Pharmaceutical preparations, part seven

Abstract

To improve the light stability of halogenated isoquinoline derivatives in aqueous compositions. To provide technology. [Solution] The following general formula (1) TIFF2026140964000023.tif40170 [In the formula, X represents a halogen atom.] An aqueous composition containing a compound represented by or a salt thereof, or a solvate thereof, with a wavelength of 3 A pharmaceutical preparation housed in packaging that blocks light rays between 00 and 335 nm.

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] ripasargil represented by (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4 -diazepan-1-yl]sulfonyl]isoquinoline) and the following structural formula:

[0005]

Chemical Formula

[0006] 4-bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl sulfonyl]isoquinoline and other halogenated isoquinoline derivatives exhibit Rho kinase inhibi tory activity and other pharmacological effects (see, for example, Patent Documents 1 and 2), and are known to be useful for the prevention or treatment of eye diseases. Specifically, it has been reported that these compounds are useful for the prevention or treatment of ocular hypertension, glaucoma and the like (see, for example, Patent Document 3), or for the prevention or treatment of fundus diseases such as age-related macular degeneration (see, for example, Patent Document 4).

[0007] Therefore, establishing a technology for stably formulating these halogenated isoquinoline derivatives, for example, as ophthalmic preparations and the like is extremely useful.

Prior Art Literature

Patent Literature

[0008] [Patent Document 1] Patent No. 4212149 [Patent Document 2] International Publication No. 2006 / 115244 Pamphlet [Patent Document 3] International Publication No. 2006 / 068208 Brochure [Patent Document 4] Patent No. 5557408 [Overview of the project] [Problems that the invention aims to solve]

[0009] The present inventors have developed a method for producing lipasudil, a halogenated isoquinoline derivative, as an ophthalmic agent, etc. In formulating the drug, we first evaluated the photostability of lipasudil. It was revealed that the substance itself is extremely stable to light. The photostability of organic compounds is It is thought to depend on its structure and not on its state (solid, liquid, etc.). Ophthalmic agents, etc. Typically, it is a composition containing water (aqueous composition), but Lipasdil is incorporated into aqueous compositions. However, it was expected that no problems would arise with photostability.

[0010] However, upon further investigation by the inventors, it was found, quite unexpectedly, that lipasudil itself Although the body is stable to light, by incorporating it into an aqueous composition... It became clear that the material becomes unstable in response to light, and the amount of decomposition products gradually increases with exposure to light. Therefore, the present invention relates to halogenated isoquinoline derivatives such as lipasudil in aqueous compositions. The objective is to provide technology that improves the stability of the device against light. [Means for solving the problem]

[0011] As a result of further intensive studies conducted by the present inventors to solve the above problem, they found that the aqueous composition of ripasudil photodegradation in the composition is caused by irradiation with light having a wavelength around 300 nm, and by containing the aqueous composition in a package that blocks light of the above wavelength, a pharmaceutical preparation with improved photostability can be obtained, and thus the present invention has been completed.

[0012] That is, the present invention provides the following <1> to <4>. <1> A compound represented by the following general formula (1)

[0013]

Chemical Formula

[0014] [in the formula, X represents a halogen atom.] an aqueous composition comprising the compound represented by the formula, or a salt thereof, or a solvate thereof, which is contained in a package that blocks light with a wavelength of 3 00 to 335 nm, which is a pharmaceutical preparation. <2> A step of containing the aqueous composition comprising the compound represented by the general formula (1), or a salt thereof, or a solvate thereof in a package that blocks light with a wavelength of 300 to 335 nm,[which is a method for improving the photostability of the aqueous composition of the compound represented by general formula (1), or a salt thereof, or a solvate thereof . <3> An aqueous composition comprising the compound represented by general formula (1), or a salt thereof, or a solvate thereof, which is characterized by being contained in a package that blocks light with a wavelength of 300 to 335 nm . <4> A method for storing the compound represented by general formula (1), or a salt thereof, or a solvate thereof, which comprises a step of containing the aqueous composition comprising the compound, or a salt thereof, or a solvate thereof in a package that blocks light with a wavelength of 300 to 335 nm,[[which is a method for storing the compound represented by general formula (1), or a salt thereof, or a solvate thereof Law. [Effects of the Invention]

[0015] According to the present invention, halogenated isoquinoline derivatives such as lipasudil are used in aqueous compositions. This can improve stability against light. [Modes for carrying out the invention]

[0016] This specification is not limited to these, but discloses, for example, the following embodiments of the invention. do. [1] The following general formula (1)

[0017] [ka]

[0018] [In the formula, X represents a halogen atom.] An aqueous composition containing a compound represented by or a salt thereof, or a solvate thereof, with a wavelength of 3 A pharmaceutical preparation housed in packaging that blocks light rays between 00 and 335 nm. [2] The pharmaceutical preparation according to [1], wherein the compound represented by the general formula (1) is lipasudil. . [3] The packaging blocks light rays with wavelengths of 300 to 370 nm, [1] or [2] The pharmaceutical preparation described in [2]. [4] The packaging blocks light rays with wavelengths of 300 to 395 nm, [1] or [2] The pharmaceutical preparation described in [2]. [5] The packaging blocks light rays with wavelengths of 270 to 335 nm, [1] or [2] The pharmaceutical preparation described in [2]. [6] The packaging blocks light rays with wavelengths of 270 to 370 nm, [1] or [2] The pharmaceutical preparation described in [2]. [7] The packaging blocks light rays with wavelengths of 270 to 395 nm, [1] or [2] The pharmaceutical preparation described in [2]. [8] A pharmaceutical preparation according to any one of [1] to [7], wherein the inside of the packaging is visible. [9] Primary packaging, A substance that prevents the transmission of ultraviolet light (preferably selected from ultraviolet scattering agents and ultraviolet absorbing agents) One or more types; more preferably zinc oxide, titanium dioxide, and a benzotriazole-based ultraviolet absorber. A container containing one or more selected types (preferably made of plastic; more preferably made of poly A container made of olefin resin or polyester resin (preferably a container for eye drops) A packaging body (preferably a packaging body that allows the contents to be seen); or, A substance that prevents the transmission of ultraviolet light (preferably selected from ultraviolet scattering agents and ultraviolet absorbing agents) One or more types; more preferably zinc oxide, titanium dioxide, and a benzotriazole-based ultraviolet absorber. A component containing one or more selected types (preferably a heat-shrinkable film (shrink film)) A container (preferably made of plastic; more preferably of polyolefin resin) equipped with a )) The packaging is a container (preferably an eye drop container) made of polyester resin (preferably (Packaging that allows the contents to be seen); A pharmaceutical preparation described in any of [1] to [8].

[10] As a secondary packaging, A substance that prevents the transmission of ultraviolet light (preferably selected from ultraviolet scattering agents and ultraviolet absorbing agents) One or more types; more preferably zinc oxide, titanium dioxide, and a benzotriazole-based ultraviolet absorber. A bag containing one or more selected types (preferably made of plastic; more preferably made of polio A bag (preferably an eye drop dispensing bag) made of refin resin or polyester resin. Packaging (preferably packaging that allows the contents to be seen); and paper box A pharmaceutical preparation comprising one or more selected from [1] to [9].

[11] The primary packaging is a container made of polyolefin resin, any of [1] to

[10] The pharmaceutical preparation described above.

[12] The primary packaging is a container made of polyester resin, any of [1] to

[10] The pharmaceutical preparation described.

[0019]

[13] Contains a compound represented by the general formula (1) above, a salt thereof, or a solvate thereof. The process includes the step of encapsulating the aqueous composition in packaging that blocks light rays with wavelengths of 300 to 335 nm. The aqueous composition of the compound represented by the general formula (1) above, its salt, or its solvate. A method for improving the photostability of a material.

[14] The method according to

[13] , wherein the compound represented by the general formula (1) is lipasudil. .

[15] The packaging blocks light rays with wavelengths of 300 to 370 nm.

[13] Or the method described in

[14] .

[16] The packaging blocks light rays with wavelengths of 300 to 395 nm.

[13] Or the method described in

[14] .

[17] The packaging blocks light rays with wavelengths of 270 to 335 nm.

[13] Or the method described in

[14] .

[18] The packaging blocks light rays with wavelengths of 270 to 370 nm.

[13] Or the method described in

[14] .

[19] The packaging blocks light rays with wavelengths of 270 to 395 nm.

[13] Or the method described in

[14] .

[20] The method described in any of

[13] to

[19] , wherein the inside of the packaging can be seen. .

[21] Primary packaging, A substance that prevents the transmission of ultraviolet light (preferably selected from ultraviolet scattering agents and ultraviolet absorbing agents) One or more types; more preferably zinc oxide, titanium dioxide, and a benzotriazole-based ultraviolet absorber. A container containing one or more selected types (preferably made of plastic; more preferably made of poly A container made of olefin resin or polyester resin (preferably a container for eye drops) A packaging body (preferably a packaging body that allows the contents to be seen); or, A substance that prevents the transmission of ultraviolet light (preferably selected from ultraviolet scattering agents and ultraviolet absorbing agents) One or more types; more preferably zinc oxide, titanium dioxide, and a benzotriazole-based ultraviolet absorber. A component containing one or more selected types (preferably a heat-shrinkable film (shrink film)) A container (preferably made of plastic; more preferably of polyolefin resin) equipped with a )) The packaging is a container (preferably an eye drop container) made of polyester resin (preferably (Packaging that allows the contents to be seen); The method described in any of

[13] to

[20] .

[22] As a secondary packaging, A substance that prevents the transmission of ultraviolet light (preferably selected from ultraviolet scattering agents and ultraviolet absorbing agents) One or more types; more preferably zinc oxide, titanium dioxide, and a benzotriazole-based ultraviolet absorber. A bag containing one or more selected types (preferably made of plastic; more preferably made of polio A bag (preferably an eye drop dispensing bag) made of refin resin or polyester resin. Packaging (preferably packaging that allows the contents to be seen); and paper box A method described in any of

[13] to

[21] , comprising one or more selected from the above.

[23] The primary packaging is a container made of polyolefin resin,

[13] to

[22] Please describe the method.

[24] The primary packaging is a container made of polyester resin, any of

[13] to

[22] Or the method of description.

[0020]

[25] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, and a carbon Acid anhydrase inhibitors, prostaglandin F2α derivatives, sympathetic agonists, parasympathetic agonists One or more drugs selected from the group consisting of drugs, calcium channel blockers, and cholinesterase inhibitors. A pharmaceutical preparation containing any of the following: [1] to

[12] .

[26] The aqueous composition further contains latanoprost, nipradilol, dorzolamide, b Contains one or more selected from the group consisting of linzolamide, timolol, and salts thereof. A pharmaceutical preparation described in any of [1] to

[12] .

[27] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, and a carbon Acid anhydrase inhibitors, prostaglandin F2α derivatives, sympathetic agonists, parasympathetic agonists One or more drugs selected from the group consisting of drugs, calcium channel blockers, and cholinesterase inhibitors. The method described in any of

[13] to

[24] , which includes the content.

[28] The aqueous composition further contains latanoprost, nipradilol, dorzolamide, b Contains one or more selected from the group consisting of linzolamide, timolol, and salts thereof. The method described in

[13] to

[24] .

[0021] In the general formula (1) above, the halogen atoms are fluorine, chlorine, and bromine atoms. Examples include the following. In the above general formula (1), the halogen atoms are fluorine and bromine. Atoms are preferred, and fluorine atoms are particularly preferred. Furthermore, in the general formula (1) above, the carbon constituting the homopiperazine ring substituted with a methyl group The primary atom is a chiral carbon. Therefore, stereoisomerism occurs, but the compound is represented by general formula (1). A substance can contain any stereoisomer, or it may have only one stereoisomer, or it may have various stereoisomers. A mixture of any proportion is also acceptable. The compound represented by the general formula (1) is one in which the absolute configuration is S A compound with a specific configuration is preferred.

[0022] The salt of the compound represented by the general formula (1) is not limited to any pharmaceutically acceptable salt. It is not specified, and specifically, for example, hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide Inorganic salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, etc. Hacitate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluene Examples include organic salts such as sulfonates, naphthalene sulfonates, and camphor sulfonates. Hydrochloride salts are preferred. Furthermore, the compound represented by the general formula (1) or its salt is a hydrate or an alcoholic, etc. It may be a solvate, but a hydrate is preferred.

[0023] The compound represented by the general formula (1) above, or a salt thereof, or a solvate thereof, is: Physically, for example, Lipasdil (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepa [I-1-yl]sulfonyl]isoquinoline) or its salts or solvates thereof; 4-Bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl Isoquinoline or its salts or solvates thereof; These are some examples.

[0024] The compounds represented by the general formula (1) above, their salts, or their solvates include: Pasudil or its salts or their solvates, 4-bromo-5-[[(2S)-2-methyl [Tyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline or its salt or These solvates are preferred, and lipasudil or its salts or their solvates are more preferred. Furthermore, lipasudil or its hydrochloride or hydrate thereof is more preferable, and the following structure formula:

[0025] [ka]

[0026] Lipasdil hydrochloride hydrate (lipasdil 1-hydrochloride dihydrate) represented by [formula] is particularly preferred.

[0027] Compounds represented by the general formula (1) above, salts thereof, or solvates thereof are known. It can be manufactured by known methods. Specifically, for example, lipasudil or its salts or the These solvates are described in International Publication No. 1999 / 020620, International Publication No. 200 It can be manufactured using the methods described in the 6 / 057397 pamphlet. Also, 4- Bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl] Soquinoline or its salts or solvates thereof, International Publication No. 2006 / 115244 It can be manufactured using the methods described in the pamphlet.

[0028] Compounds represented by the general formula (1) or salts thereof in aqueous compositions or solvations thereof The amount of substance contained is not particularly limited and should be considered as appropriate depending on the applicable disease, the patient's gender, age, symptoms, etc. It is fine to decide by doing so, but from the viewpoint of obtaining excellent pharmacological effects, the amount of the aqueous composition relative to the total volume is generally It is preferable to contain 0.01 to 10 w / v% of the compound represented by formula (1) in terms of its free form. It is preferable to contain 0.02-8 w / v%, and more preferably 0.04-6 w / v%. It is particularly preferable to use lipasudil as the compound represented by general formula (1). In some cases, from the viewpoint of obtaining excellent pharmacological effects, lipasdi is added to the total volume of the aqueous composition. Contains 0.05-5 w / v% of the free form of 170 It is preferable to have it, more preferably to contain 0.1-3 w / v%, and 0.1-2 w / v It is particularly preferable to contain %.

[0029] In this specification, “aqueous composition” means a composition containing at least water, and The properties include liquid (solution or suspension) and semi-solid (ointment). For the water inside, for example, purified water, water for injection, or sterile purified water can be used. The water content in the aqueous composition is not particularly limited, but is preferably 5% by mass or more. 0% by mass or more is more preferable, 50% by mass or more is even more preferable, and 90% by mass or more is even more preferable. More preferably, and particularly preferably 90 to 99.8% by mass.

[0030] Aqueous compositions are prepared, for example, according to known methods described in the General Provisions for Preparations of the Sixteenth Edition of the Japanese Pharmacopoeia, etc. Therefore, it can be made into various dosage forms. The dosage forms include those that can be contained in the packaging described later. There are no particular limitations as long as they exist, but for example, injectables, inhaled solutions, eye drops, eye ointments, ear drops, Nasal sprays, enemas, topical solutions, sprays, ointments, gels, oral solutions, syrups, etc. For example, the dosage form would be one that advantageously utilizes the pharmacological effects of the compound represented by general formula (1). From the standpoint of use, eye disease preparations, specifically eye drops and eye ointments, are preferred, with eye drops being particularly preferred. It seems so.

[0031] In addition to those mentioned above, aqueous compositions may be used as additives in pharmaceuticals, quasi-drugs, etc., depending on the dosage form. It may contain additives. Examples of such additives include inorganic salts, isotonic agents, and ki Raters, stabilizers, pH adjusters, preservatives, antioxidants, viscosity enhancers, surfactants, solubilizers Examples include suspending agents, cooling agents, dispersants, preservatives, oily bases, emulsion bases, water-soluble bases, etc. It can be done.

[0032] Examples of such additives include, for instance, ascorbic acid and potassium aspartate. Sodium bisulfite, alginic acid, sodium benzoate, benzyl benzoate, ip Silon-aminocaproic acid, fennel oil, ethanol, ethylene vinyl acetate copolymer , sodium edetate, tetrasodium edetate, potassium chloride, calcium chloride hydrate, Sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride solution, Ruboxyvinyl polymer, anhydrous sodium sulfite, anhydrous sodium carbonate, d-camphor, dl-camphor, xylitol, citric acid hydrate, sodium citrate hydrate, glycerin Gluconic acid, L-glutamic acid, L-sodium glutamate, creatinine, chloroglycerides Guhexidine gluconate solution, chlorobutanol, sodium dihydrogen crystalline phosphate, gerani All, chondroitin sulfate sodium, acetic acid, potassium acetate, sodium acetate hydrate, Titanium dioxide, gellan gum, dibutylhydroxytoluene, potassium bromide, benzoyl bromide Decinium tartaric acid, sodium hydroxide, polyoxyl 45 stearate, purified lanolin D-sorbitol, sorbitol solution, sorbic acid, potassium sorbate, taurine, charcoal Sodium hydrogen oxyphosphate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, Tyroxapol, sodium dehydroacetate, trometamol, concentrated glycerin, concentrated mixed Copherol, white petrolatum, peppermint water, peppermint oil, concentrated benzalkonium chloride solution 50, Ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, Methyl parahydroxybenzoate, sodium hyaluronate, human serum albumin, hydroxyethyl Hypodium cellulose, hydroxypropylcellulose, hypromellose, glacial acetic acid, pyrosulfite Sodium, phenylethyl alcohol, glucose, propylene glycol, bergamot Oil, benzalkonium chloride, benzalkonium chloride solution, benzyl alcohol, benz Zethonium chloride, benzethonium chloride solution, borax, boric acid, povidone, polyoxyen Tylene (200) polyoxypropylene glycol (70), sodium polystyrene sulfonate Thorium, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl aluminum Kohl (partially hydrolyzed), d-borneol, macrogol 4000, macrogol 60 00, D-mannitol, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous dihydrate phosphate Sodium phosphate, methanesulfonic acid, methylcellulose, l-menthol, monoethanol Amine, aluminum monostearate, polyethylene glycol monostearate, yu Potassium oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, bonito flakes, Phosphate, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate Examples include sodium dihydrogen phosphate monohydrate, malic acid, and petrolatum.

[0033] Examples of additives include potassium chloride, calcium chloride hydrate, sodium chloride, and salt. Magnesium chloride, glycerin, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, water Sodium oxide, sodium bicarbonate, sodium carbonate hydrate, concentrated glycerin, hydrochloride Cethylcellulose, hydroxypropylcellulose, hypromellose, borax, boric acid Povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, monostearate Polyethylene glycol, polyvinyl alcohol (partially saponified), macrogol 400 0, Macrogol 6000, Anhydrous Citric Acid, Anhydrous Sodium Monohydrogen Phosphate, Anhydrous Dihydrogen Phosphate Sodium hydrogen, methylcellulose, monoethanolamine, phosphoric acid, sodium hydrogen phosphate Potassium dihydrogen hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate Monohydrate, sodium hyaluronate, glucose, l-menthol, etc. are preferred.

[0034] The aqueous composition may also contain other active ingredients depending on the disease or other condition being treated, in addition to those mentioned above. It is acceptable to have it. Examples of such medicinal ingredients include bunazosin hydrochloride and other bunazosin compounds. α1 receptor blockers containing salts thereof or solvates thereof; brimonidine tartrate, etc. Any brimonidine or its salts or their solvates, apraclonidine or its α2 receptor agonists containing salts or solvates thereof; such as carteolol hydrochloride Roll or its salts or solvates thereof, nipradilol or its salts or the Solvates of timolol, timolol maleate, timolol or its salts, or their solvents Betaxol or its salts, such as betaxolol hydrochloride, or their solvates. levovunol or its salts, such as levovunol hydrochloride, or their solvates, Funolol or its salts or solvates thereof, methypranolol or its salts or Beta-blockers containing those solvates; dorzolamide hydrochloride or similar dorzolamide or its Salts or solvates thereof, brinzolamide or its salts or solvates thereof, aceta Zolamide or its salts or their solvates, dichlorphenamide or its salts or Carbonic anhydrase containing those solvates, metazolamide or its salts, or those solvates Isopropyl unoprostone or its salts or their solvates, taflup Rost or its salts or their solvates, travoprost or its salts or their solvates of bimatoprost or its salts or their solvates, latanoprost or or its salt or solvates, cloprostenol or its salt or its solvent Prostaglands containing fluprostenol, its salts, or their solvates Dipivefrin F2α derivatives; dipivefrin hydrochloride, or dipivefrin or its salts or their solutions Epinephrine, including antiparasitic agents, epinephrine, epinephrine borate, and epinephrine hydrochloride. Sympathomimetic agents containing the salt thereof or solvates thereof; distigmine bromide or These include salts thereof or their solvates, pilocarpine, pilocarpine hydrochloride, and pilocarpine nitrate. Pyrocarpine salts or their salts or solvates thereof, carbachol or similar Parasympathetic drugs containing salts or solvates thereof; lomerizine hydrochloride and other lomerizine-containing drugs Calcium channel blockers containing their salts or solvates; demepotassium or its Salts or solvates thereof, ecothiophates or salts thereof or solvates thereof, phi Cholinesterase inhibitors containing zostigmine or its salts or solvates thereof, etc. These include, and one or more of these can be combined. Other active ingredients include latanoprost, nipradilol, dorzolamide, and brinzola. Preferably, one or more selected from the group consisting of mido, timolol, and salts thereof.

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

[0036] In this specification, “packaging” means packaging that directly or indirectly contains the aqueous composition. This refers to the body. Furthermore, among the packaging bodies, the container that directly contains the aqueous composition (for example, an aqueous container) A container for eye drops in which the composition is directly filled is specifically referred to as a "primary packaging." Among these, a packaging that indirectly contains the aqueous composition (i.e., further contains the primary packaging) Packaging: For example, eye drop dispensing bags (bags that contain eye drop containers), etc. are specifically referred to as "secondary packaging." The packaging, under the storage conditions normally expected for pharmaceutical preparations, will be within the wavelength range described below. It is sufficient if it can block out ambient light; whether or not it is airtight is not a requirement. Furthermore, the packaging is defined as a "sealed container" or "airtight container" as defined in the General Rules of the Sixteenth Revised Japanese Pharmacopoeia. This concept encompasses both "airtight container" and "sealed container."

[0037] In the case where the pharmaceutical preparation comprises a secondary packaging, at least the primary packaging and the secondary packaging Either one of them should block light rays in the wavelength range described later. This applies not only during distribution and storage. Even when in use, the compound represented by general formula (1) or its salt or solvate thereof From the viewpoint of suppressing decomposition, at least the primary packaging blocks light rays in the wavelength range described later. It is preferable to do so.

[0038] The form of the packaging is not particularly limited to being able to contain the aqueous composition. Furthermore, the dosage form, intended use of the pharmaceutical preparation, whether it is a primary or secondary packaging, etc., should be appropriately selected and set. That would be sufficient. Specifically, such a package form could be, for example, an injection as the primary packaging. Containers for medications, containers for inhalants, containers for sprays, bottle-shaped containers, tube-shaped containers, containers for eye drops Examples include containers, nasal spray containers, ear drop containers, bag containers, etc. Also, as secondary packaging Packaging bags (e.g., eye drop dispensing bags), boxes (e.g., cardboard boxes), bottles (e.g., glass bottles), etc. Examples include cans (for example, aluminum cans, etc.). In the case where the packaging comprises both a primary packaging and a secondary packaging, the general formula is (1 From the viewpoint of advantageously utilizing the pharmacological effects of the compound represented by ), the primary packaging is for eye drops. A preferred configuration is one in which the container is a secondary packaging material, and the secondary packaging material is an eye drop packaging bag.

[0039] The material of the packaging is not particularly limited and should be selected appropriately according to the form of the packaging. Specifically, examples include glass, plastic, cellulose, pulp, rubber, and metal. It can be done. The material of the primary packaging that directly contains the aqueous composition should have properties such as processability, squeezeability, and durability. From this perspective, it is preferable that the material be made of plastic or similar. As for the material of the secondary packaging, from the viewpoint of processability, plastic, cellulose, and It is preferable that it be made of rubber, paper, or the like.

[0040] In the case of plastic packaging, the resin used is either synthetic or natural resin. It is preferable that it be a thermoplastic resin, specifically, for example, a polyolefin resin, polyester Polyphenylene ether resins, polycarbonate resins, polysulfone resins Examples include resins, polyamide resins, polyvinyl chloride resins, and styrene resins. It is preferable to use one or more of these in combination, and further, a mixture of these (polymer) Alloy) too.

[0041] In one embodiment, the material of the primary packaging is preferably a polyolefin resin. As specifically disclosed in Test Examples 7 and 8 below, the aqueous composition contained in the primary packaging When stored at high temperatures for a long period of time, discoloration may occur, but the primary packaging material is polyolefin. When using a resin-based material, it was found that ΔYI is kept relatively low, resulting in excellent storage stability. Ta. In this embodiment, at least the portion of the primary packaging that comes into contact with the aqueous composition It is sufficient if it is made of polyolefin resin, and furthermore, another material is laminated on the outside, etc. Even if this is the case, it falls under the category of "primary packaging made of polyolefin resin". In addition, in this specification, "made of polyolefin resin" means that the material has at least This means that it contains a portion of polyolefin resin, for example, polyolefin resin A mixture of two or more resins (polymer alloy) with other resins is also called "polyolefin resin." It will be displayed in "".

[0042] Here, the polyolefin resin is not particularly limited, and is a polymer of a single monomer (homopoly It may be a monomer, or it may be a copolymer of multiple monomers. In the case of copolymers, the polymerization mode is not particularly limited, and random polymerization is also possible. Block polymerization is also acceptable. Furthermore, its stereoregularity (tacticity) is not particularly limited. stomach. Examples of such polyolefin resins include, specifically, polyethylene (more details For example, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene Polyethylene (including medium-density polyethylene), polypropylene, cyclic polyolefin, poly(4-methyl) Tylpentene, polytetrafluoroethylene, ethylene-propylene copolymer, ethylene α-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid Examples include copolymers, ethylene-vinyl acetate copolymers, and ethylene-ethyl acrylate copolymers. These can be used in combination of one or more types. Polyolefin resins are also available. Therefore, from the viewpoint of keeping the ΔYI value low, polyethylene and polypropylene are preferred. Propylene is particularly preferred.

[0043] In another aspect, the primary packaging material is preferably a polyester resin. It seems so. As specifically disclosed in Test Examples 9 and 10 below, the aqueous mixture contained in the primary packaging When the product is stored at low temperatures, crystals may precipitate. When used as a resin system, it was found that such crystal precipitation is relatively less likely to occur, resulting in excellent storage stability. did. In this embodiment, at least the portion of the primary packaging that comes into contact with the aqueous composition It is sufficient if it is made of polyester resin, and furthermore, another material is laminated on the outside, etc. Even if this is the case, it falls under the category of "primary packaging made of polyester resin." Furthermore, in this specification, "made of polyester resin" means that at least a part of its material is This means that it contains polyester resin, for example, polyester resin and other resins A mixture of two or more resins (polymer alloy) is also included in "polyester-based resin." .

[0044] Here, the dicarboxylic acids and diols that constitute the polyester resin are not particularly limited, Examples of carboxylic acids include phthalic acid, terephthalic acid, and 2,6-naphthalenedicarboxylic acid. However, examples of diols include ethylene glycol, 1,3-propanediol, and 1,4 Examples include butanediol, 1,4-cyclohexanedimethanol, and bisphenol. Furthermore, even if it is a polymer of a single type of polyester unit, multiple types of polyester units It may also be a polymer of multiple polyester units. The polymerization method is not particularly limited and may be random polymerization or block polymerization. Furthermore, its stereochemical properties The tactic is not particularly limited. Examples of such polyester resins include, for instance, polyalkylene terephthalate. Poly(Terephthalate, Polybutylene Terephthalate, etc.) Alkylene naphthalates (e.g., polyethylene naphthalates, polybutylene naphthalates) Polycycloalkylene terephthalate (e.g., poly(1,4-cyclohexyl) (e.g., dimethylene terephthalate), polyarylate (e.g., bisphenol and phthalate) Homopolyesters such as resins composed of acids, and these homopolyester units as the main components Examples include copolyesters containing the aforementioned homopolyesters, and copolymers of the homopolyesters. These can be used in combination of one or more types. Polyester resins include... From the viewpoint of suppressing crystal precipitation, polyethylene terephthalate is preferred.

[0045] The wavelength range of light blocked by the packaging is 30, considering the normal storage environment for pharmaceutical products. While the range of 0-335nm is sufficient, from the perspective of further improving stability against light, 3 00 to 370 nm is preferred, and 300 to 395 nm is more preferred. In particular, 300 nm is preferred. Considering use under storage conditions where there is a high risk of exposure to wavelengths below m, 270-335 nm is preferred, 270-370 nm is more preferred, and 270-395 nm is particularly preferred. stomach.

[0046] In this specification, "blocking light rays" in the wavelength range means "blocking light rays" in the wavelength range. This means that the average transient rate is 40% or less. Therefore, for example, "wavelength 300-335 "Packaging that blocks nm light" means that the average light transmittance of 300-335 nm is 40 This refers to packaging that is below %. Furthermore, the average value of the light transmittance of the packaging material in the aforementioned wavelength range is used to improve its stability against light. From the perspective of improving performance, it is preferable that the percentage be 30% or less, and more preferably 25% or less. It is more preferably 20% or less, and even more preferably 15% or less, It is even more preferable that it be 0% or less, and particularly preferable that it be 5% or less. In this specification, the measurement of the average value of light transmittance in a specific wavelength range is performed using a spectrophotometer. After measuring the light transmittance of the packaging in air at 0.5 nm intervals within that range, It can be measured by calculating the average value. For example, a spectrophotometer is U -3900 (Hitachi High-Technologies Corporation) is one example.

[0047] The specific means for blocking light rays in the aforementioned wavelength range are not particularly limited, but for example, One method involves using a material that blocks light rays in a specified wavelength range, and more specifically, for example, A method for incorporating a substance that blocks light rays in the aforementioned wavelength range into the packaging (for example, glass or a method of adding a substance that blocks light rays in the aforementioned wavelength range to a resin and molding it into a container shape, etc. ); Light rays within the wavelength range are directed onto the surface of the packaging (at least one of the inner or outer surfaces of the packaging). A method of providing a component (e.g., a film, etc.) containing a substance that blocks (e.g., resin) A substance that blocks light rays in the aforementioned wavelength range is added to form a heat-shrinkable film, which is then placed on the outer surface of the container. Methods of wrapping around it, etc.); Light rays within the wavelength range are directed onto the surface of the packaging (at least one of the inner or outer surfaces of the packaging). A method of applying a substance that blocks it; A method in which a substance that blocks light rays in the aforementioned wavelength range is used as the main material of the packaging (for example, a container as the main material) (Methods such as constructing it with metal or cardboard) These are some examples.

[0048] The substance that blocks light rays in the aforementioned wavelength range is not particularly limited, but it is important to be able to see inside the packaging. From the standpoint of enabling this, substances that block the transmission of ultraviolet light, such as UV absorbers and UV scatterers, are preferred. Specifically, examples of ultraviolet scattering agents include titanium dioxide and zinc oxide. Furthermore, as an ultraviolet absorber, 2-(2H-benzotriazol-2-yl)-p- Cresol (e.g., Tinuvin P: BASF), 2-(2H-benzotriazole-2) -yl)-4,6-bis(1-methyl-1-phenylethyl)phenol (e.g., Tinu Vin 234: BASF, 2-(3,5-di-t-butyl-2-hydroxyphenyl) Nzotriazole (e.g., Tinuvin 320: BASF), 2-[5-chloro(2H)-be [Nzotriazole-2-yl]-4-methyl-6-(tert-butyl)phenol (for example) Tinuvin 326 (BASF), 2-(3,5-di-t-butyl-2-hydroxyphenicol) (Lu)-5-chlorobenzotriazole (e.g., Tinuvin 327: BASF), 2-(2H -benzotriazol-2-yl)-4,6-di-tert-pentylphenol (for example, 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) ), methyl 3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4 Reaction product of -hydroxyphenyl)propionate and polyethylene glycol 300 ( For example, Tinuvin 213 (BASF), 2-(2H-benzotriazol-2-yl)- 6-Dodecyl-4-methylphenol (e.g., 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-Tetramethylbutyl)-6-(2H-benzotriazol-2-yl)phenol Benzotriazole-based UV absorbers such as 2,2-bis{[2-cyano-3,3-dife [Nylacryloyloxy]methyl}propane-1,3-diyl=bis(2-cyano-3, 3-Diphenylacrylate) (e.g., Uvinul 3030 FF: BASF), 2-Cyanol- 3,3-Ethyl diphenylacrylate (e.g., Uvinul 3035: BASF), 2-Shea 2-ethylhexyl no-3,3-diphenylacrylate (e.g., Uvinul 3039:BAS) Cyanoacrylate-based UV absorbers such as those from Company F; 2-(4,6-diphenyl-1,3,5 -Triadin-2-yl)-5-[(hexyl)oxy]phenol (e.g., Tinuvi Triazine-based UV absorbers such as n 1577 ED:BASF; octabenzone (e.g., Chi massorb 81 (BASF), 2,2'-dihydroxy-4,4'-dimethoxybenzopheno (For example, Uvinul 3049: BASF), 2,2'-4,4'-tetrahydrobenzophenose Non (e.g., Uvinul 3050: BASF), oxybenzone, hydroxymethoxyben Zophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonate, dihydrophenone sulfonate Droxydimethoxybenzophenone, Dihydroxydimethoxybenzophenone disulfone Sodium benzoate, dihydroxybenzophenone, tetrahydroxybenzophenone, etc. Zophenone-based UV absorbers; methyl diisopropylcinnamate, cinoxate, diparameth Glyceryl mono-2-ethylhexanoate xycinnamate, isopropyl paramethoxycinnamate Diisopropyl cinnamate mixture, 2-ethylhexyl paramethoxycinnamate , cinnamic acid-based UV absorbers such as benzyl cinnamate; para-aminobenzoic acid, para-aminobenzoic acid Ethyl benzoate, glyceryl para-aminobenzoate, amyl para-dimethylaminobenzoate, para 2-ethylhexyl dimethylaminobenzoate, 4-[N,N-di(2-hydroxypropyl [Lu]amino]ethyl benzoate and other benzoic acid ester-based UV absorbers; ethylene salicylate Glycol, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate Salicylic acid-based UV absorbers such as yl, homomenthyl salicylate, and methyl salicylate; gua Iazulene; 2-ethyl dimethoxybenzylidene dioxoimidazolidinepropionate Xyl; 2,4,6-Tris[4-(2-ethylhexyloxycarbonyl)anilino] 1,3,5-triazine; parahydroxyanisole; 4-tert-butyl-4'-methoxy Cydibenzoylmethane; Phenylbenzimidazole sulfonic acid; 2-(4-diethyl) Examples include mino-2-hydroxybenzoyl)-hexyl benzoate. The wavelength range For example, a substance that blocks the light rays can be made by appropriately combining one or more of these substances. It should be set to block light rays in the specified wavelength range. In terms of quality, titanium dioxide and benzotriazole-based UV absorbers are preferred.

[0049] When a substance that blocks light rays in the aforementioned wavelength range is included in the material or components of the packaging, The proportion of each component varies depending on the type of substance, the packaging, the materials of other components, etc., but for example, packaging In the body material or other components, 0.001 to 50% by mass, preferably 0.002 to 25% by mass, Particularly preferable is a value of about 0.01 to 10% by mass.

[0050] In this specification, "light-blocking packaging" means that only a portion of the packaging blocks light. This also includes cases where the line is blocked. For such packaging, the inner surface is used as the reference point. Preferably, 10% or more of the total surface area is the part that blocks light rays, and 30% It is more preferable that the above-mentioned portion is the portion that blocks light rays, and that 50% or more of the portion blocks light rays. It is even more preferable that the portion that cuts off the light is the portion that blocks 70% or more of the light. That is particularly preferable.

[0051] It is preferable that the contents of the packaging be visible (observable) to the naked eye. If possible, it would be possible to inspect for foreign matter contamination during the manufacturing process of pharmaceutical preparations. This offers advantages such as allowing users of the formulation to check the remaining amount of the contents (aqueous composition). In this specification, "interior visible" means that the interior is visible from at least a portion of the outer surface of the packaging. This refers to a state in which the skin is visible (for example, the sides of an eye drop container, which are usually roughly cylindrical, are visible). Even if visibility is obstructed by film or similar material, if the bottom surface is visible, the interior is "visible." "That's what you could say. Furthermore, visibility is sufficient if the packaging has a certain level of transparency, for example... If, then, the average value of the light transmittance in the visible light region (450-750 nm) is approximately 30% or higher (more preferable). It is sufficient if approximately 40% or more is secured; particularly preferably approximately 50% or more. It is not limited to that.

[0052] As specific embodiments of the packaging, the following embodiments are preferred, for example. 1) The primary packaging contains a substance that prevents the transmission of ultraviolet light (more preferably, an ultraviolet scattering agent and ultraviolet light). One or more absorbents selected from the following; particularly preferred are zinc oxide, titanium dioxide, and benzotriazon A container (made of plastic, more preferably) containing one or more UV absorbers selected from the 3D UV absorber family. Preferably, a container made of polyolefin resin or polyester resin (preferably for eye drops) A packaging body (more preferably a packaging body in which the contents can be seen) that is a container for use; 2) The primary packaging contains a substance that prevents the transmission of ultraviolet light (more preferably, an ultraviolet scattering agent and ultraviolet light). One or more absorbents selected from the following; particularly preferred are zinc oxide, titanium dioxide, and benzotriazon A component (preferably a heat-shrinkable film) that has been kneaded with one or more UV absorbers selected from the 3D UV absorbers. A container (preferably made of plastic) with shrink film wrapped around the sides; Preferably, a container made of polyolefin resin or polyester resin (preferably, eye drop container) A packaging body that serves as a container for the drug (more preferably, a packaging body that allows the contents to be seen); 3) The secondary packaging contains a substance that prevents the transmission of ultraviolet light (preferably an ultraviolet scattering agent and an ultraviolet absorbing agent). One or more agents selected from the following; more preferably, zinc oxide, titanium dioxide, and benzotriazole. A bag (preferably made of plastic) containing one or more UV absorbers selected from the UV absorber family. Preferably, a bag made of polyolefin resin or polyester resin (preferably, eye drops) A packaging body (preferably a packaging body that allows the contents to be seen) that is a drug dispensing bag; 4) A packaging body in which the secondary packaging body is a paper box that houses a container (preferably a container for eye drops).

[0053] The means of containing the aqueous composition in the packaging are not particularly limited and can be done by conventional methods according to the form of the packaging, etc. Filling or similar methods can be used.

[0054] The diseases to which the pharmaceutical preparation can be applied are not particularly limited, and the drug contains the compound represented by the general formula (1) above. You should select the appropriate one depending on the physiological effects and other factors. Specifically, for example, the Rho kinase inhibitory effect of the compound represented by general formula (1), and Based on its intraocular pressure-lowering effect, it can be used as a preventive or therapeutic agent for ocular hypertension and glaucoma. Glaucoma can be further categorized into, for example, primary open-angle glaucoma, normal-tension glaucoma, and aqueous humor glaucoma. Hyperglaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed Combined glaucoma, steroid glaucoma, lens capsule glaucoma, pigment glaucoma, amyloid glaucoma, Examples include neovascular glaucoma and malignant glaucoma.

[0055] Furthermore, as disclosed in Japanese Patent Publication No. 5557408, fundus diseases (mainly retinal Lesions that manifest in the membrane and / or choroid. Specifically, for example, fundus changes due to hypertension and arteriosclerosis. This includes conditions such as central retinal artery occlusion, central retinal vein occlusion, and retinal vein occlusion. Retinal vein occlusion such as branch retinal vein occlusion, diabetic retina disease, diabetic macular edema, diabetic maculopathy, Eales disease, Coats disease Retinal vascular congenital anomalies such as isease, von Hippel disease, pulseless disease ess disease), macular disease (central serous chorioretinopathy), Cystoid macular edema, age-related macular degeneration myopic macular degeneration), macular hole, myopic macular degeneration ), retinovitreous interface macular degeneration, drug-toxic macular degeneration, hereditary macular degeneration, etc., (rhegmatogenous Examples include retinal detachment (tractional, exudative, etc.), retinitis pigmentosa, and retinopathy of prematurity. A preventive or therapeutic agent, more preferably for the prevention of diabetic retinopathy, diabetic macular edema, or age-related macular degeneration. It can be used as a therapeutic agent. [Examples]

[0056] Next, the present invention will be further described with reference to examples, but the present invention is not limited in any way to these examples. isn't it. In the following test examples, ripasudil 1-hydrochloride dihydrate is used, for example, in International Publication No. 20 It can be manufactured using the method described in pamphlet No. 06 / 057397. Furthermore, in the following test examples, the measurement of lipasudil and its related substances using HPLC was performed. An ODS column was used as the column, and 0.01 mol / L phosphate buffer and acetone were used as the mobile phase. Nitriles were analyzed using a UV-125 (280 nm) spectrophotometer as the detector. .

[0057] [Test Example 1] Evaluation of the photostability of lipasudil The light stability of lipasudil can be determined by checking for the presence or absence of decomposition products upon exposure to light. I evaluated it. In other words, powdered lipasudil 1-hydrochloride dihydrate is placed in a glass petri dish to a thickness of 3 mm or less. After spreading it out to this extent, use the photostability tester (LT-120A: Nagano Science Co., Ltd.) Using a D65 fluorescent lamp as the light source, under conditions of 25°C, 4000 lux of light was generated. The irradiation dose was set to 400,000, 800,000, or 1,200,000 lux·hr.

[0058] To confirm the presence or absence of photodegradation products of lipasudil, lipasudil was applied to samples before and after exposure. The presence or absence of an increase in ripasdil-related substances was evaluated. Related substances were identified using HPLC as ripasdil-related substances. The peak area was evaluated as the ratio (%) of the peak area of ​​related substances to the total peak area. The results are shown in Table 1.

[0059] [Table 1]

[0060] As shown in Table 1, despite the increase in cumulative irradiation dose, the amount of lipasudil-related substances remained the same. There was virtually no increase, and no photodegradation products were observed. Based on the above test results, compounds represented by general formula (1), such as lipasudil, or It has been revealed that the salts or solvates thereof are extremely stable to light.

[0061] [Test Example 2] Evaluation of the photostability of lipasudil in aqueous compositions The light-resistant stability of lipasudil when incorporated into an aqueous composition was tested in the same manner as in Test Example 1, under the same conditions as in Test Example 1. The evaluation was performed by checking for the presence or absence of decomposition products caused by light. In other words, per 100 mL, 0.4896 g of lipasudil 1-hydrochloride dihydrate (lipasudil) 0.4g of free form of zirconia, 0.4g of anhydrous sodium dihydrogen phosphate, glycerin 2.136g, benzalkonium chloride 0.002g, sodium hydroxide appropriate amount (p Prepare an aqueous composition containing H 6.0) and sterile purified water (residue), and then combine it with polypropylene. It was placed in a transparent container made of Len. After that, it was tested using a light stability test apparatus (LT-120A: Nagano Sa Using Jens Corporation, with a D65 fluorescent lamp as the light source, under conditions of 25°C, 4000 Irradiate with lux of light so that the cumulative irradiation dose is 300,000, 600,000, or 1,200,000 lux·hr. did.

[0062] To confirm the presence or absence of photodegradation products of lipasudil, an increase in lipasudil-related substances was observed. The absence of any substance was evaluated. Related substances were identified using HPLC, and are derived from lipasudil and its related substances. It was evaluated as a percentage of the total peak area. The results are shown in Table 2.

[0063] [Table 2]

[0064] As shown in the results in Table 2, the amount of related substances increases in proportion to the increase in cumulative irradiation dose, and exposure It was revealed that decomposition products were generated. The D65 fluorescent lamp used as the light source was 300n This device emits light with wavelengths of m or greater. The photodegradation reaction of organic compounds depends on the strength of specific bonds in the compound, and consequently on the structure of the compound. It depends on the structure. Therefore, the stability to light (ease of photodegradation) is usually determined by the type of organic compound. It should show a similar trend regardless of its state (solid, liquid, etc.). However, in Test Example 1 And from the results of 2, surprisingly, compounds represented by general formula (1), such as lipasudil, were found to be... Alternatively, their salts or solvates are themselves stable to light, but aqueous It is clear that the property of becoming unstable to light only occurs when it is incorporated into the composition. It became softer.

[0065] [Test Example 3] Confirmation of the wavelength of light that causes the decomposition of lipasudil in aqueous compositions, Part 1 Regarding the photodegradation of lipasudil in aqueous compositions confirmed in Test Example 2, what light rays are responsible for it? The wavelength is irradiated with light having a specific range of wavelengths, and the presence or absence of decomposition products due to exposure is confirmed. Confirmed by verification. In other words, per 100 mL, 0.0612 g of lipasudil 1-hydrochloride dihydrate (lipasudil) (0.05g as free form of zill), 1.19g boric acid, 0.42g potassium chloride, Benzalkonium chloride 0.002g, sodium hydroxide appropriate amount (pH 6.7) and Prepare an aqueous composition containing sterile purified water (residue), and put it in a transparent polypropylene container. It was then placed in a container. Subsequently, a spectroscopic irradiation device equipped with an optical filter (spectroscopic unit: HSU- Using a 100S exposure and a MAX-302FBD light source (both from Asahi Spectroscopic Co., Ltd.), approximately 270°C was observed. ~335nm, 320~395nm, 370~435nm, 430~470nm, 470 ~530nm, 525~575nm, 570~630nm, 625~675nm or 66 Light with wavelengths in the range of 0 to 740 nm was irradiated under conditions of 25°C. Light rays of this wavelength also emit an irradiation energy of approximately 15 W·h / m 2 That's what I decided.

[0066] To confirm the presence or absence of photodegradation products of lipasudil, the same method as in Test Example 1 was used to determine whether lipasudil was produced. We evaluated whether there was an increase in sudil-related substances. The results are shown in Table 3.

[0067] [Table 3]

[0068] As shown in Table 3, an increase in related substances was observed when irradiated with light of wavelengths above 370 nm. However, a significant increase in related substances was observed with irradiation at shorter wavelengths, particularly 270-335 nm. The addition was approved. Furthermore, one of the tests used to confirm the storage stability of pharmaceuticals is the photostability test, but in this test... The guidelines stipulate that a D65 light source should be used. A D65 light source is... Internationally recognized as the standard for outdoor daylight as defined in ISO 10977 (1993). These are defined by the spectral distribution values ​​in the wavelength range of 300 to 830 nm. Therefore, under the storage conditions normally expected for pharmaceuticals, waves of 300 nm or greater are considered to be harmful. Considering the long-range light is considered sufficient. Based on the above points, compounds represented by general formula (1), such as lipasudil, or In ensuring the photostability of aqueous compositions containing salts or solvates thereof, in particular, 30 It was concluded that blocking light rays with wavelengths of 0 to 335 nm is important.

[0069] [Test Example 4] Confirmation of the wavelength of light that causes the decomposition of lipasudil in aqueous compositions, Part 2 The aqueous composition was changed to the following two types, and the wavelength of the irradiated light was set to 270-335 nm. The same method as in Test Example 3 was used, except for setting the wavelength to 320-395 nm or 370-435 nm. An experiment was conducted. <Aqueous composition A> Per 100 mL: 0.0612 g of lipasudil 1 hydrochloride dihydrate (lipasudil free (0.05g as a whole), anhydrous sodium dihydrogen phosphate 0.4g, potassium chloride 0. 78g, benzalkonium chloride 0.002g, sodium hydroxide appropriate amount (pH 6. 7) and sterile purified water (residue) were prepared to make an aqueous composition A. <Aqueous composition B> Per 100 mL: 0.0612 g of lipasudil 1 hydrochloride dihydrate (lipasudil free (0.05g as a whole), potassium chloride 0.98g, benzalkonium chloride 0.0 Water containing 0.2g of sodium hydroxide (pH 6.7) and sterile purified water (residue). A composition was prepared and designated as aqueous composition B. The results are shown in Table 4.

[0070] [Table 4]

[0071] As shown in Table 4, regardless of the differences in the composition of the aqueous composition, wavelengths of 370 nm or higher No increase in related substances was observed with light irradiation; rather, an increase was observed at shorter wavelengths, particularly 270-335 Hz. A significant increase in related substances was observed upon irradiation with light ray m. From the test results of the above test examples 3 and 4, it can be seen that lipasudil, represented by the general formula (1), Ensuring the photostability of aqueous compositions containing the compound or its salt or solvates thereof. In doing so, regardless of its composition, it is important to block light rays with wavelengths of 300-335 nm in particular. It was concluded that these are important.

[0072] [Test Example 5] Aqueous solution contained in a plastic container (primary packaging) containing a UV absorber. Confirmation of the stabilization of lipasudil in the composition. Based on the results obtained in Test Examples 3 and 4, an aqueous composition containing lipasdil was subjected to UV absorption. We attempted to stabilize the product by placing it in a container containing an astringent. In other words, per 100 mL, 0.4896 g of lipasudil 1-hydrochloride dihydrate (lipasudil) 0.4g of free form of zirconia, 0.4g of anhydrous sodium dihydrogen phosphate, glycerin 2.136g, benzalkonium chloride 0.002g, sodium hydroxide appropriate amount (p Prepare an aqueous composition containing H 6.0) and sterile purified water (residue), and apply the following UV treatment The solution is housed in a polypropylene eye drop container containing a light-absorbing agent, and then subjected to a photostability test (LT) apparatus. Using -120A (Nagano Science Co., Ltd.), with a D65 fluorescent lamp as the light source, at 25°C Under these conditions, 4000 lux of light is applied so that the cumulative irradiation dose is 1.2 million lux·hr. Ta.

[0073] Lipasudil-related substances were evaluated for samples before and after exposure using the same method as in Test Example 1. Ta. The results are shown in Table 5.

[0074] <Plastic container containing UV absorbers> A polypropylene eye drop container containing a benzotriazole-based UV absorber is used. The average light transmittance of the container was 7.2% at 300-335nm (Note: 300- Average 6.7% at 370nm; average 11.7% at 270-335nm; 270-370nm Average 9.8% at 300-395nm; average 10.2% at 300-395nm; average 11% at 270-395nm. It was 0.8%. The container was almost transparent externally, and its contents were visible (for example, visible light). The light transmittance in the region (450~750nm) exceeds 65% at all wavelengths. The average was 76.2%. The light transmittance was measured using a spectrophotometer (U-3900: Hitachi High-Technologies). After cutting the container into plate-like pieces, they are set in the optical path so that light is incident approximately perpendicularly, and then 0 Measurements were taken every 0.5 nm. The average value of the light transmittance was calculated as the light transmittance at 0.5 nm intervals within a given wavelength range. It was calculated as the average of the rates.

[0075] [Table 5]

[0076] Based on the results shown in Table 5, the aqueous composition containing lipasudil was light-transmitted at 300-335 nm. The average transient rate is 7.2% (for 300-370nm, the average is 6.7%; for 270-335nm). m: average 11.7%; 270-370nm: average 9.8%; 300-395nm: average 1 0.2%; average 11.8% at 270 to 395 nm), it was revealed that the photostability of ripasudil in the aqueous composition is improved.

[0077] [Test Example 6] In a container (primary package) provided with a shrink film blended with an ultraviolet light scattering agent Confirmation of stabilization of ripasudil in the contained aqueous composition In the same manner as in Test Example 5, an aqueous composition containing ripasudil was placed in a container blended with an ultraviolet light scattering agent and an attempt was made to achieve stabilization by containing the composition therein. Specifically, instead of a container blended with an ultraviolet absorber, a container provided with a shrink film blended with the following ultraviolet light scattering agent was used, and instead of a D65 fluorescent lamp as a light source, a white fluorescent lamp (used in hospital dispensing rooms and the like) was used, and the test was carried out by the same method as in Test Example 5. The results are shown in Table 6.

[0078] <Container provided with a shrink film blended with an ultraviolet light scattering agent> A white shrink film obtained by kneading 40 to 45% by mass of titanium oxide as an ultraviolet light scattering agent (heat-shrinkable film) manufactured by Iwata Label Co., Ltd. was wrapped around the side surface of a conventional polypropylene eye drop container that does not contain an ultraviolet absorber, an ultraviolet light scattering agent, or the like according to a conventional method, and this wrapped product was used. The average light transmittance of the titanium oxide-containing shrink film is 0.3% averaged over 300 to 335 nm (note: average 0.4% over 300 to 370 nm; average over 270 to 335 nm is 0.1%; average 0.3% over 270 to 370 nm; average 0.4% over 300 to 395 nm; average 0.3% over 270 to 395 nm). Since the shrink film is not transparent, the content cannot be visually checked from the side surface of the container as it is It was not in a state where it could be recognized (for example, the light transmittance in the visible light region (450~750nm) was The average was 1.1%. Therefore, a slit about 5 mm wide was made in the lower half of the side of the container, and inside The container volume was made visible (it was not possible to block the light in this area). Also, since shrink film is not wrapped around the bottom of the container, the contents can be seen from the bottom. It was visible. The light transmittance was measured using a spectrophotometer (U-3900: Hitachi High-Technologies), and the value was 0 Measurements were taken every 0.5 nm. The average value of the light transmittance was calculated as the light transmittance at 0.5 nm intervals within a given wavelength range. It was calculated as the average of the rates.

[0079] [Table 6]

[0080] The results shown in Table 6 indicate that the aqueous composition containing lipasudil is light-transmitted at 300-335 nm. The average transient rate is 0.3% (Note: The average is 0.4% at 300-370nm; 270-335nm). Average 0.1% at m; average 0.3% at 270-370nm; average 0% at 300-395nm. By housing it in a container with 4%; an average of 0.3% at 270-395 nm, in an aqueous composition It was revealed that the photostability of lipasudil is improved.

[0081] From the results of test examples 5 and 6, compounds represented by general formula (1), such as lipasudil, A aqueous composition containing a salt thereof or a solvate thereof is exposed to light with a wavelength of 300 to 335 nm. By housing in a packaging that blocks the line, the chemicals represented by general formula (1) in the aqueous composition It was confirmed that the photostability of the material improved.

[0082] Furthermore, even when a transparent ophthalmic solution bag made of polyethylene blended with an ultraviolet absorber (Seisan Nihon Co., Ltd.) is used as the secondary package instead of the containers used in Test Examples 5 and 6, the same result can be obtained.   The average light transmittance of the ophthalmic solution bag is 0.4% on average in the range of 300 to 335 nm; 1.4% on average in the range of 300 to 370 nm; 0.2% on average in the range of 270 to 335 nm; 270 to 37 0 nm: 0.9% on average; 300 to 395 nm: 3.6% on average; 270 to 395 nm: average was 2.7%. In addition, the container was white and translucent in appearance, with the contents visible (for example, the light transmittance in the visible light region (450 to 750 nm) exceeded 45% at all wavelengths and was 70.6% on average.).

[0083] [Test Example 7] Storage Test Part 1 After preparing aqueous compositions having the formulations shown in Table 7 by a conventional method, the pharmaceutical preparations were produced by placing the compositions into containers made of polyethylene (PE), poly propylene (PP), or polyvinyl chloride (PVC).   Each obtained pharmaceutical preparation was stored at 60°C for 3 months, and the color difference (ΔYI) before and after storage was measured using a color difference meter (spectrophotometer CM-700d: Konica Minolta Sensing, Inc.), and samples with a ΔYI value of 5 or more were rated as ×, and samples with a ΔYI value of less than 5 were rated as ○. The results are shown in Table 8.

[0084]

Table 7

[0085]

Table 8

[0086] As shown in Table 8, the aqueous composition containing lipasudil was made of polyethylene (PE), When stored in polyolefin resin containers such as polypropylene (PP), it may be subjected to high temperatures for extended periods. Even when stored for an extended period, the value of ΔYI was kept low, whereas polyvinyl chloride ( When the container was made of PVC, the value of ΔYI increased.

[0087] [Test Example 8] Preservation Test Part 2 After preparing the aqueous compositions of the formulations shown in Table 9 by conventional methods, polyethylene (PE) or poly The pharmaceutical preparation was manufactured in a container made of polypropylene (PP). Each obtained pharmaceutical preparation was stored at 60°C for 3 months, and the color difference (ΔYI) before and after storage was measured. The measurement was performed using a spectrophotometer (CM-700d: Konica Minolta Sensing, Inc.), and Δ We evaluated YI values ​​of 5 or greater as × and values ​​less than 5 as ○. The results are shown in Table 10.

[0088] [Table 9]

[0089] [Table 10]

[0090] As shown in Table 10, even when the aqueous composition formulation is changed, polyethylene When contained in a polyolefin resin container such as one made of (PE) or polypropylene (PP) Furthermore, even when stored at high temperatures for extended periods, the value of ΔYI remained low.

[0091] From the results of the above test examples 7 and 8, the compounds represented by general formula (1), such as lipasudil, Aqueous compositions containing a substance, its salt, or solvates thereof, made from polyolefin resin When stored in a container, ΔYI was kept low, demonstrating excellent storage stability. .

[0092] [Test Example 9] Preservation Test Part 3 After preparing the aqueous compositions of the formulations shown in Table 11 by conventional methods, polyethylene terephthalate The pharmaceutical preparation was manufactured in a container made of PET or polyvinyl chloride (PVC). Each obtained pharmaceutical preparation was stored at 0°C for 2 days, and then visually evaluated for the presence or absence of crystal precipitation. Note that ○ indicates no crystal precipitation was observed, and × indicates crystal precipitation was observed. The results are shown in Table 12.

[0093] [Table 11]

[0094] [Table 12]

[0095] As shown in Table 12, the aqueous composition containing lipasudil was used in polyethylene terephthalate When stored in a polyester resin container such as PET, when stored at low temperatures In contrast to the case where crystal precipitation was not observed in the container made of polyvinyl chloride (PVC), When exposed to water, crystal precipitation was observed.

[0096] [Test Example 10] Preservation Test Part 4 After preparing the aqueous compositions shown in Table 13 by conventional methods, polyethylene terephthalate (PE) is used. The pharmaceutical preparation was manufactured using a container made of T. The obtained pharmaceutical formulation was stored at 0°C for 21 days, and then visually evaluated for the presence or absence of crystal precipitation. Note that ○ indicates no crystal precipitation was observed, and × indicates crystal precipitation was observed. The results are shown in Table 14.

[0097] [Table 13]

[0098] [Table 14]

[0099] As shown in Table 14, even when the aqueous composition formulation is changed, polyethylene When stored in a polyester resin container such as terephthalate (PET), it can be stored at low temperatures. Even in this case, no crystal precipitation was observed.

[0100] From the results of the above test examples 9 and 10, the chemical represented by general formula (1), which is represented by lipasudil, A water-based composition containing a compound or a salt thereof, or a solvate thereof, made of polyester resin When stored in a container, crystal precipitation is relatively less likely to occur even at low temperatures, improving storage stability. It became clear that it was superior.

[0101] [Manufacturing Examples 1-27] The ingredients and quantities listed in Tables 15 to 17 (amount per 100 mL of aqueous composition (g)) are included. An aqueous composition containing the substance was prepared by a conventional method, and this was used in Test Example 5 as a benzotriazole-based violet. The product is manufactured by placing it in a polypropylene eye drop container (primary packaging) that incorporates an external radiation absorber. Examples 1-27 of pharmaceutical formulations can be manufactured.

[0102] [Table 15]

[0103] [Table 16]

[0104] [Table 17]

[0105] [Manufacturing Examples 28-54] In manufacturing examples 1-27, the container material was changed from polypropylene to polyethylene. Aside from that, the same containers used in Test Example 5 were used to produce the pharmaceutical formulations of Manufacturing Examples 28-54. It can be manufactured.

[0106] [Manufacturing Examples 55-81] In manufacturing examples 1-27, a benzotriazole-based UV absorber was incorporated into the container. Instead of a polypropylene eye drop container, the titanium dioxide-containing shrink wrap used in Test Example 6 was used. Using a polypropylene eye drop container (primary packaging) with film wrapped around the sides, We can manufacture pharmaceutical formulations as shown in examples 55-81.

[0107] [Manufacturing Examples 82-108] In manufacturing examples 1-27, a benzotriazole-based UV absorber was incorporated into the container. Instead of polypropylene eye drop containers, polyethylene eye drop containers (wavelength 300~ (A material that does not block light rays in the 335nm range) is used, and furthermore, the aforementioned ultraviolet absorber is arranged The eye drops are placed in a transparent polyethylene dispensing bag (manufactured by Nippon Seisan Co., Ltd.) (secondary packaging). It can manufacture pharmaceutical formulations as shown in manufacturing examples 82-108.

[0108] [Manufacturing Examples 109-135] In manufacturing examples 1-27, a benzotriazole-based UV absorber was incorporated into the container. Polyethylene terephthalate eye drop containers instead of polypropylene eye drop containers. (A material that does not block light rays in the wavelength range of 300-335 nm is used, and furthermore, a paper box ( By placing the contents in a secondary packaging, the pharmaceutical formulations shown in manufacturing examples 109 to 135 can be produced.

[0109] [Manufacturing Examples 136-270] In manufacturing examples 1-135, the same amount of 4-bromo was used instead of lipasudil 1-hydrochloride dihydrate. -5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinol Phosphorus-based preparations can be manufactured by conventional methods as pharmaceutical formulations, as shown in manufacturing examples 136-270. [Industrial applicability]

[0110] According to the present invention, a pharmaceutical formulation with excellent stability can be provided, which can be suitably utilized in the pharmaceutical industry and the like. It can be used.

Claims

[Claim 1] The invention described in the application.

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