripasudil. In particular, when one or more types selected from the group consisting of citric acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of suppressing softening during high-temperature storage of polypropylene containers, it is preferable to contain 0.003 to 5 parts by mass, more preferably 0.03 to 2 parts by mass, and even more preferably 0.07 to 7 parts by mass of one or more types selected from the group consisting of citric acid, its salts, and solvates thereof per 1 part by mass, calculated as the free form of Ripasudil. In particular, when one or more types selected from the group consisting of acetic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of suppressing softening during high-temperature storage of polypropylene containers, it is preferable to contain 0.003 to 2 parts by mass, more preferably 0.03 to 1 part by mass, and even more preferably 0.02 to 0.8 parts by mass of one or more types selected from the group consisting of acetic acid, its salts, and solvates thereof per 1 part by mass, calculated as the free form of Ripasudil. In particular, when one or more types selected from the group consisting of sorbic acid, its salts, and solvates thereof are used as the lower aliphatic carboxylic acids, from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage, it is preferable to contain 0.04 to 3 parts by mass, more preferably 0.03 to 1.5 parts by mass, and even more preferably 0.3 to 0.7 parts by mass of one or more types selected from the group consisting of sorbic acid, its salts, and solvates thereof per 1 part by mass, calculated as the free form of Ripasudil.

[0031] <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, by setting the amount of dissolved oxygen in the Ripasudil-containing aqueous composition to 8.5 mg / L or more, further adding one or more selected from the group consisting of boric acids and lower aliphatic carboxylic acids to the Ripasudil-containing aqueous composition, and storing the aqueous composition in a polypropylene container, softening of the polypropylene container during high-temperature storage can be suppressed.

[0032] In the present invention, the amount of dissolved oxygen in the Ripasudil-containing aqueous composition must be 8.5 mg / L or more (more preferably 8.5 to 13 mg / L, even more preferably 8.5 to 12 mg / L, even more preferably 8.5 to 11 mg / L, even more preferably 8.5 to 10 mg / L, and particularly preferably 8.5 to 9.5 mg / L), but is preferably 8.7 mg / L or more (more preferably 8.7 to 13 mg / L, even more preferably 8. It is preferably 7 to 12 mg / L, even more preferably 8.7 to 11 mg / L, even more preferably 8.7 to 10 mg / L, and particularly preferably 8.7 to 9.5 mg / L), and particularly preferably 9 mg / L or more (more preferably 9 to 13 mg / L, even more preferably 9 to 12 mg / L, even more preferably 9 to 11 mg / L, even more preferably 9 to 10 mg / L, and particularly preferably 9 to 9.5 mg / L).

[0033] In the present invention, the amount of dissolved oxygen refers to a value measured by a membrane electrode method, particularly a polarographic method (a membrane polarographic method). Examples of the dissolved oxygen meter used to measure the amount of dissolved oxygen by such a method include a portable waterproof dissolved oxygen meter, model number AS720 (manufactured by AS ONE Corporation). In the present invention, the amount of dissolved oxygen is measured when the pharmaceutical preparation is continuously stored under the specified storage conditions (storage method). That is, for example, for a pharmaceutical preparation whose storage method is specified as "room temperature storage", the amount of dissolved oxygen in the Ripasudil-containing aqueous composition in 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. Under the normally expected storage conditions, if the amount of dissolved oxygen is 8.5 mg / L or more, softening of the polypropylene container containing the Ripasudil-containing aqueous composition during high-temperature storage can be suppressed.

[0034] 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.

[0035] <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 even more preferably 90 to 99.8 w / v%.

[0036] 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.

[0037] 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 ascorbic acid, sodium hydrogen sulfite, alginic acid, sodium benzoate, benzyl benzoate, fennel oil, ethanol, ethylene-vinyl acetate copolymer, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride solution, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, xylitol, glycerin, gluconic acid, creatinine, chlorhexidine, chlorobutanol, crystalline diphosphate, Sodium hydrogen, geraniol, sodium chondroitin sulfate, titanium oxide, gellan gum, dibutyl hydroxytoluene, potassium bromide, benzododecyl bromide, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution, taurine, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyloxapol, trometamol, concentrated glycerin, concentrated mixed tocopherols, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride solution 50, ethyl paraoxybenzoate , butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin, sodium pyrosulfite, phenylethyl alcohol, glucose, propylene glycol, bergamot oil, benzalkonium chloride, benzalkonium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, povidone, polyoxyethylene (200), polyoxypropylene glycol (70), sodium polystyrene sulfonate, polysorbate 80, polyoxyethylene hydrogenated castor oil Examples include oil 60, polyvinyl alcohol (partially saponified), d-borneol, macrogol 4000, macrogol 6000, D-mannitol, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methanesulfonic acid, l-menthol, monoethanolamine, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, ryuuno, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, and petrolatum.

[0038] Preferred examples of additives include potassium chloride, calcium chloride 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.

[0039] 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.

[0040] The pH of the aqueous composition is not particularly limited, but is preferably 4 to 9, more preferably 4.5 to 8, and even more preferably 5 to 7. The osmotic pressure ratio to physiological saline is not particularly limited, but is preferably 0.6 to 3, and more preferably 0.6 to 2.

[0041] <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.

[0042] 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.

[0043] In the present invention, the term "polypropylene 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 polypropylene. Therefore, for example, a container in which a polypropylene layer is provided as the inner layer that comes into contact with the aqueous composition and a resin of another material is laminated on the outer side of the polypropylene layer also falls under the category of "polypropylene container". In the present invention, "made of polypropylene" means that at least a part of the material contains polypropylene, and for example, a mixture (polymer alloy) of two or more resins, including polypropylene and a resin other than polypropylene, is also included in "made of polypropylene".

[0044] 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 polypropylene 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;

[0045] When a substance that blocks ultraviolet light transmission is kneaded into the container, the mixing ratio varies depending on the type of substance, but may be, for example, about 0.001 to 50 mass %, preferably 0.002 to 25 mass %, and more preferably 0.01 to 10 mass % in the container.

[0046] 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.

[0047] 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.

[0048] <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.

[0049] 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.

[0050] <Significance of other terms> In the present invention, "high temperature storage" means storage at a temperature higher than room temperature (1 to 30°C) which a pharmaceutical preparation may accidentally encounter during distribution or storage after production, and more specifically, for example, storage at 60°C or higher. In the present invention, "softening" of a polypropylene container refers to a decrease in the magnitude of the force required to deform the polypropylene container to the same extent as before storage due to high-temperature storage of a pharmaceutical preparation. For example, when the polypropylene container is an eye drop container, "softening" can be evaluated by comparing the magnitude of "the force required to dispense one drop of the content from the eye drop container" measured in the following Test Example 1 before and after high-temperature storage.

[0051] In this specification, "suppression" of softening of containers means that by taking the technical measures of the present invention, the degree of "softening" is relatively reduced compared to when said measures are not taken, and does not mean that polypropylene containers will not soften at all. For example, if the evaluation target contains boric acid, and a comparison target that does not contain the said boric acid but has equivalent components, dissolved oxygen content, polypropylene container, etc. is prepared and stored under the same high temperature conditions, the evaluation target will show a relatively reduced degree of "softening" compared to the comparison target.

[0052] <Method for inhibiting softening and method for producing pharmaceutical preparation> The present invention also relates to a method for producing an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof, which is contained in a polypropylene container, comprising the steps of adjusting the amount of dissolved oxygen to 8.5 mg / L or more, and adding one or more components selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids The present invention also relates to a method for inhibiting softening of a polypropylene container, which comprises the step of incorporating Furthermore, the present invention relates to a method for producing an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof, which is contained in a polypropylene container, comprising the steps of adjusting the amount of dissolved oxygen to 8.5 mg / L or more, and adding one or more components selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids The present invention also relates to a method for producing a pharmaceutical preparation in which softening of a polypropylene container is suppressed, the method comprising the step of incorporating In the above method, the order of the step of incorporating Ripasudil into the aqueous composition, the step of incorporating boric acid or lower aliphatic carboxylic acid into the aqueous composition, and the step of placing the aqueous composition in a polypropylene 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 if 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 suppressing softening of polypropylene containers" or the "method for producing pharmaceutical preparations" disclosed in this 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.

[0053] The present invention discloses, for example, embodiments of the following aspects, but is in no way limited thereto. [1A] The following ingredients (A) and (B): (A) Ripasudil or a salt thereof, or a solvate thereof; (B) one or more selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids and a dissolved oxygen content of 8.5 mg / L or more (preferably 8.7 mg / L or more, and more preferably 9 mg / L or more), which is contained in a polypropylene container. [2A] The following ingredients (A) and (B): (A) Ripasudil or a salt thereof, or a solvate thereof; (B) one or more selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids and a dissolved oxygen content of 8.5 to 13 mg / L (preferably 8.7 to 13 mg / L, and more preferably 9 to 13 mg / L), which is contained in a polypropylene container. [3A] The following ingredients (A) and (B): (A) Ripasudil or a salt thereof, or a solvate thereof; (B) one or more selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids and a dissolved oxygen content of 8.5 to 12 mg / L (preferably 8.7 to 12 mg / L, and more preferably 9 to 12 mg / L), which is contained in a polypropylene container. [4A] The following ingredients (A) and (B): (A) Ripasudil or a salt thereof, or a solvate thereof; (B) one or more selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids and a dissolved oxygen content of 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, and more preferably 9 to 11 mg / L), which is contained in a polypropylene container. [5A] The following ingredients (A) and (B): (A) Ripasudil or a salt thereof, or a solvate thereof; (B) one or more selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids and a dissolved oxygen content of 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, and more preferably 9 to 10 mg / L), which is contained in a polypropylene 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 preparation according to any one of [1A] to [6A], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, citric acid, acetic acid, sorbic acid, salts thereof, and solvates thereof. [8A] The pharmaceutical preparation according to any one of [1A] to [6A], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid, a salt thereof, and a solvate thereof. [9A] The pharmaceutical preparation according to any one of [1A] to [8A], wherein the polypropylene container is an eye drop container. [10A] The pharmaceutical preparation according to any of [1A] to [8A], wherein the container hardness (the magnitude of the force required to dispense one drop of the internal solution from an ophthalmic solution container, which means the maximum load required when an ophthalmic solution container is laid horizontally on a flat surface and a probe of a texture analyzer is pressed vertically downward from above near the center of the body of the container as in Test Example 1, until one drop of the internal solution is dispensed from the ophthalmic solution container) after storage at 60°C for one week is 50% or more (preferably 60% or more, more preferably 70% or more, and even more preferably 75% or more) before storage.

[0054] [1B] A step of adjusting the amount of dissolved oxygen in an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof, which is contained in a polypropylene container, to 8.5 mg / L or more (preferably 8.7 mg / L or more, more preferably 9 mg / L or more), and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids A method for inhibiting softening of a polypropylene container, comprising the step of incorporating: [2B] A step of adjusting the amount of dissolved oxygen in an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof contained in a polypropylene container to 8.5 to 13 mg / L (preferably 8.7 to 13 mg / L, more preferably 9 to 13 mg / L), and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) and (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids A method for inhibiting softening of a polypropylene container, comprising the step of incorporating: [3B] A step of adjusting the amount of dissolved oxygen in an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof contained in a polypropylene container to 8.5 to 12 mg / L (preferably 8.7 to 12 mg / L, more preferably 9 to 12 mg / L), and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) and (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids A method for inhibiting softening of a polypropylene container, comprising the step of incorporating: [4B] A step of adjusting the amount of dissolved oxygen in an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof contained in a polypropylene container to 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, more preferably 9 to 11 mg / L), and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) and (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids A method for inhibiting softening of a polypropylene container, comprising the step of incorporating: [5B] A step of adjusting the amount of dissolved oxygen in an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof contained in a polypropylene container to 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, more preferably 9 to 10 mg / L), and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) and (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids A method for inhibiting softening of a polypropylene container, comprising the step of incorporating: [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 of [1B] to [6B], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, citric acid, acetic acid, sorbic acid, salts thereof, and solvates thereof. [8B] The method according to any one of [1B] to [6B], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid, a salt thereof, and a solvate thereof. [9B] The method according to any one of [1B] to [8B], wherein the polypropylene container is an eye drop container. [10B] The method according to any of [1B] to [8B], wherein the container hardness (the magnitude of the force required to dispense one drop of the internal solution from an eye drop container, which means the maximum load required when an eye drop container is laid horizontally on a flat surface as in Test Example 1, and a probe of a texture analyzer is pressed vertically downward from above near the center of the body of the container, causing one drop of the internal solution to be dispensed from the eye drop container) after storage at 60°C for one week is 50% or more (preferably 60% or more, more preferably 70% or more, and even more preferably 75% or more) before storage.

[0055] [1C] A step of adjusting the amount of dissolved oxygen in an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof, which is contained in a polypropylene container, to 8.5 mg / L or more (preferably 8.7 mg / L or more, more preferably 9 mg / L or more), and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) to (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids 1. A method for producing a pharmaceutical preparation in which softening of a polypropylene container is suppressed, the method comprising the step of incorporating [2C] A step of adjusting the amount of dissolved oxygen in an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof contained in a polypropylene container to 8.5 to 13 mg / L (preferably 8.7 to 13 mg / L, more preferably 9 to 13 mg / L), and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) and (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids 1. A method for producing a pharmaceutical preparation in which softening of a polypropylene container is suppressed, the method comprising the step of incorporating [3C] A step of adjusting the amount of dissolved oxygen in an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof contained in a polypropylene container to 8.5 to 12 mg / L (preferably 8.7 to 12 mg / L, more preferably 9 to 12 mg / L), and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) and (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids 1. A method for producing a pharmaceutical preparation in which softening of a polypropylene container is suppressed, the method comprising the step of incorporating [4C] A step of adjusting the amount of dissolved oxygen in an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof contained in a polypropylene container to 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, more preferably 9 to 11 mg / L), and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) and (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids 1. A method for producing a pharmaceutical preparation in which softening of a polypropylene container is suppressed, the method comprising the step of incorporating [5C] A step of adjusting the amount of dissolved oxygen in an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof contained in a polypropylene container to 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, more preferably 9 to 10 mg / L), and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) and (B-2): (B-1) Boric acids (B-2) Lower aliphatic carboxylic acids 1. A method for producing a pharmaceutical preparation in which softening of a polypropylene container is suppressed, the method comprising the step of incorporating [6C] The production method according to any one of [1C] to [5C], wherein the boric acid compound is at least one selected from the group consisting of boric acid, a salt thereof, and a solvate thereof. [7C] The production method according to any one of [1C] to [6C], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of epsilon-aminocaproic acid, edetic acid, citric acid, acetic acid, sorbic acid, salts thereof, and solvates thereof. [8C] The method according to any one of [1C] to [6C], wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid, salts thereof, and solvates thereof. [9C] The method according to any one of [1C] to [8C], wherein the polypropylene container is an eye drop container. [10C] The manufacturing method according to any one of [1C] to [8C], wherein the container hardness (the magnitude of the force required to dispense one drop of the internal solution from an eye drop container, which means the maximum load required when an eye drop container is laid horizontally on a flat surface and a texture analyzer probe is pressed vertically downward from above near the center of the body of the container as in Test Example 1, causing one drop of the internal solution to be dispensed from the eye drop container) after storage at 60°C for one week is 50% or more (preferably 60% or more, more preferably 70% or more, and even more preferably 75% or more) before storage. EXAMPLES

[0056] The present invention will now be described in further detail with reference to examples, but the present invention is not limited to these in any way. In the following test examples, Ripasudil monohydrochloride dihydrate can be prepared, for example, by the method described in WO 2006 / 057397.

[0057] [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 then the amount of dissolved oxygen was measured and monitored while blowing in nitrogen gas, oxygen gas or air to adjust the amount of dissolved oxygen as shown in Table 1. The amount of dissolved oxygen was measured using a dissolved oxygen meter (portable waterproof dissolved oxygen meter, model AS720: manufactured by AS ONE Corporation) at an ambient temperature of 25°C. The aqueous composition with the adjusted dissolved oxygen content was poured into a polypropylene (PP) eye drop container to prepare a pharmaceutical preparation. The polypropylene eye drop container had a hollow cylindrical shape with a diameter of about 2 cm and a height of about 2.8 cm, and the thickness of the container at the body was about 0.4 mm.

[0058] Each pharmaceutical preparation was stored at 60° C. for one week, and the container hardness (the amount of force required to dispense one drop of the oral solution from the eye drop container) was measured before and after one week of storage at 60° C. In order to prevent the influence of temperature on the container hardness, the containers stored at 60° C. for one week were removed from the incubator and left to stand overnight in a measurement room set at a room temperature of 25° C. before being used for measurement. The "magnitude of force required to dispense one drop of the liquid content from an eye drop container" (hereinafter also referred to as "Force") was measured using a texture analyzer (TA.XTplus Texture Analyser: manufactured by Stable Micro Systems) by the following method. That is, the eye drop container without the cap was laid horizontally on a flat surface and fixed with a grip, and the probe of the texture analyzer was pressed vertically downward from above near the center of the container body (near the center at a height of about 1.4 cm from the bottom of the container) at a speed of 1 mm / sec, pressing the container body until one drop of the liquid for internal use was dispensed from the eye drop container. The maximum load (gf) until one drop of the liquid for internal use was dispensed from the eye drop container was measured, and this maximum load was taken as the "magnitude of force required to dispense one drop of the liquid content from the eye drop container."

[0059] From the measured force before storage and after one week of storage at 60°C, the "percentage (%) of container hardness after one week of storage at 60°C to the container hardness before storage" was calculated according to the following formula, and used as an index of the change in hardness of the propylene container due to high-temperature storage.

[0060] (Number 1) The ratio (%) of the container hardness after storage at 60℃ for 1 week to the container hardness before storage = Force after storage at 60℃ for 1 week / Force before storage × 100

[0061] The results are shown in Table 1.

[0062] [Table 1]

[0063] As shown in the results in Table 1, in Reference Example 1 in which an aqueous composition not containing Ripasudil was contained in a polypropylene container, the container hardness (the amount of force required to dispense one drop of the internal solution from the eye drop container) was 87.1% of that before storage after storage at 60°C for 1 week, and although some softening of the container was confirmed, the degree of softening was not significant. On the other hand, in Reference Example 2 in which an aqueous composition containing Ripasudil was contained in a polypropylene container, the container hardness (the amount of force required to dispense one drop of the internal solution from the eye drop container) was significantly reduced to 28.0% of that before storage after storage at 60°C for 1 week, and significant softening of the container was confirmed. From the above test results, it was found that when an aqueous composition containing Ripasudil is stored in a polypropylene container under high temperature conditions, the container will soften over time.

[0064] [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 a conventional method, and then the amount of dissolved oxygen was measured and monitored while blowing in nitrogen gas, oxygen gas or air to adjust the amount of dissolved oxygen as shown in Table 2. The amount of dissolved oxygen was measured using a dissolved oxygen meter (portable waterproof dissolved oxygen meter model AS720: manufactured by AS ONE Corporation) at an ambient temperature of 25°C. The aqueous composition with an adjusted dissolved oxygen content was placed in the same polypropylene (PP) eye drop container as used in Test Example 1 to prepare a pharmaceutical preparation.

[0065] Each of the obtained pharmaceutical preparations was stored at 60°C for 1 week, and the container hardness (the amount of force required to dispense one drop of the oral solution from the eye drop container) before and after 1 week of storage at 60°C was measured in the same manner as in Test Example 1, and the "percentage (%) of the container hardness after 1 week of storage at 60°C to the container hardness before storage" was calculated and used as an index of the change in hardness of the propylene container due to high-temperature storage. The results are shown in Table 2. In Table 2, "Comparative Example 1" is the same sample as "Reference Example 2" in Test Example 1.

[0066] [Table 2]

[0067] As shown in the results in Table 2, when the Ripasudil-containing aqueous composition contained in a polypropylene container did not contain boric acid (Comparative Example 1) or had a dissolved oxygen content of less than 8.5 mg / L (Comparative Example 2), as was confirmed in Test Example 1, the container hardness (the amount of force required to dispense one drop of the oral solution from the eye drop container) decreased to less than 50% of the value before storage (28.0% and 48.9%, respectively) after storage at 60°C for one week, confirming a significant softening of the container. On the other hand, when the dissolved oxygen content of the Ripasudil-containing aqueous composition contained in a polypropylene container was set to 8.5 mg / L or more and boric acid was added (Examples 1 and 2), storage at 60°C for one week increased the container hardness (the amount of force required to dispense one drop of the oral solution from the eye drop container) to a high value exceeding approximately 70% of that before storage, demonstrating that softening of the container was suppressed.

[0068] From the above, it was revealed that when the dissolved oxygen content of an aqueous composition containing Ripasudil contained in a polypropylene container is set to 8.5 mg / L or more and a boric acid such as boric acid is added, softening of the container during high-temperature storage is suppressed.

[0069] [Test Example 3] Preservation test Part 3 The test was carried out in the same manner as in Test Example 2, except that an aqueous composition containing the components and amounts shown in Table 3 per 100 mL was used instead of the aqueous composition containing the components and amounts shown in Table 2 per 100 mL. The results are shown in Table 3.

[0070] [Table 3]

[0071] As shown in the results in Table 3, when sodium edetate hydrate was added to the Ripasudil-containing aqueous composition instead of boric acid in Examples 1 and 2 (Examples 3 and 4), similarly, after storage at 60°C for one week, the container hardness (the amount of force required to dispense one drop of the oral solution from the eye drop container) increased to a high value exceeding approximately 70% of that before storage, demonstrating that softening of the container was suppressed.

[0072] From the above, it has become clear that even when the dissolved oxygen content of a Ripasudil-containing aqueous composition contained in a polypropylene container is set to 8.5 mg / L or more and the composition contains lower aliphatic carboxylic acids represented by one or more types selected from the group consisting of edetic acid, its salts, and their solvates, softening of the container during high-temperature storage is suppressed.

[0073] [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 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 polypropylene eye drop container to obtain the pharmaceutical preparations of Manufacturing Examples 1 to 5.

[0074] [Table 4]

[0075] [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 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 polypropylene eye drop container to obtain the pharmaceutical preparations of Preparation Examples 6 to 10.

[0076] [Table 5]

[0077] [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 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 polypropylene eye drop container to obtain the pharmaceutical preparations of Preparation Examples 11 to 15.

[0078] [Table 6]

[0079] [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 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 polypropylene eye drop container to obtain the pharmaceutical preparations of Manufacturing Examples 16 to 20.

[0080] [Table 7]

[0081] [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 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 polypropylene eye drop container to obtain the pharmaceutical preparations of Preparation Examples 21 to 25.

[0082] [Table 8]

[0083] [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 9 by blowing in nitrogen gas, oxygen gas or air while measuring and monitoring the amount of dissolved oxygen. This was then placed in a polypropylene eye drop container to obtain the pharmaceutical preparations of Manufacturing Examples 26 to 30.

[0084] [Table 9] [Industrial Applicability]

[0085] 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. The following components (A) and (B): (A) Ripasudil or a salt thereof, or a solvate thereof; (B) one or more selected from the group consisting of the following components (B-1) to (B-2): (B-1) One or more selected from the group consisting of boric acid, its salts, and solvates thereof (B-2) One or more selected from the group consisting of edetic acid, its salts, and solvates thereof A pharmaceutical preparation comprising an aqueous composition having a dissolved oxygen content of 8.5 mg / L or more, the composition being contained in a polypropylene 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. A method for producing an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof, the method comprising the steps of: adjusting the amount of dissolved oxygen in the aqueous composition to 8.5 mg / L or more and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) to (B-2): (B-1) One or more selected from the group consisting of boric acid, its salts, and solvates thereof (B-2) One or more selected from the group consisting of edetic acid, its salts, and solvates thereof A method for inhibiting softening of a polypropylene container, comprising the step of incorporating:

6. 6. The method according to claim 5, wherein the aqueous composition has a dissolved oxygen content of 8.5 to 13 mg / L.

7. 6. The method according to claim 5, wherein the aqueous composition has a dissolved oxygen content of 8.5 to 12 mg / L.

8. 6. The method according to claim 5, wherein the aqueous composition has a dissolved oxygen content of 8.5 to 11 mg / L.

9. A method for producing an aqueous composition containing Ripasudil or a salt thereof, or a solvate thereof, the method comprising the steps of: adjusting the amount of dissolved oxygen in the aqueous composition to 8.5 mg / L or more and adding to the aqueous composition one or more components selected from the group consisting of the following components (B-1) to (B-2): (B-1) One or more boric acids selected from the group consisting of boric acid, its salts, and solvates thereof (B-2) One or more selected from the group consisting of edetic acid, its salts, and solvates thereof 1. A method for producing a pharmaceutical preparation in which softening of a polypropylene container is suppressed, the method comprising the step of incorporating

10. The method according to claim 9, wherein the aqueous composition has a dissolved oxygen content of 8.5 to 13 mg / L.

11. The method according to claim 9, wherein the aqueous composition has a dissolved oxygen content of 8.5 to 12 mg / L.

12. The method according to claim 9, wherein the aqueous composition has a dissolved oxygen content of 8.5 to 11 mg / L.

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