Medicament

Abstract

To provide a technique for suppressing freezing of a ripasudil-containing aqueous composition stored in a polyolefin resin-made vessel and having an amount of oxygen dissolved of ≥ 8. 5mg / L when stored at a low temperature.SOLUTION: A pharmaceutical preparation in which an aqueous composition containing ripasudil or salts thereof or solvates thereof and lower aliphatic carboxylic acids and having an amount of dissolved oxygen of 8. 5mg / L or more is contained in a polyethylene vessel.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] The following structural formula:

[0003] [ka]

[0004] Ripasudil (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4 -diazepan-1-yl]sulfonyl]isoquinoline) has Rho kinase inhibitory activity, etc. It is known to have pharmacological effects (for example, Patent Document 1) and to be useful in the prevention and treatment of eye diseases. Specifically, for example, it is used for the prevention or treatment of ocular hypertension, glaucoma, etc. (for example, Patent Document 2). It is also useful for preventing or treating diseases of the ocular fundus such as age-related macular degeneration (for example, Patent Document 3). It has been reported that a high-performance drug containing ripasudil hydrochloride hydrate as an active ingredient "Glanatec" (registered trademark) and "Glaalf" are available as preventive and therapeutic agents for ocular hypertension and glaucoma. The drug "A" (registered trademark) has been developed and marketed in several countries, including Japan (Non-Patent Documents 1 and 2). . Therefore, we will establish a technology to stably formulate Ripasudil as an ophthalmic agent, etc. That is extremely useful.

[0005] In addition, the aqueous composition containing Ripasudil or a salt thereof or a solvate thereof may be used in a polyethylene glycol-based liquid. By storing it in a container made of polyolefin resin such as polyethylene or polypropylene, it can withstand high temperatures. It has been reported that discoloration after long-term storage can be suppressed by using this method (Patent Document 4). In addition, both Glanatec and Glaalpha contain ripasudil hydrochloride hydrate. The pharmaceutical product is an aqueous composition contained in an eye drop container body made of polypropylene. [Prior art documents] [Patent documents]

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

[0007] [Non-Patent Document 1] Pharmaceutical interview form "Glanatec (registered trademark) eye drops 0.4%" Kowa Company, Ltd., September 2023 [Non-patent document 2] Pharmaceutical interview form "Gla Alpha (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). and an aqueous composition containing Ripasudil or a salt thereof or a solvate thereof (hereinafter referred to as "Ripasudil"). The storage stability of the "Sujiru-containing aqueous composition" was investigated. However, when the Ripasudil-containing aqueous composition is contained in a polyolefin resin container, When the product was stored at room temperature (1-30°C), no problems occurred. When stored under low temperature conditions of -5°C, the aqueous composition containing Ripasudil When the dissolved oxygen content is 8.5 mg / L or more, the aqueous composition may freeze over time. It turns out that there will be problems.

[0009] To address this problem, for example, the amount of dissolved oxygen in the Ripasudil-containing aqueous composition may be adjusted to a low level. This problem can be solved by adjusting the amount of dissolved oxygen in the Ripasudil-containing aqueous composition to a low level. To do this, for example, replace the dissolved oxygen with an inert gas by nitrogen purging or by vacuum desorption. However, implementing these methods requires a great deal of effort and cost. is required. Therefore, the present invention is a product that is contained in a polyolefin resin container and has a dissolved oxygen content of 8. A technology to prevent freezing of an aqueous composition containing ripasudil at 5 mg / L or more during low-temperature storage. The purpose is to provide. [Means for solving the problem]

[0010] The present inventors have further studied to solve the above problems, and have found that the dissolved oxygen content is 8.5 The aqueous composition containing Ripasudil is further formulated with edetic acid and its salts and and solvates thereof, The aqueous composition is placed in a polyolefin resin container, preferably a polyethylene resin container. It was found that freezing during cryopreservation was specifically suppressed when the material was stored in a plastic container. The invention was completed.

[0011] That is, the present invention relates to a method for producing a compound of ripasudil or a salt thereof or a solvate thereof with a lower aliphatic and a carboxylic acid, and an aqueous composition having a dissolved oxygen content of 8.5 mg / L or more is The present invention provides a pharmaceutical preparation housed in a polyethylene container. The present invention also provides a method for reducing dissolved oxygen in a patient, comprising administering to the patient a solution of Ripasudil or a salt thereof or a solvate thereof. A process of adding lower aliphatic carboxylic acids to an aqueous composition having an amount of 8.5 mg / L or more. and freezing the aqueous composition, comprising the steps of: placing the aqueous composition in a polyethylene container. The present invention provides a method for suppressing the Furthermore, the present invention provides a pharmaceutical composition containing Ripasudil or a salt thereof or a solvate thereof, and a dissolved acid A lower aliphatic carboxylic acid is contained in an aqueous composition having a carboxylic acid content of 8.5 mg / L or more. and freezing the aqueous composition, comprising the steps of: The present invention provides a method for producing a pharmaceutical preparation in which the above-mentioned effects are suppressed. [Effects of the Invention]

[0012] According to the present invention, the product is contained in a polyolefin resin container and has a dissolved oxygen content of 8.5 This can prevent freezing of an aqueous composition containing Ripasudil at a concentration of 100 mg / L or more during low-temperature storage. DETAILED DESCRIPTION OF THE INVENTION

[0013] In this specification, "w / v%" means mass to volume percentage, specifically, 100 ml It means the mass (g) of each component contained per L of composition.

[0014] <Ripasudil or its salt or solvate> In the present invention, ripasudil (chemical name: 4-fluoro-5-[[(2S)-2-methyl

[0033] The compound (1,4-diazepan-1-yl]sulfonyl]isoquinoline) may be a salt. The salt of Pasdil is not particularly limited as long as it is a pharmaceutically acceptable salt, and specific examples thereof include Inorganic acid salts such as hydrochlorides, sulfates, nitrates, hydrofluorides, hydrobromides; acetates, tartar Acid salts, lactate, citrate, fumarate, maleate, succinate, methanesulfonate Salt, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalene Examples include organic acid salts such as sulfonates and camphorsulfonates, and hydrochlorides are preferred. Furthermore, Ripasudil or a salt thereof may be a solvate such as a hydrate or an alcohol solvate. It is preferably a hydrate.

[0015] In the present invention, Ripasudil or a salt thereof or a solvate thereof includes Ripasudil More preferably, the compound has the following structural formula:

[0016] [ka]

[0017] Ripasudil hydrochloride hydrate (Ripasudil monohydrochloride dihydrate) represented by the following formula is particularly preferred.

[0018] Ripasudil or a salt thereof or a solvate thereof is known and can be produced by a known method. Specifically, for example, Ripasudil or a salt thereof or a solvate thereof is International Publication No. 1999 / 020620, International Publication No. 2006 / 057397 It can be manufactured by the method described in Fret.

[0019] The content of Ripasudil or a salt thereof or a solvate thereof in the aqueous composition is not particularly limited. It should be decided based on the disease to be treated, the patient's sex, age, symptoms, etc. In order to obtain the desired pharmacological effect, the total volume of the aqueous composition was calculated based on the free form of Ripasudil. 0.01 w / v% or more, preferably 0.02 w / v% or more, and more preferably 0.0 It may contain 4 w / v% or more, and 10 w / v% or less, preferably 8 w / v% or less, particularly In particular, from the viewpoint of obtaining excellent pharmacological effects, Ripasudil or a salt thereof or a solvate thereof is used in an amount of free of the total volume of the aqueous composition. The content is preferably 0.05 to 5 w / v% in terms of the total body weight, and more preferably 0.1 to 3 w / v%. It is more preferable that the content is 0.1 to 2 w / v%, and even more preferable that the content is 0.3 to 0.5 w / v%. It is particularly preferable that the content is 1 / v %.

[0020] <Lower aliphatic carboxylic acids> In the present invention, "lower aliphatic carboxylic acids" refer to carboxylic acids in which one or more carbon atoms are replaced by a nitrogen atom. Lower aliphatic carboxylic acids and their salts (e.g., sodium salts, carboxylic acids, etc.) which may be substituted; alkali metal salts such as sodium salts; alkaline earth metal salts such as calcium salts and magnesium salts; One or more compounds selected from the group consisting of ammonium salts and their solvates (hydrates, etc.) It means above. 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. However, from the viewpoint of preventing freezing during low-temperature storage of the Ripasudil-containing aqueous composition, 2 to 12 is preferred, 4 to 12 is more preferred, and 6 to 12 is particularly preferred. Of the atoms, some of the carbon atoms other than those that make up the carboxyl group are Although the nitrogen atom may be substituted, the freezing of the Ripasudil-containing aqueous composition during low-temperature storage is From the viewpoint of suppression, the number of nitrogen atoms substituted is preferably 1 to 2. may be linear or branched, and may be saturated or unsaturated. good.

[0021] The number of carboxyl groups in the lower aliphatic carboxylic acids is not limited. From the viewpoint of preventing freezing during low-temperature storage of the silica-containing aqueous composition, 1 to 4 silicas are preferred. The lower aliphatic carboxylic acids are used from the viewpoint of preventing freezing of the Ripasudil-containing aqueous composition during storage at low temperatures. Therefore, the compound may further have 1 to 3 hydrophilic substituents other than the carboxyl group. Specific examples of the hydrophilic substituent include a hydroxyl group and an amino group. The lower aliphatic carboxylic acids are known compounds and may be produced by known methods. Commercially available products may be used. The lower aliphatic carboxylic acids may be used in combination with other components or in the form of salts. A complex may be used, and an aqueous composition containing such a salt or a component that has formed a complex may be used. The "aqueous composition containing a lower aliphatic carboxylic acid" also includes such a composition.

[0022] Specific examples of such lower aliphatic carboxylic acids include adipic acid; Aspartic acid, sodium L-aspartate, magnesium L-aspartate, etc. One or more selected from the group consisting of paraginic acid, its salts, and solvates thereof; One selected from the group consisting of 1-aminocaproic acid, its salts, and solvates thereof Edetic acid, edetate calcium sodium hydrate, edetate sodium hydrate, edetate edetic acid and its salts, such as edetate tetrasodium hydrate and anhydrous edetate disodium; one or more selected from the group consisting of citric acid, calcium citrate, and solvates thereof; Citric acid hydrate, sodium citrate hydrate, sodium dihydrogen citrate, disodium citrate Citric acid and its salts such as sodium, anhydrous citric acid, anhydrous sodium citrate, and one or more selected from the group consisting of succinic acid, monosodium succinate, succinic acid, From the group consisting of succinic acid and its salts, such as disodium succinate hexahydrate, and solvates thereof one or more selected from the group consisting of acetic acid, ammonium acetate, potassium acetate, calcium acetate, sodium acetate Acetic acid and its salts such as thorium hydrate, glacial acetic acid, anhydrous sodium acetate, and solvates thereof one or more selected from the group consisting of tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL- Tartaric acid and its salts, such as sodium tartrate and sodium potassium tartrate, and their solutions one or more selected from the group consisting of sorbates such as sorbic acid and potassium sorbate; One or more selected from the group consisting of acids, their salts, and solvates thereof; lactic acid, sodium lactate Lactic acid and its salts, such as sodium solution, calcium lactate hydrate, and aluminum lactate, and one or more selected from the group consisting of solvates of the above compounds; propionic acid, sodium propionate, etc. one or more selected from the group consisting of propionic acid, its salts, and solvates thereof; One or more members selected from the group consisting of fumaric acid, its salts, and solvates thereof; malein one or more selected from the group consisting of acids, their salts, and solvates thereof; malonic acid and its salts; and one or more selected from the group consisting of salts thereof and solvates thereof; malic acid, DL-malic acid malic acid, its salts such as sodium DL-malate, and their solvates These may be used alone or in combination of two or more. It can be used in combination. These lower aliphatic carboxylic acids are all known and can be produced by known methods. Alternatively, commercially available products may be used.

[0023] The lower aliphatic carboxylic acids include those that inhibit freezing of the Ripasudil-containing aqueous composition during low-temperature storage. From the viewpoint of epsilon-aminocaproic acid, edetic acid, citric acid, acetic acid, sorbic acid and and at least one selected from the group consisting of hydroxybenzoates, salts thereof, and solvates thereof. The group consisting of silane-aminocaproic acid, edetic acid, their salts, and their solvates More preferably, one or more selected from edetic acid, its salts, and solvates thereof Particularly preferred are at least one selected from the group consisting of: and salts thereof, and solvates thereof, Compared with other lower aliphatic carboxylic acids, the freezing of the aqueous composition containing Ripasudil during low-temperature storage is significantly suppressed.

[0024] The content of lower aliphatic carboxylic acids in the aqueous composition is not particularly limited, but From the viewpoint of preventing freezing during low-temperature storage of the aqueous composition, 0.001% of the total volume of the aqueous composition w / v or more, preferably 0.01 w / v% or more, more preferably 0.05 w / v% or more, Particularly preferably, it may contain 0.1 w / v% or more, and 5 w / v% or less, preferably 3 It may contain up to 0.5 w / v%, and particularly preferably 1 w / v%. Among them, epsilon-aminocaproic acid and its salts as lower aliphatic carboxylic acids are When one or more compounds selected from the group consisting of benzophenone-3, benzophenone-4, benzophenone-5, benzophenone-6, benzophenone-7, benzophenone-8, benzophenone-9, benzophenone-10, benzophenone-11, benzophenone-12, benzophenone-13, benzophenone-14, benzophenone-15, benzophenone-16, benzophenone-17, benzophen From the viewpoint of preventing freezing of the aqueous composition containing zirconia during low-temperature storage, 0. The content is preferably 0.03 to 3 w / v%, and more preferably 0.07 to 1 w / v%. It is particularly preferable that the content is 0.2 to 0.5 w / v %. Among them, lower aliphatic carboxylic acids include edetic acid and its salts and their solvents. When one or more solvents selected from the group consisting of hydrates are used, the aqueous composition containing Ripasudil is To prevent freezing during low-temperature storage of the composition, the amount of water added is 0.0003 to 0.0001% of the total volume of the aqueous composition. It is preferable that the content is 3 w / v%, and more preferably 0.007 to 0.2 w / v%. It is particularly preferable that the content be 0.02 to 0.1 w / v %. Among them, lower aliphatic carboxylic acids include citric acid and its salts and their solvents. When one or more solvents selected from the group consisting of hydrates are used, the aqueous composition containing Ripasudil is From the viewpoint of preventing freezing during low-temperature storage of the composition, 0.006 to 2 wt.% of the total volume of the aqueous composition It is preferable that it contains 0.04 to 0.4 w / v%, more preferably 0. It is particularly preferable that the content is 0.7 to 0.2 w / v%. Among these, lower aliphatic carboxylic acids include acetic acid and its salts and solvates thereof. In the case where one or more substances selected from the group consisting of From the viewpoint of preventing freezing during low-temperature storage, 0.003 to 2 w / v% of the total volume of the aqueous composition It is preferable to contain 0.03 to 0.3 w / v%, more preferably 0.07 to 0.3 w / v%. It is particularly preferable that the content is up to 0.2 w / v%. Among them, as lower aliphatic carboxylic acids, sorbic acid and its salts and their When one or more solvates are used, the aqueous solution containing Ripasudil From the viewpoint of preventing freezing during low-temperature storage of the composition, 0.02 to 0.8 It is preferable that the content is 0.09 to 0.4 w / v%, and more preferable that the content is 0.09 to 0.4 w / v%. It is particularly preferable that the content is 0.07 to 0.2 w / v %.

[0025] In addition, the aqueous composition contains Ripasudil or a salt thereof or a solvate thereof and a lower aliphatic carbonyl group. The mass ratio of the carboxylic acids is not particularly limited, but it is preferable that the Ripasudil-containing aqueous composition is stored at low temperatures. From the viewpoint of preventing freezing during freezing, lower aliphatic Carboxylic acids are used in an amount of 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 It may contain 8 parts by mass or less, preferably 4 parts by mass or less, particularly preferably 3 parts by mass or less. It may contain less than 1 part. Among these, epsilon-aminocaproic acid and its salts as lower aliphatic carboxylic acids, When one or more solvates thereof are used, From the viewpoint of preventing freezing during low-temperature storage of the aqueous composition containing Ripasudil, For 1 part by mass, epsilon-aminocaproic acid and its salts and solvates thereof Preferably, the content of one or more selected from the group consisting of 0.05 to 2.5 parts by mass, and more preferably 0.2 to 2.5 parts by mass of The content is more preferably 2 parts by mass, and particularly preferably 0.5 to 1.5 parts by mass. Among these, edetic acid and its salts as lower aliphatic carboxylic acids and solvents thereof are also preferred. When one or more compounds selected from the group consisting of hydrates are used, the aqueous composition containing Ripasudil From the viewpoint of preventing freezing during low-temperature storage, for 1 part by mass of Ripasudil in free form, , edetic acid, its salts, and solvates thereof, The content is preferably 0.03 to 2 parts by mass, and more preferably 0.01 to 1 part by mass, It is particularly preferable that the content be 0.02 to 0.5 parts by mass. Among these, lower aliphatic carboxylic acids include citric acid and its salts and their solvents. When one or more compounds selected from the group consisting of hydrates are used, the aqueous composition containing Ripasudil From the viewpoint of preventing freezing during low-temperature storage, for 1 part by mass of Ripasudil in free form, citric acid, its salts, and solvates thereof in an amount of 0.0 The content is preferably 0.03 to 5 parts by mass, and more preferably 0.03 to 2 parts by mass, It is particularly preferable that the content be 0.07 to 7 parts by mass. Among these, lower aliphatic carboxylic acids include acetic acid and its salts and solvates thereof. When one or more selected from the group consisting of: From the viewpoint of preventing freezing during low-temperature storage, vinegar is used for 1 part by mass of Ripasudil converted to its free form. 0.003 to 2% of one or more selected from the group consisting of acids, their salts, and solvates thereof It is preferably contained in an amount of 0.03 to 1 part by mass, more preferably 0.02 to 1 part by mass. It is particularly preferable that the content be 0.8 parts by mass or less. Among these, sorbic acid and its salts and their solvents are also preferred as lower aliphatic carboxylic acids. When one or more solvents selected from the group consisting of hydrates are used, the aqueous composition containing Ripasudil is From the viewpoint of preventing freezing during low-temperature storage of the product, the amount of and one or more selected from the group consisting of sorbic acid, its salts, and solvates thereof. The content is preferably 0.04 to 3 parts by mass, and more preferably 0.03 to 1.5 parts by mass. The content is preferably 0.3 to 0.7 parts by mass, and particularly preferably 0.3 to 0.7 parts by mass.

[0026] <Dissolved oxygen content> In the present invention, the amount of dissolved oxygen in the Ripasudil-containing aqueous composition is 8.5 mg / L or more. As shown in the test examples below, the dissolved oxygen content of the Ripasudil-containing aqueous composition is 8. If the concentration is 0.5 mg / L or higher, freezing may occur over time during low-temperature storage. The aqueous composition further contains lower aliphatic carboxylic acids, and the aqueous composition is By storing it in a polyethylene container, freezing over time during low-temperature storage is suppressed. possible. Therefore, according to the means for solving the problems of the present invention, the dissolved oxygen is inactivated by, for example, nitrogen purging. To reduce and maintain the amount of dissolved oxygen, the solution is replaced with an acidic gas or vacuum degassed. It does not require a great deal of effort or cost, and can be easily and inexpensively stored at low temperatures. A pharmaceutical product containing a Ripasudil-containing aqueous composition that is inhibited from freezing and has good storage stability and is contained in a container. A pharmaceutical formulation can be obtained.

[0027] In the present invention, the amount of dissolved oxygen in the Ripasudil-containing aqueous composition is 8.5 mg / L or more (or more preferably 8.5 mg / L or more). More preferably, it is 8.5 to 13 mg / L, even more preferably, it is 8.5 to 12 mg / L, and even more preferably Preferably, it is 8.5 to 11 mg / L, even more preferably 8.5 to 10 mg / L, and particularly preferably 8.5-9.5mg / L), but should be 8.7mg / L or higher (more preferably 8. 7 to 13 mg / L, more preferably 8.7 to 12 mg / L, and even more preferably 8.7 to 11 mg / L, even more preferably 8.7 to 10 mg / L, particularly preferably 8.7 to 9.5 mg / L), and 9 mg / L or more (more preferably 9 to 13 mg / L, and Preferably, the concentration is 9 to 12 mg / L, more preferably 9 to 11 mg / L, and even more preferably It is particularly preferable that the concentration is 9 to 10 mg / L, and particularly preferably 9 to 9.5 mg / L.

[0028] In the present invention, the amount of dissolved oxygen is measured by a diaphragm electrode method, particularly a polarographic method (diaphragm polar The value measured by the logarithmic method is used to measure the amount of dissolved oxygen by such a method. As a dissolved oxygen meter, for example, the portable waterproof dissolved oxygen meter model number AS720 (AS ONE Corporation) Examples include products manufactured by the Company. In the present invention, the amount of dissolved oxygen is determined by the amount of dissolved oxygen that is continuously maintained when the pharmaceutical preparation is stored under the specified storage conditions (storage method). For example, if the storage method is set to "store at room temperature," For pharmaceutical preparations, the meaning of "room temperature" as defined in the 18th Revised Japanese Pharmacopoeia (1-30°C) According to the above, a pharmaceutical preparation containing Ripasudil stored at any temperature in the range of 1 to 30°C is The amount of dissolved oxygen in the composition can be measured. If the amount is 9 mg / L or more, it is likely that the substance has been exposed to a low temperature environment due to some accident during distribution or storage. When exposed, freezing can be advantageously inhibited.

[0029] No special process is required to achieve a dissolved oxygen content of 8.5 mg / L or more in the Ripasudil-containing aqueous composition. For example, the stirring speed or stirring speed may be adjusted so as to incorporate air when mixing the aqueous composition. Adjustment of the stirring blades, etc., in the manufacturing process normally assumed for the Ripasudil-containing aqueous composition By using this simple method, a person skilled in the art can appropriately increase the dissolved oxygen content to 8.5 mg / L or more. Therefore, according to the present invention, the amount of dissolved oxygen is significantly reduced compared to actively and forcibly adjusting and maintaining the amount of dissolved oxygen at a low value. This requires less effort and cost. However, within the scope of not imposing an excessive burden on labor and costs, A means such as blowing oxygen gas may be employed. In this specification, "aqueous composition with a dissolved oxygen content of 8.5 mg / L or more" means an aqueous composition with a dissolved oxygen content of 8.5 mg / L or more. Not limited to aqueous compositions intentionally "adjusted" to a concentration of 8.5 mg / L or more, This also includes cases where the amount of dissolved oxygen naturally fluctuates within the range after the product is manufactured. The same applies when the amount of dissolved oxygen is in another range of values.

[0030] <Aqueous composition> In the present invention, the term "aqueous composition" means a composition containing at least water, and its properties The form of the composition may be liquid (solution or suspension) or semi-solid (ointment). Examples of water that can be used include purified water, water for injection, and sterilized purified water. The content of water in the aqueous composition is not particularly limited, but is preferably 5 w / v% or more. 20 w / v% or more is more preferable, 50 w / v% or more is even more preferable, and 90 w / v% or more is The above range is even more preferable, and 90 to 99.8 w / v % is particularly preferable.

[0031] The aqueous composition can be prepared according to a known method, for example, as described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition. The dosage form can be one that can be accommodated in the container described below. The present invention is not particularly limited as long as it is suitable for the purpose, but examples thereof include injections, inhalation solutions, eye drops, eye ointments, ear drops, and eye drops. Nasal liquid, enema, topical liquid, spray, ointment, cream, gel, oral liquid, As for dosage forms, those that take advantage of the pharmacological action of Ripasudil are From this viewpoint, agents for eye diseases, specifically eye drops and eye ointments, are preferred, with eye drops being particularly preferred.

[0032] In addition to the above, the aqueous composition may contain additives used in pharmaceuticals, quasi-drugs, etc. Such additives may include, for example, inorganic salts, isotonicity agents, chelating agents, stabilizing agents, etc. pH adjuster, preservative, antioxidant, thickener, surfactant, solubilizer, suspending agent, detergent Examples of the additives include cooling agents, dispersants, preservatives, oily bases, emulsion bases, and water-soluble bases. 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, chlorobu Tanol, crystalline sodium dihydrogen phosphate, geraniol, sodium chondroitin sulfate , titanium oxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzo bromide Dodecinium, Sodium Hydroxide, Polyoxyl 45 Stearate, Purified Lanolin, D- Sorbitol, sorbitol liquid, taurine, sodium bicarbonate, sodium carbonate hydrate , sodium thiosulfate hydrate, thimerosal, tyloxapol, trometamol, concentrated gluten Serine, concentrated mixed tocopherols, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium Umium chloride solution 50, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, Propyl benzoate, methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin amine, sodium pyrosulfite, phenylethyl alcohol, glucose, propylene glycol Benzalkonium Chloride, Benzalkonium Chloride Solution, Benzyl Alcohol, Bergamot Oil Alcohol, benzethonium chloride, benzethonium chloride solution, borax, boric acid, povidone Polyoxyethylene (200) Polyoxypropylene glycol (70), Polystyrene Sodium ethylene sulfonate, Polysorbate 80, Polyoxyethylene hydrogenated castor oil 60 , polyvinyl alcohol (partially saponified), d-borneol, macrogol 4000, Macrogol 6000, D-mannitol, anhydrous sodium phosphate monobasic, anhydrous diphosphate Sodium hydrogen, methanesulfonic acid, l-menthol, monoethanolamine, monosterol Polyethylene glycol distearate, eucalyptus oil, potassium iodide, sulfuric acid, hydroxyquinoline sulfate Phosphorus, liquid paraffin, rhododendron, phosphoric acid, sodium hydrogen phosphate hydrate, phosphoric acid dihydrate potassium hydroxide, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, petrolatum, etc. Illustrated.

[0033] Additives include, for example, potassium chloride, calcium chloride hydrate, sodium chloride, salt Magnesium chloride, glycerin, sodium hydroxide, sodium bicarbonate, sodium carbonate Hydrate, concentrated glycerin, borax, boric acid, povidone, polysorbate 80, polyoxyethylene Styrene hydrogenated castor oil, polyethylene glycol monostearate, polyvinyl alcohol (Partially saponified), Macrogol 4000, Macrogol 6000, Anhydrous Sodium Hydrogen Phosphate Sodium dihydrogen phosphate anhydrous, monoethanolamine, phosphoric acid, sodium hydrogen phosphate Thorium hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate Preferred are menthol monohydrate, sodium hyaluronate, glucose, l-menthol, and the like.

[0034] The aqueous composition may further contain, in addition to the above, other ingredients other than Ripasudil depending on the disease to be treated, etc. It may contain a medicinal ingredient. Examples of such medicinal ingredients include bunazosin hydrochloride. α1 receptor blockers including bunazosin or its salts or solvates thereof; Brimonidine or its salts such as brimonidine tartrate or solvates thereof, apraclonidine α2 receptor agonists, including benzodiazepine or its salts or solvates; carteolol hydrochloride carteolol or its salts or solvates thereof, nipradilol or its salts or solvates thereof, timolol or its salts such as timolol maleate or solvates thereof, betaxolol or a salt thereof such as betaxolol hydrochloride, or solvates thereof, levobunolol or a salt thereof such as levobunolol hydrochloride, or solvates thereof, befunolol or its salts or solvates thereof, metipranolol or β-blockers including their salts or solvates; netarsudil mesilate and other netarsudil mesilate Rho kinase inhibitors including rusudil or its salts or solvates thereof; dorzolami dorzolamide or its salts or solvates thereof, brinzolamide or or its salts or solvates thereof, acetazolamide or its salts or solvates thereof , dichlorphenamide or its salt or solvate thereof, methazolamide or its salt Carbonic anhydrase inhibitors, including salts or solvates thereof; isopropyl unoprostone or or a salt thereof or a solvate thereof, tafluprost or a salt thereof or a solvate thereof, Travoprost or its salt or solvate thereof, bimatoprost or its salt or or a solvate thereof, latanoprost or a salt thereof or a solvate thereof, cloprost fluprostenol or its salt or a solvate thereof, fluprostenol or its salt, or Prostaglandin F2α derivatives including their solvates; dipivefrin hydrochloride and other dipivefrin derivatives Pivefrin or its salts or solvates thereof, epinephrine, epinephrine borate epinephrine hydrochloride or a salt thereof, or a solvate thereof Symptom-modifying drugs: distigmine bromide or its salts or solvates thereof, pilocarpine pilocarpine or a salt thereof such as pilocarpine hydrochloride, pilocarpine nitrate, or parasympathomimetic compounds containing carbachol or its salts or solvates thereof Drugs; including lomerizine or its salts such as lomerizine hydrochloride or their solvates Sodium antagonists; demecarium or its salts or solvates thereof, echothiophate or or its salts or solvates thereof, physostigmine or its salts or solvates thereof Cholinesterase inhibitors, including hydrates; Omidenepag and other hydrates, such as Omidenepag isopropyl; EP2 receptor agonists including EP2 receptor agonists, salts thereof, and solvates thereof are also included. One or more types can be combined. Other active ingredients include brimonidine, latanoprost, nipradilol, and dorzolamine. amide, brinzolamide, timolol and omidenepagisopropyl and their salts It is preferable to use one or more selected from the group consisting of:

[0035] The pH of the aqueous composition is not particularly limited, but is preferably 4 to 9, more preferably 4.5 to 8. The osmotic pressure ratio relative to physiological saline is not particularly limited, but is preferably 5 to 7. A range of 0.6 to 3 is preferred, and a range of 0.6 to 2 is particularly preferred.

[0036] <Container> In the present invention, the term "container" refers to a package that directly contains the aqueous composition. The containers are defined as "sealed containers," "airtight containers," and "sealed containers" in the General Provisions of the 18th Revised Japanese Pharmacopoeia. This concept encompasses both "containers" and "containers."

[0037] The shape of the container is not particularly limited as long as it can accommodate the aqueous composition. The container shape may be appropriately selected and set depending on the dosage form, the purpose of the pharmaceutical preparation, etc. Specific examples of such containers include injection containers, inhalant containers, spray containers, bottle-shaped containers, etc. Examples include containers, tube-shaped containers, eye drop containers, nasal drop containers, ear drop containers, and bag containers. It can be obtained.

[0038] In the present invention, the term "polyethylene container" refers to a container that comes into contact with at least the aqueous composition. Therefore, for example, a container in which the part that comes into contact with the aqueous composition is made of polyethylene. A container that has an inner polyethylene layer and another resin layer laminated on the outside. In this case, polyethylene is not particularly limited, and examples include Low density polyethylene (including linear low density polyethylene), high density polyethylene, medium density polyethylene These may be used alone or in combination of two or more. In this specification, "made of polyethylene" means that at least a part of the material is made of polyethylene. This means that the material contains polyethylene, for example, polyethylene and other resins other than polyethylene. Mixtures of two or more resins with fat (polymer alloys) are also included in the category of "polyethylene."

[0039] Polyethylene containers also contain ultraviolet absorbers and ultraviolet scattering agents that prevent ultraviolet light from passing through. It is preferable to incorporate a substance that improves the stability of Ripasudil against light. Specific examples of such substances include titanium oxide as an ultraviolet scattering agent; Examples of ultraviolet absorbers include zinc oxide. (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 3 20: BASF), 2-[5-chloro(2H)-benzotriazol-2-yl]-4 -methyl-6-(tert-butyl)phenol (e.g., Tinuvin 326:B ASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)-5-chlorobenzyl benzotriazole (e.g., Tinuvin 327: BASF), 2-(2H-benzotriazole) triazol-2-yl)-4,6-di-tert-pentylphenol (e.g., Ti Nuvin PA328: BASF), 2-(2H-benzotriazol-2-yl) -4-(1,1,3,3-tetramethylbutyl)phenol (e.g., Tinuvin 329: BASF), 2,2'-methylenediaminebis[6-(2H-benzotriazole- 2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol (e.g., Tin UVIN 360 (BASF), methyl 3-(3-(2H-benzotriazole-2- (5-tert-butyl-4-hydroxyphenyl)propionate and polyethylene reaction products of ethylene glycol 300 (e.g., Tinuvin 213: BASF), 2 -(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol (e.g. For example, Tinuvin 571 (BASF), 2-(2'-hydroxy-3',5'- Di-t-amylphenyl)benzotriazole, 2-[2'-hydroxy-3'-(3' ',4'',5'',6''-Tetrahydrophthalimidomethyl)-5'-methylphenyl benzotriazole, 2,2'-methylenebis[4-(1,1,3,3-tetramethyl benzotriazole], such as benzotriazole Azole UV absorbers; 2,2-bis{[2-cyano-3,3-diphenylacryloyl 2-Cyano-3,3-diphenyl methylpropane-1,3-diyl bis(2-cyano-3,3-diphenyloxy)methyl acrylate) (e.g., Uvinul 3030 FF: BASF), 2-cyano- Ethyl 3,3-diphenylacrylate (e.g., Uvinul 3035: BASF) , 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (e.g., Uvinu 3039: BASF) and other cyanoacrylate ultraviolet absorbers; Phenyl-1,3,5-triazin-2-yl)-5-[(hexyl)oxy]-pheno triazine-based UV light absorbers such as Tinuvin 1577 ED (BASF) Absorbent: Octabenzone (e.g., Chimassorb 81: BASF), 2,2 '-Dihydroxy-4,4'-dimethoxybenzophenone (e.g., Uvinul 30 49: BASF), 2,2'-4,4'-tetrahydrobenzophenone (e.g., UV Inul 3050: BASF), oxybenzone, hydroxymethoxybenzophenone Benzophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonate, dihydroxy Dimethoxybenzophenone, dihydroxydimethoxybenzophenone sodium disulfonate Benzophenones such as benzophenone, dihydroxybenzophenone, and tetrahydroxybenzophenone UV absorbers: methyl diisopropylcinnamate, cinoxate, di-para-methoxycinnamate Glyceryl cinnamate, mono-2-ethylhexanoate, isopropyl di-methoxycinnamate Isopropyl cinnamate mixture, 2-ethylhexyl p-methoxycinnamate, cinnamic acid Cinnamic acid-based ultraviolet absorbers such as benzyl paraaminobenzoate; para-aminobenzoic acid, ethyl para-aminobenzoate , glyceryl para-aminobenzoate, amyl para-dimethylaminobenzoate, para-dimethyl 2-Ethylhexyl aminobenzoate, 4-[N,N-di(2-hydroxypropyl)amino]benzoate Benzoate ester ultraviolet absorbers such as ethyl benzoate; ethylene glycol salicylate ol, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, Salicylic acid-based ultraviolet absorbers such as homomenthyl licylate and methyl salicylate; guaiazule Dimethoxybenzylidene dioxoimidazolidinepropionic acid 2-ethylhexyl ester; 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3, 5-Triazine; parahydroxyanisole; 4-tert-butyl-4'-methoxydiamine Benzoylmethane; Phenylbenzimidazole sulfonic acid; 2-(4-diethylamino -2-hydroxybenzoyl)-hexyl benzoate.

[0040] In addition, when a substance that blocks ultraviolet light transmission is kneaded into the container, the mixing ratio of the substance Although it varies depending on the type, for example, in a container, 0.001 to 50% by mass, preferably 0. The content may be about 0.02 to 25% by mass, and particularly preferably about 0.01 to 10% by mass.

[0041] The interior of the container is preferably visible (observable) to the naked eye. This makes it possible to inspect for foreign matter contamination during the manufacturing process of pharmaceutical preparations. This provides the user with the advantage of being able to check the remaining amount of the contents (aqueous composition). It is sufficient that the recognizability is ensured on at least a part of the container surface (for example, eye drops). Even if the sides of the container are obscured by shrink film, the bottom is visible. If the inside of the container can be seen from a part of the surface, it can be said that it is visible. This allows the aqueous composition in the container to be confirmed.

[0042] The means for storing the aqueous composition in the container is not particularly limited, and the aqueous composition can be filled in a conventional manner according to the shape of the container. Just fill it in etc.

[0043] <Pharmaceutical preparations> In the present invention, the indications for the "pharmaceutical preparation" are not particularly limited, and the pharmacological action of Ripasudil It may be selected appropriately depending on the purpose. Specifically, for example, based on the Rho kinase inhibitory activity and intraocular pressure lowering activity of Ripasudil, It can be used as a preventive or therapeutic agent for ocular hypertension and glaucoma. More specifically, for example, primary open-angle glaucoma, normal tension glaucoma, aqueous overproduction glaucoma, acute Closed-angle glaucoma, chronic closed-angle glaucoma, plateau iris syndrome, Mixed glaucoma, steroid glaucoma, capsular glaucoma, pigmentary glaucoma, amyloid glaucoma , neovascular glaucoma, and malignant glaucoma.

[0044] In addition, as disclosed in Japanese Patent No. 5557408, the use of ophthalmologic treatment for eye fundus diseases (mainly retinal diseases) Lesions occurring in the retina and / or choroid. Specifically, for example, fundus changes due to hypertension and arteriosclerosis Central retinal artery occlusion, central retinal vein occlusion in occlusion and branch retinal vein occlusion retinal vein occlusion, diabetic retinopathy, diabetic macular edema, Diarrhea maculopathy, Eales disease, Coats disease Congenital retinal vascular abnormalities such as von Hippel disease e), pulseless disease, macular disease (central chorioretinopathy (central serous chorioretinopathy), cystoid macula Edema (cystoid macular edema), age-related macular degeneration (age-rel macular degeneration), macular hole hole), myopic macular degeneratio n), vitreoretinal macular degeneration, drug-induced macular degeneration, hereditary macular degeneration, etc.), (rhegmatogenous (including retinal detachment (e.g., tractional, exudative, etc.), retinitis pigmentosa, and retinopathy of prematurity.) and more preferably for preventing diabetic retinopathy, diabetic macular edema, or age-related macular degeneration. Or it can be used as a therapeutic agent. Furthermore, as disclosed in Japanese Patent No. 5657252, prevention of corneal endothelial damage and / or can also be used as a therapeutic agent.

[0045] <Significance of other words> In the present invention, "low-temperature storage" refers to the storage of a pharmaceutical preparation after its manufacture, during distribution, or during storage. This refers to storage at temperatures lower than room temperature (1-30°C) that may be encountered accidentally, specifically, For example, storage at -5°C is envisaged. In the present invention, "freezing" does not necessarily mean that the entire Ripasudil-containing aqueous composition is frozen. This concept is not limited to the above and includes the case where only a part of the material is frozen. In the present invention, "suppression" of freezing means taking the technical measures disclosed in this specification. This will prevent the "freezing" from occurring for a relatively long period of time compared to when the measure is not taken. or by taking the technical measures disclosed in this specification, if such measures are not taken. The extent of "freezing" at the same time is suppressed compared to the This means that the freezing rate is small, and does not necessarily mean that the Ripasudil-containing aqueous composition will not absolutely freeze. This does not mean that For example, if the evaluation target contains edetic acid as a lower aliphatic carboxylic acid, In addition, a comparison sample that does not contain edetic acid but has the same ingredients and dissolved oxygen content was prepared. When stored under the same low-temperature storage conditions, the evaluation target lasted for a relatively longer period than the comparison target. The degree of "freezing" is suppressed, or the degree of "freezing" is suppressed at the same time. means.

[0046] <Method for preventing freezing and method for producing pharmaceutical preparations> The present invention also provides a method for reducing dissolved oxygen in a patient, comprising administering to the patient a solution of Ripasudil or a salt thereof or a solvate thereof. A process of adding lower aliphatic carboxylic acids to an aqueous composition having an amount of 8.5 mg / L or more. and storing the aqueous composition in a polyethylene container. It also relates to a method for inhibiting freezing during storage. Furthermore, the present invention provides a pharmaceutical composition containing Ripasudil or a salt thereof or a solvate thereof, and a dissolved acid A lower aliphatic carboxylic acid is contained in an aqueous composition having a carboxylic acid content of 8.5 mg / L or more. and freezing the aqueous composition during cryopreservation, the freezing step comprising the steps of: The present invention also relates to a method for producing a pharmaceutical preparation in which the above-mentioned effects are suppressed. In the above method, the step of incorporating Ripasudil into the aqueous composition, a step of incorporating phosphoric acids into an aqueous composition; and a step of placing the aqueous composition in a polyethylene container. The order of the process does not matter. In addition, the amount of dissolved oxygen in the aqueous composition is 8.5 mg / L or more. There is no particular problem with mixing, and the dissolved oxygen content of the aqueous composition is 8.5 mg / L or more, the "method for inhibiting freezing" or "method for producing pharmaceutical preparations" disclosed in this specification This may fall under the following category. The meaning of other various terms, the amount of each ingredient, etc. are all explained in the "pharmaceutical preparation" above. It is the same as

[0047] The present invention is not limited to these, but for example, the following embodiments are disclosed. Show. [1A] Ripasudil or its salt or a solvate thereof and a lower aliphatic carboxylic acid The dissolved oxygen content is 8.5 mg / L or more (preferably 8.7 mg / L or more, particularly preferably A pharmaceutical composition containing an aqueous composition of 1 mg / L or more (preferably 9 mg / L or more) in a polyethylene container. Agent. [2A] Ripasudil or its salt or a solvate thereof and a lower aliphatic carboxylic acid The dissolved oxygen content is 8.5 to 13 mg / L (preferably 8.7 to 13 mg / L, particularly The aqueous composition (preferably 9 to 13 mg / L) is contained in a polyethylene container. Pharmaceutical preparations. [3A] Ripasudil or its salt or a solvate thereof and a lower aliphatic carboxylic acid The dissolved oxygen content is 8.5 to 12 mg / L (preferably 8.7 to 12 mg / L, particularly An aqueous composition containing 1,000 mg of hydroxybenzoates (preferably 9 to 12 mg / L) is contained in a polyethylene container. Pharmaceutical preparations. [4A] Ripasudil or its salt or a solvate thereof and a lower aliphatic carboxylic acid The dissolved oxygen content is 8.5 to 11 mg / L (preferably 8.7 to 11 mg / L, particularly an aqueous composition containing 1,000 mg of hydroxybenzoates (preferably 9 to 11 mg / L) in a polyethylene container; Pharmaceutical preparations. [5A] Ripasudil or its salt or a solvate thereof and a lower aliphatic carboxylic acid The dissolved oxygen content is 8.5 to 10 mg / L (preferably 8.7 to 10 mg / L, particularly The aqueous composition (preferably 9 to 10 mg / L) is contained in a polyethylene container. Pharmaceutical preparations. [6A] Lower aliphatic carboxylic acids include epsilon-aminocaproic acid, edetic acid, citric acid, one selected from the group consisting of acetic acid, sorbic acid, salts thereof, and solvates thereof; The pharmaceutical formulation according to any one of [1A] to [5A], wherein the pharmaceutical formulation contains one or more species. [7A] Lower aliphatic carboxylic acids include edetic acid, its salts, and solvates thereof. The pharmaceutical formulation according to any one of [1A] to [5A], wherein the pharmaceutical formulation is one or more selected from the group consisting of: [8A] After low-temperature storage (preferably at -5°C, particularly preferably at -5°C for 2 weeks) [1A] to [7A], wherein the freezing of the aqueous composition is suppressed. Pharmaceutical preparations of.

[0048] [1B] Contains ripasudil or its salt or a solvate thereof, and has a dissolved oxygen content of 8.5 mg / L or more (preferably about 8.7 mg / L or more, particularly preferably 9 mg / L or more) A step of adding a lower aliphatic carboxylic acid to the aqueous composition, and a step of adding a lower aliphatic carboxylic acid to the aqueous composition. A method for preventing freezing of an aqueous composition during cryogenic storage, comprising the step of placing the aqueous composition in a polyethylene container. [2B] Contains ripasudil or its salt or a solvate thereof, and has a dissolved oxygen content of 8.5 ~13mg / L (preferably 8.7-13mg / L, particularly preferably 9-13mg / L) A step of adding a lower aliphatic carboxylic acid to an aqueous composition, and A method for preventing freezing of an aqueous composition during low-temperature storage, comprising the step of placing the aqueous composition in a polyethylene container. [3B] Contains Ripasudil or its salt or a solvate thereof, and has a dissolved oxygen content of 8.5 ~12mg / L (preferably 8.7-12mg / L, particularly preferably 9-12mg / L) A step of adding a lower aliphatic carboxylic acid to an aqueous composition, and A method for preventing freezing of an aqueous composition during low-temperature storage, comprising the step of placing the aqueous composition in a polyethylene container. [4B] Contains Ripasudil or its salt or a solvate thereof, and has a dissolved oxygen content of 8.5 ~11 mg / L (preferably 8.7 to 11 mg / L, particularly preferably 9 to 11 mg / L) A step of adding a lower aliphatic carboxylic acid to an aqueous composition, and A method for preventing freezing of an aqueous composition during low-temperature storage, comprising the step of placing the aqueous composition in a polyethylene container. [5B] Contains Ripasudil or its salt or a solvate thereof, and has a dissolved oxygen content of 8.5 ~10mg / L (preferably 8.7-10mg / L, particularly preferably 9-10mg / L) A step of adding a lower aliphatic carboxylic acid to an aqueous composition, and A method for preventing freezing of an aqueous composition during low-temperature storage, comprising the step of placing the aqueous composition in a polyethylene container. [6B] Lower aliphatic carboxylic acids include epsilon-aminocaproic acid, edetic acid, citric acid, one selected from the group consisting of acetic acid, sorbic acid, salts thereof, and solvates thereof; The method according to any one of [1B] to [5B], wherein the number of species is at least one. [7B] Lower aliphatic carboxylic acids are selected from edetic acid, its salts, and solvates thereof. The method according to any one of [1B] to [6B], wherein the compound is one or more selected from the group consisting of:

[0049] [1C] Contains ripasudil or its salt or a solvate thereof, and has a dissolved oxygen content of 8.5 mg / L or more (preferably 8.7 mg / L or more, particularly preferably 9 mg / L or more) a step of incorporating a lower aliphatic carboxylic acid into the aqueous composition, and a step of dissolving the aqueous composition in polyethylene. A method for producing a pharmaceutical preparation that is inhibited from freezing during cryogenic storage, comprising the step of placing the preparation in a polyethylene container. [2C] Contains ripasudil or its salt or a solvate thereof, and has a dissolved oxygen content of 8.5 ~13mg / L (preferably 8.7-13mg / L, particularly preferably 9-13mg / L) A step of adding a lower aliphatic carboxylic acid to an aqueous composition, and Manufacture of a pharmaceutical preparation that is prevented from freezing during cryogenic storage, comprising a step of storing the preparation in a polyethylene container. method. [3C] Contains ripasudil or its salt or a solvate thereof, and has a dissolved oxygen content of 8.5 ~12mg / L (preferably 8.7-12mg / L, particularly preferably 9-12mg / L) A step of adding a lower aliphatic carboxylic acid to an aqueous composition, and Manufacture of a pharmaceutical preparation that is prevented from freezing during cryogenic storage, comprising a step of storing the preparation in a polyethylene container. method. [4C] Contains ripasudil or its salt or a solvate thereof, and has a dissolved oxygen content of 8.5 ~11 mg / L (preferably 8.7 to 11 mg / L, particularly preferably 9 to 11 mg / L) A step of adding a lower aliphatic carboxylic acid to an aqueous composition, and Manufacture of a pharmaceutical preparation that is prevented from freezing during cryogenic storage, comprising a step of storing the preparation in a polyethylene container. method. [5C] Contains Ripasudil or its salt or a solvate thereof, and has a dissolved oxygen content of 8.5 ~10mg / L (preferably 8.7-10mg / L, particularly preferably 9-10mg / L) A step of adding a lower aliphatic carboxylic acid to an aqueous composition, and Manufacture of a pharmaceutical preparation that is prevented from freezing during cryogenic storage, comprising a step of storing the preparation in a polyethylene container. method. [Example]

[0050] The present invention will now be further described with reference to examples, but the present invention is not limited to these examples. isn't it. In the following test examples, Ripasudil monohydrochloride dihydrate is used, for example, as described in International Publication No. 20 It can be produced by the method described in the pamphlet of No. 06 / 057397.

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

[0052] Each of the obtained pharmaceutical preparations was stored at -5°C for 2 weeks, and the freezing of the aqueous composition in the container after storage was examined. The case where freezing did not occur was evaluated as ◯, and the case where freezing occurred was evaluated as ×. Furthermore, if freezing occurred, comments were made on the appearance. The results are shown in Table 1. The amount of dissolved oxygen was rounded to one decimal place.

[0053] [Table 1]

[0054] As shown in Table 1, the dissolved oxygen level is 8.5 mg / L or more, specifically 9 mg / L. When the aqueous composition containing Ripasudil was placed in a polyolefin resin container (Examples 1 and 2), ) was confirmed to have frozen the entire aqueous composition after storage at -5°C for 2 weeks. A Ripasudil-containing aqueous composition having an amount of less than 8.5 mg / L (3 or 6 mg / L) was used as a polio inhibitor. When stored in a resin container (Examples 3 to 6), the freezing was the same after the same storage. This indicates that such freezing reduces the dissolved acid in the Ripasudil-containing aqueous composition. It is clear that this phenomenon depends on the amount of dissolved oxygen and occurs when the amount of dissolved oxygen is 8.5 mg / L or more. This is what happened. In addition, an aqueous composition containing no Ripasudil and having a dissolved oxygen content of 8.5 mg / L or more was used as a polio vaccine. When stored in a olefin resin container (Example 7, Example 8), the dissolved oxygen level is 8.5 mg / L or more. When the Ripasudil-containing aqueous composition was placed in a glass container (Example 9), it was also possible to preserve it at low temperature. No freezing was observed after the procedure. This indicates that the aqueous composition is It is clear that this is due to the fact that the product contains ethanol and is stored in a polyolefin resin container. It became like this.

[0055] From the above, it is possible to determine the dissolved amount of the Ripasudil-containing aqueous composition contained in the polyolefin resin container. When the oxygen level is high, 8.5 mg / L or more, freezing during cryopreservation is a specific problem. It was found that this phenomenon occurs.

[0056] [Test Example 2] Preservation test No. 2 An aqueous composition containing the ingredients and amounts shown in Table 2 in 100 mL was prepared by a conventional method. By blowing nitrogen gas, oxygen gas or air into the tank while measuring and monitoring the amount of dissolved oxygen. The amount of dissolved oxygen was adjusted as shown in Table 2. The aqueous composition with the adjusted dissolved oxygen content is placed in a polyethylene (PE) or polypropylene (PP) container. The pharmaceutical preparation was prepared by placing the medicine in an eye drop container made of PEG-100. The amount of dissolved oxygen was measured using a portable waterproof dissolved oxygen meter at an ambient temperature of 25°C. This was done using a dissolved oxygen meter (Model AS720: manufactured by AS ONE Corporation).

[0057] Each of the obtained pharmaceutical preparations was stored at -5°C for 2 weeks, and the freezing of the aqueous composition in the container after storage was examined. The absence or presence of the substance was evaluated in the same manner as in Test Example 1. The results are shown in Table 2. The amount of dissolved oxygen was rounded to one decimal place.

[0058] [Table 2]

[0059] As shown in Table 2, the dissolved oxygen level is 8.5 mg / L or more, specifically 9 mg / L. A pharmaceutical preparation of Comparative Example 1 in which a Ripasudil-containing aqueous composition was contained in a polyethylene container, and The aqueous composition containing Ripasudil, which has a dissolved oxygen content of 8.5 mg / L or more, further contains edetate sodium. A composition containing thorium hydrate and containing the aqueous composition in a polypropylene container. In the pharmaceutical preparations of Comparative Example 2, the entire aqueous composition was frozen after storage at -5°C for 2 weeks. On the other hand, it was confirmed that the amount of dissolved oxygen in the aqueous composition containing Ripasudil was 8.5 mg / L or more. The aqueous composition further contains sodium edetate hydrate, and the aqueous composition is placed in a polyethylene container. In the pharmaceutical preparation of Example 1 contained in a container, no freezing was observed after similar storage. Ta. From the above, it is possible to add edema to an aqueous composition containing Ripasudil, which has a dissolved oxygen content of 8.5 mg / L or more. a low-molecular-weight compound represented by one or more selected from the group consisting of acetic acid, its salts, and solvates thereof; and aliphatic carboxylic acids are contained in the aqueous composition, and the aqueous composition is mixed with a polyolefin resin. When the container is made of polyethylene, the requirements are not met. It was revealed that freezing during low-temperature storage can be relatively suppressed compared to

[0060] In addition, as lower aliphatic carboxylic acids, edetic acid and its salts and solvates thereof are epsilon-aminocaproic acid, citric acid, One or more selected from the group consisting of acetic acid, sorbic acid, salts thereof, and solvates thereof When the above is used, a similar effect of inhibiting freezing during cryopreservation can be confirmed.

[0061] [Test Example 3] Preservation test No. 3 An aqueous composition containing the ingredients and amounts shown in Table 3 in 100 mL was prepared by a conventional method. By blowing nitrogen gas, oxygen gas or air into the tank while measuring and monitoring the amount of dissolved oxygen. The amount of dissolved oxygen was adjusted as shown in Table 3. The aqueous composition with an adjusted dissolved oxygen content is placed in a polyethylene (PE) eye drop container and dispensed into a medical device. A drug formulation was prepared. The amount of dissolved oxygen was measured using a portable waterproof dissolved oxygen meter at an ambient temperature of 25°C. This was done using a dissolved oxygen meter (Model AS720: manufactured by AS ONE Corporation).

[0062] Each of the obtained pharmaceutical preparations was stored at -5°C for 2 weeks, and the freezing of the aqueous composition in the container after storage was examined. The absence or presence of the substance was evaluated in the same manner as in Test Example 1. The results are shown in Table 3. The amount of dissolved oxygen was rounded to one decimal place.

[0063] [Table 3]

[0064] As shown in Table 3, the dissolved oxygen content was 11.0 mg / L and 13.0 mg / L, respectively. / L of a Ripasudil-containing aqueous composition containing sodium edetate hydrate, and In the pharmaceutical preparations of Examples 2 and 3, the aqueous composition was placed in a polyethylene container. As with the pharmaceutical preparation of Example 1, no freezing was observed after storage at -5°C for 2 weeks. .

[0065] [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. By blowing nitrogen gas, oxygen gas or air into the tank while measuring and monitoring the amount of dissolved oxygen. The dissolved oxygen content was adjusted as shown in Table 3, and the solution was placed in a polyethylene eye drop container. As a result, pharmaceutical preparations of Preparation Examples 1 to 5 were obtained.

[0066] [Table 4]

[0067] [Manufacturing Examples 6 to 10] An aqueous composition containing the ingredients and amounts shown in Table 5 in 100 mL was prepared by a conventional method. By blowing nitrogen gas, oxygen gas or air into the tank while measuring and monitoring the amount of dissolved oxygen. The dissolved oxygen content was adjusted as shown in Table 4, and the solution was placed in a polyethylene eye drop container. As a result, pharmaceutical preparations of Preparation Examples 6 to 10 were obtained.

[0068] [Table 5]

[0069] [Manufacturing 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. By blowing nitrogen gas, oxygen gas or air into the tank while measuring and monitoring the amount of dissolved oxygen. The dissolved oxygen content was adjusted as shown in Table 5, and the solution was placed in a polyethylene eye drop container. As a result, pharmaceutical preparations of Preparation Examples 11 to 15 were obtained.

[0070] [Table 6]

[0071] [Manufacturing Examples 16-20] An aqueous composition containing the ingredients and amounts shown in Table 7 in 100 mL was prepared by a conventional method. By blowing nitrogen gas, oxygen gas or air into the tank while measuring and monitoring the amount of dissolved oxygen. The dissolved oxygen content was adjusted as shown in Table 6, and the solution was placed in a polyethylene eye drop container. As a result, pharmaceutical preparations of Preparation Examples 16 to 20 were obtained.

[0072] [Table 7]

[0073] [Manufacturing Examples 21-25] An aqueous composition containing the ingredients and amounts shown in Table 8 in 100 mL was prepared by a conventional method. By blowing nitrogen gas, oxygen gas or air into the tank while measuring and monitoring the amount of dissolved oxygen. The dissolved oxygen content was adjusted as shown in Table 7, and the solution was placed in a polyethylene eye drop container. As a result, pharmaceutical preparations of Preparation Examples 21 to 25 were obtained.

[0074] [Table 8]

[0075] [Manufacturing Examples 26-30] An aqueous composition containing the ingredients and amounts shown in Table 9 in 100 mL was prepared by a conventional method. By blowing nitrogen gas, oxygen gas or air into the tank while measuring and monitoring the amount of dissolved oxygen. The dissolved oxygen content was adjusted as shown in Table 8, and the solution was placed in a polyethylene eye drop container. As a result, pharmaceutical preparations of Preparation Examples 26 to 30 were obtained.

[0076] [Table 9] [Industrial Applicability]

[0077] According to the present invention, a pharmaceutical preparation having excellent storage stability can be provided, which is suitable for the pharmaceutical industry, etc. can be used for.

Claims

1. A pharmaceutical preparation for the prevention or treatment of ocular hypertension or glaucoma, which comprises an aqueous composition having a dissolved oxygen content of 8.5 mg / L or more, which contains ripasudil or a salt thereof or a solvate thereof and one or more selected from edetic acid, a salt thereof and a solvate thereof, and which is contained in a polyethylene container.

2. 2. The pharmaceutical preparation for preventing or treating ocular hypertension or glaucoma according to claim 1, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg / L.

3. 2. The pharmaceutical preparation for preventing or treating ocular hypertension or glaucoma according to claim 1, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg / L.

4. 2. The pharmaceutical preparation for preventing or treating ocular hypertension or glaucoma according to claim 1, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 11 mg / L.

5. A method for preventing freezing of a pharmaceutical preparation for the prevention or treatment of ocular hypertension or glaucoma, comprising the steps of: adding one or more selected from edetic acid, its salts, and solvates thereof to an aqueous composition containing ripasudil or a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 mg / L or more; and placing the aqueous composition in a polyethylene container.

6. 6. The method for inhibiting freezing of a pharmaceutical preparation for preventing or treating ocular hypertension or glaucoma according to claim 5, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg / L.

7. 6. The method for inhibiting freezing of a pharmaceutical preparation for preventing or treating ocular hypertension or glaucoma according to claim 5, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg / L.

8. 6. The method for inhibiting freezing of a pharmaceutical preparation for preventing or treating ocular hypertension or glaucoma according to claim 5, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 11 mg / L.

9. A method for producing a pharmaceutical preparation for the prevention or treatment of ocular hypertension or glaucoma, in which freezing of the aqueous composition is inhibited, comprising the steps of: adding one or more selected from edetic acid, its salts, and solvates thereof to an aqueous composition containing ripasudil or a salt thereof, or a solvate thereof and having a dissolved oxygen content of 8.5 mg / L or more; and placing the aqueous composition in a polyethylene container.

10. 10. A method for producing a pharmaceutical preparation for preventing or treating ocular hypertension or glaucoma, wherein the aqueous composition is inhibited from freezing, according to claim 9, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg / L.

11. 10. A method for producing a pharmaceutical preparation for preventing or treating ocular hypertension or glaucoma, wherein the aqueous composition is inhibited from freezing, according to claim 9, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg / L.

12. 10. A method for producing a pharmaceutical preparation for preventing or treating ocular hypertension or glaucoma, wherein the aqueous composition is inhibited from freezing, according to claim 9, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 11 mg / L.

13. A preventive or therapeutic agent for ocular hypertension or glaucoma, comprising an aqueous composition having a dissolved oxygen content of 8.5 mg / L or more, which contains ripasudil or a salt thereof or a solvate thereof and one or more selected from edetic acid, a salt thereof and a solvate thereof, and which is contained in a polyethylene container.

14. 14. The agent for preventing or treating ocular hypertension or glaucoma according to claim 13, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 13 mg / L.

15. 14. The preventive or therapeutic agent for ocular hypertension or glaucoma according to claim 13, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 12 mg / L.

16. 14. The agent for preventing or treating ocular hypertension or glaucoma according to claim 13, wherein the amount of dissolved oxygen in the aqueous composition is 8.5 to 11 mg / L.

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