Pharmaceutical preparations

Abstract

To provide a technology for suppressing the softening of polypropylene containers containing lipasudil-containing aqueous compositions during high-temperature storage. [Solution] The following components (A) and (B): (A) Lipasudil or its salts or solvates thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A pharmaceutical preparation comprising an aqueous composition containing a dissolved oxygen content of 8.5 mg / L or more, housed in a polypropylene container.

Description

Technical Field

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

Background Art

[0002] The following structural formula:

[0003]

Chemical Formula

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

[0005] In addition, it has been reported that 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, discoloration after long-term storage at high temperature can be suppressed (Patent Document 4). Moreover, both Granatic and Graalphα are pharmaceuticals in which an aqueous composition containing ripasudil hydrochloride hydrate is stored in a polypropylene ophthalmic 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® Ophthalmic Solution 0.4%", Kowa Co., Ltd., September 2023 [Non-Patent Document 2] Pharmaceutical Interview Form "GraAlpha (Registered Trademark) Eye Drops," Kowa Co., Ltd., June 2024 [Overview of the project] [Problems that the invention aims to solve]

[0008] Ophthalmic preparations and the like are usually compositions containing water (aqueous compositions). Therefore, the present inventors investigated the storage stability of aqueous compositions containing lipasudil or its salts or solvates (hereinafter sometimes referred to as "lipasudil-containing aqueous compositions") when stored in polyolefin resin containers. However, it has been found that when polypropylene containers are used as polyolefin resin containers, storing them under high-temperature conditions with a lipasudil-containing aqueous composition causes the containers to soften over time. Therefore, the object of the present invention is to provide a technology for suppressing the softening of polypropylene containers containing lipasudil aqueous compositions during high-temperature storage. [Means for solving the problem]

[0009] The inventors of the present invention conducted further intensive studies to solve the aforementioned problems and discovered that when the dissolved oxygen content of a lipasudil-containing aqueous composition contained in a polypropylene container is set to 8.5 mg / L or higher, and when it contains one or more lower aliphatic carboxylic acids selected from the group consisting of boric acids such as boric acid, edetic acid and its salts, and their solvates, the softening of the container during high-temperature storage is specifically suppressed, thus completing the present invention.

[0010] In other words, the present invention comprises the following components (A) and (B): (A) Lipasudil or its salts or solvates thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids The present invention provides a pharmaceutical preparation comprising an aqueous composition containing a dissolved oxygen content of 8.5 mg / L or more, housed in a polypropylene container.

[0011] Furthermore, the present invention relates to an aqueous composition containing lipasudil or its salt or solvates contained in a polypropylene container, comprising the steps of adjusting the dissolved oxygen content of the composition 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) to the composition; (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids This invention provides a method for suppressing the softening of polypropylene containers, which includes a step of incorporating a certain substance. Furthermore, the present invention relates to an aqueous composition containing lipasudil or its salts or solvates contained in a polypropylene container, comprising the steps of adjusting the dissolved oxygen content of the composition 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) to the composition; (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids This invention provides a method for manufacturing a pharmaceutical formulation in which the softening of a polypropylene container is suppressed, including a step of incorporating a certain substance.

Advantages of the Invention

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

Brief Description of the Drawings

[0013] [Figure 1] It is a schematic diagram of a test for measuring "the magnitude of the force required to drop one drop of the content liquid from an eye drop container" conducted in Test Example 1.

Embodiments for Carrying Out the Invention

[0014] In this specification, "w / v%" means mass / volume percentage, specifically, it means the mass (g) of each component contained per 100 mL of the composition.

[0015] <Repasodil or its salt or their solvates> In the present invention, repasodil (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline) may be a salt. The salt of repasodil is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide, etc.; organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate, etc. may be mentioned, and hydrochloride is preferred. Furthermore, repasodil or its salt may be a solvate such as a hydrate or an alcoholate, and a hydrate is preferred.

[0016] In the present invention, as repasodil or its salt or their solvates, repasodil or its hydrochloride or their hydrates are more preferred, and the following structural formula:

[0017] [ka]

[0018] Lipasdil hydrochloride hydrate (lipasdil 1-hydrochloride dihydrate) represented by [formula] is particularly preferred.

[0019] Lipasudil or its salts or solvates are well known and can be produced by known methods. Specifically, for example, lipasudil or its salts or solvates can be produced by methods described in International Publication No. 1999 / 020620, International Publication No. 2006 / 057397, and others.

[0020] The content of lipasudil or its salts or solvates in the aqueous composition is not particularly limited and can be determined appropriately depending on the applicable disease, the patient's sex, age, symptoms, etc. However, from the viewpoint of obtaining excellent pharmacological effects, the aqueous composition may contain 0.01 w / v% or more, preferably 0.02 w / v% or more, more preferably 0.04 w / v% or more, when converted to the free form of lipasudil, relative to the total volume of the aqueous composition, and may also contain 10 w / v% or less, preferably 8 w / v% or less, and more preferably 6 w / v% or less. In particular, from the viewpoint of obtaining excellent pharmacological effects, it is preferable to contain 0.05 to 5 w / v% of lipasudil or its salts or solvates relative to the total volume of the aqueous composition when converted to the free form, more preferably 0.1 to 3 w / v%, even more preferably 0.1 to 2 w / v%, and even more preferably 0.3 to 0.5 w / v%.

[0021] <Boric Acids> In the present invention, "boric acid compounds" means one or more selected from the group consisting of boric acid, salts of boric acid, anhydrous boric acid, anhydrous boric acid salts, solvates of boric acid, and solvates of salts of boric acid. Here, the "salts" of boric acid are not limited in any way as long as they are pharmacologically acceptable salts, but examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts; and ammonium salts. 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, but examples include hydrates. In the present invention, boric acid compounds can be used as a single component or in an appropriate combination of two or more components. Furthermore, these boric acids are all well-known and may be manufactured by known methods, or commercially available products may be used.

[0022] Examples of boric acid compounds include boric acid, ammonium borate, and borax. In the present invention, from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage, one or more boric acid compounds selected from the group consisting of boric acid and its salts are preferred, with boric acid being particularly preferred.

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

[0024] Furthermore, the mass ratio of lipasudil or its salts or solvates to boric acids in the aqueous composition is not particularly limited. However, from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage, the composition may contain 0.001 parts by mass or more, preferably 0.01 parts by mass or more, more preferably 0.05 parts by mass or more, even more preferably 0.1 parts by mass or more, and even more preferably 0.5 parts by mass or more, per 1 part by mass of free lipasudil, and may also 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 using boric acid as the boric acid, from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage, it is preferable to contain 0.3 to 7 parts by mass of boric acid, more preferably 0.7 to 5 parts by mass, and even more preferably 1 to 4 parts by mass, of boric acid per 1 part by mass of free lipasudil. Furthermore, in particular, when borax is used as the boric acid, from the viewpoint of suppressing 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 free lipasudil, 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, "lower aliphatic carboxylic acids" means one or more selected from the group consisting of lower aliphatic carboxylic acids and their salts (for example, 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 their solvates (hydrates, etc.), in which one or more carbon atoms may be replaced by nitrogen atoms. 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 the polypropylene container during high-temperature storage, 2 to 12 is preferred, 4 to 12 is more preferred, and 6 to 12 is even more preferred. Of these carbon atoms, some of the carbon atoms other than those constituting the carboxyl group may be replaced with nitrogen atoms, but from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage, it is preferable that the number of such nitrogen atom substitutions be 1 to 2. Furthermore, the carbon chain may be linear or branched, and may be saturated or unsaturated.

[0026] Furthermore, while the number of carboxyl groups in lower aliphatic carboxylic acids is not limited, 1 to 4 are preferred from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage. In addition, lower aliphatic carboxylic acids may have approximately 1 to 3 more 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. Lower aliphatic carboxylic acids are known compounds and may be produced by known methods or commercially available compounds may be used. Furthermore, lower aliphatic carboxylic acids may be those that have formed salts or complexes with other components, and aqueous compositions containing such salts or complexes are also included in the definition of "aqueous compositions containing lower aliphatic carboxylic acids."

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

[0028] As lower aliphatic carboxylic acids, from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage, one or more selected from the group consisting of epsilon-aminocaproic acid, EDTA, 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, EDTA and their salts and solvates are more preferred, and one or more selected from the group consisting of EDTA and its salts and solvates are particularly preferred. By using one or more selected from the group consisting of EDTA and its salts and solvates as lower aliphatic carboxylic acids, softening of polypropylene containers 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 of polypropylene containers during high-temperature storage, it may be 0.001 w / v or more, preferably 0.01 w / v% or more, more preferably 0.05 w / v% or more, and even more preferably 0.1 w / v% or more relative to the total volume of the aqueous composition, and may also be 5 w / v% or less, preferably 3.5 w / v% or less, and even more preferably 1 w / v%. In particular, when using one or more lower aliphatic carboxylic acids selected from the group consisting of epsilon-aminocaproic acid, its salts, and their solvates, it is preferable to contain 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, from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage. Furthermore, in particular, when using one or more lower aliphatic carboxylic acids selected from the group consisting of edetic acid, its salts, and their solvates, it is preferable that the aqueous composition contains 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, from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage. Furthermore, in particular, when using one or more lower aliphatic carboxylic acids selected from the group consisting of citric acid, its salts, and their solvates, it is preferable that the aqueous composition contains 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%, based on the total volume of the aqueous composition, from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage. Furthermore, in particular, when using one or more lower aliphatic carboxylic acids selected from the group consisting of acetic acid, its salts, and their solvates, it is preferable that the aqueous composition contains 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%, based on the total volume of the aqueous composition, from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage. Furthermore, in particular, when using one or more lower aliphatic carboxylic acids selected from the group consisting of sorbic acid, its salts, and their solvates, it is preferable that the aqueous composition contains 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%, based on the total volume of the aqueous composition, from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage.

[0030] Furthermore, the mass ratio of lipasudil or its salts or solvates to lower aliphatic carboxylic acids in the aqueous composition is not particularly limited. However, from the viewpoint of suppressing softening of polypropylene containers during high-temperature storage, the composition may contain 0.001 parts by mass or more, preferably 0.01 parts by mass or more, more preferably 0.3 parts by mass or more, more preferably 0.6 parts by mass or more, and even more preferably 0.8 parts by mass or more of lower aliphatic carboxylic acids per 1 part by mass of free lipasudil. Alternatively, it 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 using one or more selected from the group consisting of epsilon-aminocaproic acid, its salts, and their solvates as lower aliphatic carboxylic acids, from the viewpoint of suppressing softening of the polypropylene container 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 selected from the group consisting of epsilon-aminocaproic acid, its salts, and their solvates, per 1 part by mass of free lipasudil. Furthermore, in particular, when using one or more selected from the group consisting of edetic acid, its salts, and their solvates as lower aliphatic carboxylic acids, from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage, it is preferable to contain 0.003 to 2 parts by mass of one or more selected from the group consisting of edetic acid, its salts, and their solvates, per 1 part by mass of free lipasudil, more preferably 0.01 to 1 part by mass, and even more preferably 0.02 to 0.5 parts by mass. Furthermore, in particular, when using one or more lower aliphatic carboxylic acids selected from the group consisting of citric acid, its salts, and their solvates, it is preferable, from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage, 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 selected from the group consisting of citric acid, its salts, and their solvates, per 1 part by mass of the free form of lipasudil. Furthermore, in particular, when using one or more lower aliphatic carboxylic acids selected from the group consisting of acetic acid, its salts, and their solvates, it is preferable, from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage, to contain 0.003 to 2 parts by mass of one or more selected from the group consisting of acetic acid, its salts, and their solvates, per 1 part by mass of free lipasudil, more preferably 0.03 to 1 part by mass, and even more preferably 0.02 to 0.8 parts by mass. Furthermore, in particular, when using one or more lower aliphatic carboxylic acids selected from the group consisting of sorbic acid, its salts, and their solvates, it is preferable, from the viewpoint of suppressing softening of the polypropylene container during high-temperature storage, 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 selected from the group consisting of sorbic acid, its salts, and their solvates, per 1 part by mass of the free form of lipasudil.

[0031] <Dissolved oxygen amount> In the present invention, the dissolved oxygen content of the lipasudil-containing aqueous composition must be 8.5 mg / L or more. As shown in the test examples below, by setting the dissolved oxygen content of the lipasudil-containing aqueous composition to 8.5 mg / L or more, further containing one or more substances selected from the group consisting of boric acids and lower aliphatic carboxylic acids in the lipasudil-containing aqueous composition, and housing the aqueous composition in a polypropylene container, the softening of such polypropylene container during high-temperature storage can be suppressed.

[0032] In the present invention, the dissolved oxygen content of the lipasudil-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 8.7 mg / L or more (more preferably 8.7 to 13 mg / L, even more preferably 8. The concentration is preferably 7-12 mg / L, more preferably 8.7-11 mg / L, even more preferably 8.7-10 mg / L, and particularly preferably 8.7-9.5 mg / L), and particularly preferably 9 mg / L or more (more preferably 9-13 mg / L, even more preferably 9-12 mg / L, even more preferably 9-11 mg / L, even more preferably 9-10 mg / L, and particularly preferably 9-9.5 mg / L).

[0033] In this invention, the amount of dissolved oxygen refers to the value measured by the diaphragm electrode method, particularly the polarographic method (diaphragm polarographic method). Examples of dissolved oxygen meters used for measuring the amount of dissolved oxygen by such methods include the portable waterproof dissolved oxygen meter, model number AS720 (manufactured by AS ONE Corporation). In this 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 for which "storage method" is specified as "room temperature storage," the amount of dissolved oxygen in the lipasudil-containing aqueous composition of the pharmaceutical preparation stored at any temperature in the range of 1 to 30°C should be measured in accordance with the meaning of "room temperature" (1 to 30°C) as defined in the 18th edition of the Japanese Pharmacopoeia. Under normally expected storage conditions, if the amount of dissolved oxygen is 8.5 mg / L or more, softening of the polypropylene container containing the lipasudil-containing aqueous composition during high-temperature storage can be suppressed.

[0034] To achieve a dissolved oxygen content of 8.5 mg / L or higher in a lipasudil-containing aqueous composition, no special process is required. For example, by adjusting the stirring speed and blades to incorporate air during mixing of the aqueous composition, a person skilled in the art can easily achieve a dissolved oxygen content of 8.5 mg / L or higher through simple adjustments in the manufacturing process normally expected for lipasudil-containing aqueous compositions. Therefore, according to the present invention, significantly less effort and cost is required compared to actively and forcibly adjusting and maintaining a low dissolved oxygen content. In addition, means such as blowing in oxygen gas may be employed, provided that it does not impose an excessive burden on labor and cost. Furthermore, in this specification, "aqueous compositions with a dissolved oxygen content of 8.5 mg / L or more" is not limited to aqueous compositions whose dissolved oxygen content has been intentionally "adjusted" to 8.5 mg / L or more, but also includes cases where the dissolved oxygen content naturally fluctuates within that range after the manufacture of the aqueous composition. This interpretation guideline also applies when the dissolved oxygen content is within a different numerical range.

[0035] <Aqueous composition> In the present invention, "aqueous composition" means a composition containing at least water, and its properties include liquid (solution or suspension) and semi-solid (ointment). For example, purified water, water for injection, sterile purified water, etc., can be used as the water in the composition. 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 prepared in various dosage forms according to known methods, such as those described in the 18th edition of the Japanese Pharmacopoeia, General Provisions for Preparations. The dosage form is not particularly limited as long as it can be contained in the container described later, but examples include injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal drops, enemas, topical solutions, sprays, ointments, creams, gels, oral solutions, syrups, etc. As for the dosage form, from the viewpoint of advantageously utilizing the pharmacological effects of ripasudil, eye disease preparations, specifically eye drops and eye ointments, are preferred, and eye drops are particularly preferred.

[0037] In addition to those mentioned above, aqueous compositions may contain additives used in pharmaceuticals and quasi-drugs. Examples of such additives include lower aliphatic carboxylic acids, inorganic salts, isotonic agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, viscosity modifiers, surfactants, solubilizers, suspending agents, cooling agents, dispersants, preservatives, oily bases, emulsion bases, and water-soluble bases. These additives specifically include, for example, ascorbic acid, sodium bisulfite, alginic acid, sodium benzoate, benzyl benzoate, fennel oil, ethanol, ethylene vinyl acetate copolymer, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride solution, carboxyvinyl polymer, anhydrous sodium sulfite, anhydrous sodium carbonate, d-camphor, dl-camphor, xylitol, glycerin, gluconic acid, creatinine, chlorhexidine, chlorobutanol, and crystalline diphosphate. Sodium hydrogen carbonate, geraniol, sodium chondroitin sulfate, titanium dioxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzododecinium bromide, sodium hydroxide, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbitol solution, taurine, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyroxapole, trometamol, concentrated glycerin, concentrated mixed tocopherol, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride solution 50, ethynium parahydroxybenzoate 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, bonito flakes, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, petrolatum, etc.

[0038] Preferred additives include, for example, 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, l-menthol, etc.

[0039] The aqueous composition may also contain other pharmacoactive ingredients besides lipasudil, depending on the applicable disease or other condition. Examples of such active ingredients include α1 receptor blockers containing bunazosin or its salts or solvates, such as bunazosin hydrochloride; α2 receptor agonists containing brimonidine or its salts or solvates, such as brimonidine tartrate, such as brimonidine tartrate, apraclonidine or its salts or solvates; β-blockers containing carteolol or its salts or solvates, such as carteolol hydrochloride Carbonic anhydrase inhibitors including lamid or its salts or solvates, brinzolamide or its salts or solvates, acetazolamide or its salts or solvates, dichlorfenamide or its salts or solvates, metazolamide or its salts or solvates; isopropylunoprostone or its salts or solvates, tafluprost or its salts or solvates, travoprost or its salts or solvates, bimato Prostaglandin F2α derivatives including prost or its salt or solvates, latanoprost or its salt or solvates, cloprostenol or its salt or solvates, fluprostenol or its salt or solvates; sympathomimetic agents including dipivefrin hydrochloride and other dipivefrin or its salt or solvates, epinephrine, epinephrine borate, epinephrine hydrochloride and other epinephrine or its salt or solvates;Examples include parasympathetic agonists containing distigmine bromide or its salts or solvates, pilocarpine or its salts or solvates such as pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, carbachol or its salts or solvates; calcium channel blockers containing lomerizine or its salts or solvates such as lomerizine hydrochloride; cholinesterase inhibitors containing demepotassium or its salts or solvates such as demepotassium or its salts or solvates, ecothiophate or its salts or solvates, physostigmine or its salts or solvates; and EP2 receptor agonists containing omidenepag or its salts or solvates such as omidenepag isopropyl, with one or more of these being included in the formulation. Other preferred pharmacoactive ingredients include one or more selected from the group consisting of brimonidine, latanoprost, nipradilol, dorzolamide, brinzolamide, timolol, and omidenepagisopropyl, and their salts.

[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, "container" means a package that directly contains the aqueous composition. The term "container" encompasses all of the terms "sealed container," "airtight container," and "sealed container" as defined in the General Rules of the 18th Revised Japanese Pharmacopoeia.

[0042] The form of the container is not particularly limited, as long as it is capable of containing the aqueous composition, and may be appropriately selected and set according to the dosage form, the intended use of the pharmaceutical preparation, etc. Specific examples of such container forms 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-shaped containers, and the like.

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

[0044] It is preferable to further incorporate substances that inhibit the transmission of ultraviolet light, such as ultraviolet absorbers and ultraviolet scatterers, into the polypropylene container. This improves the light stability of lipasudil. Specifically, examples of such substances include titanium dioxide as an ultraviolet scatterer;Examples include zinc oxide. Furthermore, as UV absorbers, there are 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), 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), and 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'-methyllenbis[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 and polyethylene glycol 300 (e.g., Tinuvin 213: BASF), 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol (e.g., Tinuvin 571: BASF), benzotriazole-based UV 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-benzotriazole-2-yl)phenol];Cyanoacrylate-based UV absorbers such as 2,2-bis{[2-cyano-3,3-diphenylacryloyloxy]methyl}propan-1,3-diyl=bis(2-cyano-3,3-diphenylacrylate) (e.g., Uvinul 3030 FF: BASF), 2-cyano-3,3-diphenylacrylate ethyl (e.g., Uvinul 3035: BASF), and 2-cyano-3,3-diphenylacrylate 2-ethylhexyl (e.g., Uvinul 3039: BASF); triazine-based UV absorbers such as 2-(4,6-diphenyl-1,3,5-triazine-2-yl)-5-[(hexyl)oxy]-phenol (e.g., Tinuvin 1577 ED: BASF); and octabenzone (e.g., Chimassorb). Benzophenone-based UV absorbers such as 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, sodium hydroxymethoxybenzophenone sulfonate, dihydroxydimethoxybenzophenone, sodium dihydroxydimethoxybenzophenone disulfonate, dihydroxybenzophenone, tetrahydroxybenzophenone, etc.; methyl diisopropylcinnamate, cinoxate, glyceryl mono-2-ethylhexanoate diparamethoxycinnamate, isopropyl paramethoxycinnamate / diisopropyl cinnamate ester mixture, 2-ethylhexyl paramethoxycinnamate, cinnamate Cinnamic acid-based UV absorbers such as cinnamic acid; benzoic acid ester-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;Examples include 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,5-triazine; parahydroxyanisole; 4-tert-butyl-4'-methoxydibenzoylmethane; phenylbenzimidazole sulfonic acid; and 2-(4-diethylamino-2-hydroxybenzoyl)-hexyl benzoate.

[0045] When incorporating a substance that inhibits the transmission of ultraviolet light into the container, the proportion of this substance 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 more preferably 0.01 to 10% by mass in the container.

[0046] It is preferable that the inside of the container is visible to the naked eye (observable). If the inside is visible, it becomes possible to inspect for the presence of foreign matter during the manufacturing process of the pharmaceutical product, and users of the pharmaceutical product can check the remaining amount of contents (aqueous composition), among other advantages. Here, visibility only needs to be ensured on at least a part of the surface of the container (for example, even if the side of an eye drop container is obscured by shrink film, it can be said to be visible if the bottom is visible). If the inside is visible on a part of the surface of the container, the aqueous composition inside the container can be confirmed.

[0047] The means of containing the aqueous composition in the container are not particularly limited, and it may be filled by conventional methods according to the shape of the container, etc.

[0048] <Pharmaceutical preparations> In the present invention, the diseases to which the "pharmaceutical preparation" can be applied are not particularly limited and may be appropriately selected according to the pharmacological effects of ripasudil, etc. Specifically, based on the Rho kinase inhibitory effect and intraocular pressure-lowering effect of ripasudil, it can be used as a preventive or therapeutic agent for ocular hypertension and glaucoma. Here, glaucoma can be further described by including, for example, primary open-angle glaucoma, normal-tension glaucoma, aqueous humor-excessive glaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma, steroid glaucoma, lens-capsular glaucoma, pigment glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma.

[0049] Furthermore, as disclosed in Japanese Patent Publication No. 5557408, fundus diseases (lesions that primarily manifest in the retina and / or choroid; specifically, for example, fundus changes due to hypertension and arteriosclerosis, retinal vein occlusion such as central retinal artery occlusion, central retinal vein occlusion and branch retinal vein occlusion, diabetic retinopathy, diabetic macular edema, diabetic maculopathy, congenital retinal vascular anomalies such as 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) Examples include retinal degeneration, vitreous interfacial macular degeneration, drug-toxic macular degeneration, hereditary macular degeneration, retinal detachment (rhegmatogenous, tractional, exudative, etc.), retinitis pigmentosa, and retinopathy of prematurity. It can be used as a preventive or therapeutic agent for these conditions, and more preferably as a preventive or therapeutic agent for diabetic retinopathy, diabetic macular edema, or age-related macular degeneration. Furthermore, as disclosed in Japanese Patent Publication No. 5657252, it can also be used as a preventive and / or therapeutic agent for corneal endothelial disorders.

[0050] <Meaning of other terms> In this invention, "high-temperature storage" means storage at a temperature higher than room temperature (1-30°C) that a pharmaceutical preparation may accidentally encounter during distribution or storage after its manufacture, and more specifically, storage at 60°C or higher. In this invention, "softening" of a polypropylene container refers to a decrease in the amount of force required to deform the polypropylene container to the same extent as before storage, due to high-temperature storage of a pharmaceutical preparation. "Softening" can be evaluated, for example, if the polypropylene container is an eye drop container, by comparing the amount of force required to dispense one drop of the contents from the eye drop container, as measured in Test Example 1 below, before and after high-temperature storage.

[0051] In this specification, "suppression" with respect to container softening means that the degree of "softening" is relatively reduced by taking the technical means of the present invention compared to cases where such means are not taken, and does not mean that the polypropylene container will not soften at all. For example, if the product being evaluated contains boric acid, and a comparison product is prepared that is equivalent in components, dissolved oxygen content, polypropylene container, etc., except for the absence of boric acid, and stored under the same high-temperature conditions, then the degree of "softening" of the product being evaluated is relatively suppressed compared to the comparison product.

[0052] <Method for suppressing softening, method for manufacturing pharmaceutical formulations> Furthermore, the present invention relates to an aqueous composition containing lipasudil or its salts or solvates contained in a polypropylene container, comprising the steps of adjusting the dissolved oxygen content 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 acid (B-2) Lower aliphatic carboxylic acids The present invention also relates to a method for suppressing the softening of polypropylene containers, which includes a step of incorporating a certain substance. Furthermore, the present invention relates to an aqueous composition containing lipasudil or its salts or solvates contained in a polypropylene container, comprising the steps of adjusting the dissolved oxygen content 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 acid (B-2) Lower aliphatic carboxylic acids The present invention also relates to a method for manufacturing a pharmaceutical preparation in which the softening of a polypropylene container is suppressed, which includes a step of incorporating a certain substance. In the above method, the order of the steps of incorporating lipasudil into the aqueous composition, incorporating boric acid and lower aliphatic carboxylic acids into the aqueous composition, and placing the aqueous composition in a polypropylene container does not matter. Furthermore, the timing at which the dissolved oxygen content of the aqueous composition reaches 8.5 mg / L or more is not particularly important; if the dissolved oxygen content of the aqueous composition reaches 8.5 mg / L or more at any given time, it may fall under the "method for suppressing softening of polypropylene containers" or "method for producing pharmaceutical preparations" disclosed herein. The meaning of other terms and the proportions of each ingredient are all the same as those explained above for "pharmaceutical preparations."

[0053] The present invention is not limited to these, but for example, the following embodiments are disclosed. [1A] The following components (A) and (B): (A) Lipasudil or its salts or solvates thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A pharmaceutical preparation comprising an aqueous composition containing a dissolved oxygen content of 8.5 mg / L or more (preferably 8.7 mg / L or more, more preferably 9 mg / L or more), contained in a polypropylene container. [2A] The following components (A) and (B): (A) Lipasudil or its salts or solvates thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A pharmaceutical preparation comprising an aqueous composition containing a dissolved oxygen content of 8.5 to 13 mg / L (preferably 8.7 to 13 mg / L, more preferably 9 to 13 mg / L), contained in a polypropylene container. [3A] The following components (A) and (B): (A) Lipasudil or its salts or solvates thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A pharmaceutical preparation comprising an aqueous composition containing a dissolved oxygen content of 8.5 to 12 mg / L (preferably 8.7 to 12 mg / L, more preferably 9 to 12 mg / L), contained in a polypropylene container. [4A] The following components (A) and (B): (A) Lipasudil or its salts or solvates thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A pharmaceutical preparation comprising an aqueous composition containing a dissolved oxygen content of 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, more preferably 9 to 11 mg / L), contained in a polypropylene container. [5A] The following components (A) and (B): (A) Lipasudil or its salts or solvates thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A pharmaceutical preparation comprising an aqueous composition containing a dissolved oxygen content of 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, more preferably 9 to 10 mg / L), contained in a polypropylene container. [6A] A pharmaceutical preparation according to any one of [1A] to [5A], wherein the boric acid is one or more selected from the group consisting of boric acid, its salts, and solvates thereof. [7A] A pharmaceutical preparation according to any one of [1A] to [6A], wherein the lower aliphatic carboxylic acid is 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. [8A] A 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 and its salts and solvates thereof. [9A] A pharmaceutical preparation according to any of [1A] to [8A], wherein the polypropylene container is a container for eye drops. [10A] A pharmaceutical preparation according to any one of [1A] to [8A], wherein the container hardness after storage at 60°C for one week (the amount of force required to dispense one drop of oral solution from the eye drop container, as in Test Example 1, where the eye drop container is laid horizontally on a flat surface, and the probe of a texture analyzer is pressed vertically downward from above near the center of the container body, representing the maximum load until one drop of oral solution is dispensed from the eye drop container) is 50% or more of the hardness before storage (preferably 60% or more, more preferably 70% or more, and even more preferably 75% or more).

[0054] [1B] A step of providing an aqueous composition containing lipasudil or a salt thereof or a solvate thereof, contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 mg / L or more (preferably 8.7 mg / L or more, more preferably 9 mg / L or more), and the aqueous composition contains one or more components selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for suppressing the softening of a polypropylene container, comprising a step of incorporating a substance. [2B] A step of providing an aqueous composition containing lipasudil or a salt thereof or a solvate thereof, contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 13 mg / L (preferably 8.7 to 13 mg / L, more preferably 9 to 13 mg / L), and the aqueous composition is provided with one or more components selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for suppressing the softening of a polypropylene container, comprising a step of incorporating a substance. [3B] A step of providing an aqueous composition containing lipasudil or a salt thereof or a solvate thereof, contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 12 mg / L (preferably 8.7 to 12 mg / L, more preferably 9 to 12 mg / L), and the aqueous composition is provided with one or more components selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for suppressing the softening of a polypropylene container, comprising a step of incorporating a substance. [4B] A step of providing an aqueous composition containing lipasudil or a salt thereof or a solvate thereof, contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, more preferably 9 to 11 mg / L), and adding one or more components selected from the group consisting of the following components (B-1) to (B-2) to the aqueous composition; (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for suppressing the softening of a polypropylene container, comprising a step of incorporating a substance. [5B] A step of providing an aqueous composition containing lipasudil or a salt thereof or a solvate thereof, contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, more preferably 9 to 10 mg / L), and adding one or more components selected from the group consisting of the following components (B-1) to (B-2) to the aqueous composition; (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for suppressing the softening of a polypropylene container, comprising a step of incorporating a substance. [6B] The method according to any one of [1B] to [5B], wherein boric acid is one or more selected from the group consisting of boric acid, its salts, and solvates thereof. [7B] The method according to any one of [1B] to [6B], wherein the lower aliphatic carboxylic acid is 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. [8B] The method according to any one of [1B] to [6B], wherein the lower aliphatic carboxylic acid is one or more selected from the group consisting of edetic acid and its salts and solvates thereof. [9B] The method according to any of [1B] to [8B], wherein the polypropylene container is a container for eye drops. [10B] The method according to any of [1B] to [8B], wherein the container hardness after storage at 60°C for one week (the force required to dispense one drop of oral solution from the eye drop container, as in Test Example 1, where the eye drop container is laid horizontally on a flat surface, and the probe of a texture analyzer is pressed vertically downward from above near the center of the container body, representing the maximum load until one drop of oral solution is dispensed from the eye drop container) is 50% or more of the hardness before storage (preferably 60% or more, more preferably 70% or more, and even more preferably 75% or more).

[0055] [1C] A step of providing an aqueous composition containing lipasudil or a salt thereof or a solvate thereof, contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 mg / L or more (preferably 8.7 mg / L or more, more preferably 9 mg / L or more), and the aqueous composition contains one or more components selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for producing a pharmaceutical preparation in which the softening of a polypropylene container is suppressed, comprising a step of incorporating a certain substance. [2C] A step of providing an aqueous composition containing lipasudil or its salt or solvates contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 13 mg / L (preferably 8.7 to 13 mg / L, more preferably 9 to 13 mg / L), and the aqueous composition is provided with one or more components selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for producing a pharmaceutical preparation in which the softening of a polypropylene container is suppressed, comprising a step of incorporating a certain substance. [3C] A step of providing an aqueous composition containing lipasudil or its salt or solvates contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 12 mg / L (preferably 8.7 to 12 mg / L, more preferably 9 to 12 mg / L), and the aqueous composition is provided with one or more components selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for producing a pharmaceutical preparation in which the softening of a polypropylene container is suppressed, comprising a step of incorporating a certain substance. [4C] A step of providing an aqueous composition containing lipasudil or its salt or solvates contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, more preferably 9 to 11 mg / L), and the aqueous composition is provided with one or more components selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for producing a pharmaceutical preparation in which the softening of a polypropylene container is suppressed, comprising a step of incorporating a certain substance. [5C] A step of providing an aqueous composition containing lipasudil or a salt thereof or a solvate thereof, contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, more preferably 9 to 10 mg / L), and the aqueous composition is provided with one or more components selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for producing a pharmaceutical preparation in which the softening of a polypropylene container is suppressed, comprising a step of incorporating a certain substance. [6C] The manufacturing method according to any one of [1C] to [5C], wherein the boric acid is one or more selected from the group consisting of boric acid, its salts, and solvates thereof. [7C] The method for producing a lower aliphatic carboxylic acid according to any one of [1C] to [6C], wherein the lower aliphatic carboxylic acid is 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. [8C] The method for producing a lower aliphatic carboxylic acid according to any one of [1C] to [6C], wherein the lower aliphatic carboxylic acid is one or more selected from the group consisting of edetic acid and its salts and solvates thereof. [9C] The manufacturing method according to any one of [1C] to [8C], wherein the polypropylene container is a container for eye drops. A manufacturing method according to any of [1C] to [8C], wherein the container hardness after storage at 60°C for one week (the force required to dispense one drop of internal solution from the eye drop container, as in Test Example 1, where the eye drop container is laid horizontally on a flat surface, and the probe of a texture analyzer is pressed vertically downward from above near the center of the container body, representing the maximum load until one drop of internal solution is dispensed from the eye drop container) is 50% or more of the hardness before storage (preferably 60% or more, more preferably 70% or more, and even more preferably 75% or more). [Examples]

[0056] Next, the present invention will be further explained with reference to examples, but the present invention is not limited to these examples. In the following test examples, lipasudil 1-hydrochloride dihydrate can be manufactured, for example, by the method described in International Publication No. 2006 / 057397.

[0057] [Test Example 1] Preservation Test Part 1 Aqueous compositions containing the components and quantities shown in Table 1 in 100 mL were prepared by conventional methods. The dissolved oxygen content was then adjusted to the levels shown in Table 1 by blowing in nitrogen gas, oxygen gas, or air while monitoring the dissolved oxygen level. The dissolved oxygen level was measured using a dissolved oxygen meter (portable waterproof dissolved oxygen meter, model AS720, manufactured by AS ONE Corporation) under an ambient temperature of 25°C. A pharmaceutical preparation was manufactured by placing an aqueous composition with adjusted dissolved oxygen content into an eye drop container made of polypropylene (PP). The polypropylene eye drop container had a hollow cylindrical shape with a diameter of approximately 2 cm and a height of approximately 2.8 cm, and the thickness of the container body was approximately 0.4 mm.

[0058] Each pharmaceutical preparation was stored at 60°C for one week, and the container hardness (the force required to dispense one drop of the oral solution from the eye drop container) was measured before storage and after one week at 60°C. To avoid the influence of temperature on 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 to 25°C before being subjected to measurement. The "magnitude of force required to dispense one drop of solution from an eye drop container" (hereinafter also referred to as "Force") was measured using a texture analyzer (TA.XTplus Texture Analyser: Stable Micro Systems) in the following manner. Specifically, the eye drop container, with the cap removed, was laid horizontally on a flat surface and secured with a grip. The texture analyzer probe was then pressed vertically downwards from above at a speed of 1 mm / second near the center of the container body (approximately 1.4 cm above the bottom of the container), and the container body was pressed until one drop of solution was dispensed. The maximum load (gf) until one drop of solution was dispensed was measured, and this maximum load was defined as the "magnitude of force required to dispense one drop of solution from an eye drop container."

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

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

[0061] The results are shown in Table 1.

[0062] [Table 1]

[0063] As shown in Table 1, in Reference Example 1, where an aqueous composition without lipasudil was contained in a polypropylene container, storage at 60°C for one week resulted in a container hardness (the force required to dispense one drop of the oral solution from the eye drop container) of 87.1% of the pre-storage level. Although some softening of the container was observed, it was not significant. On the other hand, in Reference Example 2, where an aqueous composition containing lipasudil was contained in a polypropylene container, storage at 60°C for one week resulted in a significant decrease in container hardness (the force required to dispense one drop of the oral solution from the eye drop container) to 28.0% of the pre-storage level, indicating substantial softening of the container. From the above test results, it was found that storing the lipasudil-containing aqueous composition in a polypropylene container under high-temperature conditions causes the container to soften over time.

[0064] [Test Example 2] Preservation Test Part 2 Aqueous compositions containing the components and quantities shown in Table 2 in 100 mL were prepared by conventional methods. The dissolved oxygen content was then adjusted to the levels shown in Table 2 by blowing in nitrogen gas, oxygen gas, or air while monitoring the dissolved oxygen level. The dissolved oxygen level was measured using a dissolved oxygen meter (portable waterproof dissolved oxygen meter, model AS720, manufactured by AS ONE Corporation) under an ambient temperature of 25°C. A pharmaceutical formulation was prepared by placing an aqueous composition with adjusted dissolved oxygen content into an eye drop container made of polypropylene (PP), the same material used in Test Example 1.

[0065] Each obtained pharmaceutical preparation was stored at 60°C for one week. The container hardness (the amount of force required to dispense one drop of oral solution from the eye drop container) was measured before storage and after one week of storage at 60°C using the same method as in Test Example 1. The "percentage (%) of the container hardness after one week of storage at 60°C to the container hardness before storage" was calculated and used as an indicator of the change in hardness of propylene containers 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 Table 2, when the lipasudil-containing aqueous composition contained in a polypropylene container did not contain boric acid (Comparative Example 1), or when the dissolved oxygen content was less than 8.5 mg / L (Comparative Example 2), in both cases, similar to what 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 pre-storage level (28.0% and 48.9%, respectively) after storage at 60°C for one week, indicating a significant softening of the container. On the other hand, when the dissolved oxygen content of the lipasudil-containing aqueous composition housed in a polypropylene container was set to 8.5 mg / L or higher, and boric acid was also included (Examples 1 and 2), storage at 60°C for one week resulted in a container hardness (the amount of force required to dispense one drop of the oral solution from the eye drop container) exceeding approximately 70% of the pre-storage level, indicating that softening of the container was suppressed.

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

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

[0070] [Table 3]

[0071] As shown in Table 3, when sodium edetate hydrate was included in the lipasudil-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) exceeded approximately 70% of the pre-storage level, indicating that softening of the container was suppressed.

[0072] From the above, it was found that even when the dissolved oxygen content of a lipasudil-containing aqueous composition contained in a polypropylene container is set to 8.5 mg / L or higher, and when it contains one or more lower aliphatic carboxylic acids 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 1-5] After preparing aqueous compositions containing the components and quantities shown in Table 4 in 100 mL using conventional methods, the dissolved oxygen content was measured and monitored while blowing in nitrogen gas, oxygen gas, or air to adjust the dissolved oxygen content as shown in Table 4. These compositions were then placed in polypropylene eye drop containers to obtain the pharmaceutical formulations of Production Examples 1 to 5.

[0074] [Table 4]

[0075] [Manufacturing Examples 6-10] After preparing an aqueous composition containing the components and quantities shown in Table 5 in 100 mL using a conventional method, the dissolved oxygen content was measured and monitored while blowing in nitrogen gas, oxygen gas, or air to adjust the dissolved oxygen content as shown in Table 5. This was then placed in a polypropylene eye drop container to obtain the pharmaceutical formulations of Production Examples 6 to 10.

[0076] [Table 5]

[0077] [Manufacturing Examples 11-15] After preparing an aqueous composition containing the components and quantities shown in Table 6 in 100 mL by conventional methods, the dissolved oxygen content was measured and monitored while blowing in nitrogen gas, oxygen gas, or air to adjust the dissolved oxygen content as shown in Table 6. This was then placed in a polypropylene eye drop container to obtain the pharmaceutical formulations of Production Examples 11 to 15.

[0078] [Table 6]

[0079] [Manufacturing Examples 16-20] After preparing aqueous compositions containing the components and quantities shown in Table 7 in 100 mL using conventional methods, the dissolved oxygen content was measured and monitored while adjusting the dissolved oxygen content by blowing in nitrogen gas, oxygen gas, or air to obtain the pharmaceutical formulations of Production Examples 16-20.

[0080] [Table 7]

[0081] [Manufacturing Examples 21-25] After preparing an aqueous composition containing the components and quantities shown in Table 8 in 100 mL by conventional methods, the dissolved oxygen content was measured and monitored while blowing in nitrogen gas, oxygen gas, or air to adjust the dissolved oxygen content as shown in Table 8. This was then placed in a polypropylene eye drop container to obtain the pharmaceutical formulations of Production Examples 21 to 25.

[0082] [Table 8]

[0083] [Manufacturing Examples 26-30] After preparing an aqueous composition containing the components and quantities shown in Table 9 in 100 mL by conventional methods, the dissolved oxygen content was measured and monitored while blowing in nitrogen gas, oxygen gas, or air to adjust the dissolved oxygen content as shown in Table 9. This was then placed in a polypropylene eye drop container to obtain the pharmaceutical formulations of Production Examples 26-30.

[0084] [Table 9] [Industrial applicability]

[0085] According to the present invention, a pharmaceutical formulation with 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) Lipasdil or its salts or solvates thereof; (B) One or more selected from the group consisting of the following components (B-1) to (B-2); (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A pharmaceutical preparation comprising an aqueous composition containing a dissolved oxygen content of 8.5 mg / L or more, housed in a polypropylene container.

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

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

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

5. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the boric acid is one or more selected from the group consisting of boric acid, its salts, and solvates thereof.

6. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the lower aliphatic carboxylic acid is 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.

7. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid and its salts and solvates thereof.

8. A step of providing an aqueous composition containing lipasudil or its salt or solvates contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 mg / L or more, and one or more components selected from the group consisting of the following components (B-1) to (B-2) are added to the aqueous composition; (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for suppressing the softening of a polypropylene container, comprising a step of incorporating a substance.

9. The method according to claim 8, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 13 mg / L.

10. The method according to claim 8, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 12 mg / L.

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

12. The method according to any one of claims 8 to 11, wherein the boric acid is one or more selected from the group consisting of boric acid, its salts, and solvates thereof.

13. The method according to any one of claims 8 to 11, wherein the lower aliphatic carboxylic acid is 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.

14. The method according to any one of claims 8 to 11, wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid and its salts and solvates thereof.

15. A step of providing an aqueous composition containing lipasudil or its salt or solvates contained in a polypropylene container, wherein the dissolved oxygen content of the aqueous composition is 8.5 mg / L or more, and one or more components selected from the group consisting of the following components (B-1) to (B-2) are added to the aqueous composition; (B-1) Boric acid (B-2) Lower aliphatic carboxylic acids A method for producing a pharmaceutical preparation in which the softening of a polypropylene container is suppressed, comprising a step of incorporating a certain substance.

16. The manufacturing method according to claim 15, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 13 mg / L.

17. The manufacturing method according to claim 15, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 12 mg / L.

18. The manufacturing method according to claim 15, wherein the dissolved oxygen content of the aqueous composition is 8.5 to 11 mg / L.

19. The method for producing a product according to any one of claims 15 to 18, wherein the boric acid is one or more selected from the group consisting of boric acid, its salts, and solvates thereof.

20. The method according to any one of claims 15 to 18, wherein the lower aliphatic carboxylic acid is 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.

21. The method according to any one of claims 15 to 18, wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of edetic acid and its salts and solvates thereof.

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