Water-based composition, the lacquer

Abstract

To provide an aqueous composition having excellent preservative effects. [Solution] Lipasudil or its salt or solvates thereof, and benzethonium chloride An aqueous composition containing the following.

Description

Technical Field

[0001] The present invention relates to an aqueous composition and the like.

Background Art

[0002] Compositions containing at least water as a solvent (aqueous compositions) are less irritating to living organisms and have advantages such as being able to incorporate various components, and are widely used as pharmaceuticals, quasi-drugs, and the like. However, since they contain water, there is a problem that they are easily contaminated by microorganisms. Especially in the case of dosage forms that are often repeatedly used, such as eye drops, nasal drops, and ear drops, even when filled in a sterilized container or the like, each time of use, the aqueous composition comes into contact with non-sterile outside air, so the risk of microbial contamination increases. Therefore, preservatives (bactericides) are often incorporated into aqueous compositions to provide an anti-corrosion effect.

[0003] Examples of preservatives include parabens and quaternary ammonium type surfactants such as benzalkonium chloride. However, it has also been pointed out that such preservatives have problems such as cytotoxicity. (For example, Non-Patent Document 1), for example, when an aqueous composition is used as an eye drop, there is also a risk of causing corneal damage. Therefore, the amount of use should be kept to the minimum as much as possible. In this regard, if a formulation of an aqueous composition that exhibits an excellent anti-corrosion effect by the synergistic action of a combination of multiple components can be established, the amount of use of each preservative alone can be reduced accordingly, and ultimately, it becomes possible to provide a more safe aqueous composition.

[0004]

[0005] By the way, the following structural formula:

[0005] [ka]

[0006] Lipasdil (chemical name: 4-fluoro-5-[[(2S)-2-methyl-1,4 (-diazepan-1-yl]sulfonyl]isoquinoline), or the following structural formula:

[0007] [ka]

[0008] Represented as 4-bromo-5-[[(2S)-2-methyl-1,4-diazepan-1-yl Halogenated isoquinoline derivatives such as sulfonyl isoquinoline inhibit Rho kinase It has pharmacological effects such as harmful effects (for example, Patent Documents 1 and 2), and is used for the prevention of ocular hypertension, glaucoma, etc. It can be used as a therapeutic agent (for example, Patent Document 3), and furthermore, for the prevention or treatment of retinal diseases such as age-related macular degeneration. It has been reported to be useful as a therapeutic agent (for example, Patent Document 4), and furthermore, in eye drop formulations. It has also been reported that the product can be used as an aqueous composition (for example, Patent Document 3). However, the preservative effect of these halogenated isoquinoline derivatives has not been known until now. It is completely unknown to them. [Prior art documents] [Patent Documents]

[0009] [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] Japanese Patent No. 5557408

Non-Patent Literature

[0010]

Non-Patent Literature 1

Summary of the Invention

Problems to be Solved by the Invention

[0011] An object of the present invention is to provide an aqueous composition having an excellent antiseptic effect.

Means for Solving the Problems

[0012] Therefore, the present inventor earnestly studied to solve the above problems, and surprisingly found that the halogenated isoquinoline derivative represented by the following general formula (1) such as rispaxil has an excellent antiseptic effect. Furthermore, by combining this with a quaternary ammonium type surfactant such as benzalkonium chloride, an aqueous composition with a significantly enhanced antiseptic effect was obtained, and the present invention was completed. That is, the present invention provides the following <1> to <4>.

[0013] <1> The following general formula (1)

[0014]

Chemical Formula

[0015] [In the formula, X represents a halogen atom.] An aqueous composition containing a compound represented by the formula or a salt thereof or a solvate thereof, and a quaternary ammonium type surfactant. <2> The compound represented by the general formula (1) or a salt thereof or a solvate thereof, and A step of compounding a quaternary ammonium surfactant to impart a preservative effect to an aqueous composition. method. <3> The above general formula (1) is used to impart a preservative effect to an aqueous composition. A combination of a compound or its salt or solvate thereof and a quaternary ammonium-type surfactant. Matching. <4> Compound represented by the general formula (1) for imparting a preservative effect to an aqueous composition. Alternatively, a combination of a salt thereof or a solvate thereof with a quaternary ammonium-type surfactant. Use. [Effects of the Invention]

[0016] According to the present invention, an aqueous composition having excellent preservative effect and excellent storage stability is provided. It is possible. [Modes for carrying out the invention]

[0017] This specification is not limited to these, but discloses, for example, the following embodiments of the invention. do. [1] The following general formula (1)

[0018] [ka]

[0019] [In the formula, X represents a halogen atom.] A compound represented by or a salt thereof, or a solvate thereof, and a quaternary ammonium type interface An aqueous composition containing a property agent. [2] The aqueous composition according to [1], wherein the compound represented by the general formula (1) is lipasudil. thing. [3] The quaternary ammonium surfactant is benzalkonium chloride and benzethoni The aqueous composition according to [1] or [2], which is one or more selected from the group consisting of um chlorides. . [4] The compound represented by the general formula (1) is lipasudil, and quaternary ammonia The aqueous solution described in any of [1] to [3], wherein the M-type surfactant is benzalkonium chloride. composition. [5] An aqueous composition according to any one of [1] to [4], which is an eye drop or eye ointment. [6] Phosphate, boric acid and their salts, carbonic anhydrase inhibitors, α1 blockers and nipradi The aqueous composition described in any of [1] to [5] (chronic progressive) is one that does not contain rolls. (Excluding pharmaceuticals and film formulations for the suppression of renal impairment.)

[0020] [7] A compound represented by the general formula (1) above, or a salt thereof, or a solvate thereof, and the fourth A preservative for aqueous compositions, comprising the step of blending a ammonium-type surfactant with an aqueous composition. Method of applying effects. [8] The method according to [7], wherein the compound represented by the general formula (1) is lipasudil. [9] The quaternary ammonium surfactant is benzalkonium chloride and benzethoni The method according to [7] or [8], wherein one or more substances are selected from the group consisting of um chlorides.

[10] The compound represented by the general formula (1) is lipasudil, and a quaternary ammonia The um-type surfactant is benzalkonium chloride, as indicated in any of [7] to [9]. Law.

[11] The aqueous composition is an eye drop or an eye ointment, as described in any of [7] to

[10] . The method.

[12] The aqueous composition (a pharmaceutical and film formulation for the suppression of chronic progressive kidney disease disorders) (Excluding) phosphoric acid, boric acid and their salts, carbonic anhydrase inhibitors, α1 blockers and nipple The method described in any of [7] to

[11] , which does not include radiol.

[0021]

[13] In addition, α1 receptor blockers, α2 receptor agonists, β-blockers, carbonic anhydrase inhibitors Prostaglandin F2α derivatives, sympathetic agonists, parasympathetic agonists, calcium channels [1] Contains one or more selected from the group consisting of antidotes and cholinesterase inhibitors. Aqueous compositions as described in any of [5].

[14] Furthermore, latanoprost, nipradilol, dorzolamide, brinzolamide and [1]~[5] Contains one or more selected from the group consisting of timolol and salts thereof. An aqueous composition as described in any of the following:

[15] The aqueous composition further comprises an α1 receptor blocker, an α2 receptor agonist, a β blocker, and carbonation. Hydrogen enzyme inhibitors, prostaglandin F2α derivatives, sympathetic agonists, parasympathetic agonists, Contains one or more substances selected from the group consisting of calcium channel blockers and cholinesterase inhibitors. Do so using one of the methods described in [7] to

[11] .

[16] The aqueous composition further contains latanoprost, nipradilol, dorzolamide, and brin. It contains one or more selected from the group consisting of zolamide, timolol, and salts thereof. One of the methods described in [7] to

[11] .

[0022] <<Regarding the Invention of an Aqueous Composition>> The following will first explain in detail the meaning of the wording and other aspects of the invention relating to the "aqueous composition." do.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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:

[0027] [ka]

[0028] Lipasdil hydrochloride hydrate (lipasdil 1-hydrochloride dihydrate) represented by [formula] is particularly preferred.

[0029] 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.

[0030] 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 that, but from the viewpoint of obtaining excellent preservative effect, the total volume of the aqueous composition 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 preservative effects, a lipasdi solution 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 %.

[0031] As an example of a "quaternary ammonium surfactant," benzalkonium chloride, known as a preservative, is an example. Examples include ammonium chlorides and benzethonium chloride. Quaternary ammonium type surfactants Therefore, from the viewpoint of obtaining excellent preservative effects, benzalkonium chloride is preferred. Furthermore, quaternary ammonium surfactants are well known and may be manufactured by known methods. You can also use commercially available stones.

[0032] The content of quaternary ammonium-type surfactants in the aqueous composition is not particularly limited and should be considered as appropriate. You can decide by doing so, but from the viewpoint of obtaining excellent preservative effect, 0 of the total volume of the aqueous composition Preferably containing 0.00005~0.02 w / v%, and 0.00025~0.01 w / It is more preferable to contain v%, and particularly preferable to contain 0.00025~0.004 w / v%. Preferably, benzalkonium chloride is used as a quaternary ammonium type surfactant. If present, from the viewpoint of obtaining excellent preservative effect, add 0.0% of the total volume of the aqueous composition. Preferably containing 0.0001 to 0.01 w / v%, and 0.0005 to 0.005 w / v%. It is more preferable to include it, and particularly preferable to include 0.0005 to 0.002 w / v%. stomach.

[0033] As described in the test examples below, the compound represented by the general formula (1) above or its salt or the These solvates, when combined with quaternary ammonium-type surfactants, work synergistically. It exhibits a significantly enhanced preservative effect. For example, benzalkonium chloride, etc. By reducing the amount of quaternary ammonium surfactants used, a safer aqueous composition can be created. It is also possible to do so. In terms of the combination, from the perspective of enhancing the antiseptic effect through synergistic action, lipasudil or A combination of its salt or a solvate thereof with benzalkonium chloride is particularly preferred. stomach.

[0034] Compounds represented by the general formula (1) or salts thereof in aqueous compositions or solvations thereof The mass ratio of the substance to the quaternary ammonium-type surfactant is not particularly limited, but it is an excellent preservative. From the viewpoint of obtaining the effect, the compound represented by the general formula (1) above, or a salt thereof, or a solution thereof. For every 1 part by mass of the mediator in its free form, add 0.000 parts of a quaternary ammonium-type surfactant. Preferably, it contains 1 to 0.4 parts by mass, and more preferably 0.001 to 0.04 parts by mass. Preferably, it contains 0.00125 to 0.015 parts by mass. In particular, as a compound represented by general formula (1) or a salt thereof, or a solvate thereof, lipa Using sudil or its salt or solvates thereof, a quaternary ammonium type surfactant and When using benzalkonium chloride, from the viewpoint of obtaining excellent preservative effects, Per 1 part by mass of lipasudil or its salt or solvate thereof as a free form, ben Preferably, it contains 0.0002 to 0.2 parts by mass of salkonium chloride, and 0.002 to It is more preferable to contain 0.02 parts by mass, and more preferable to contain 0.0025 to 0.01 parts by mass. Particularly preferable.

[0035] 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.

[0036] 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. While not particularly limited, the dosage forms include injection and inhalation. Liquid preparations, eye drops, eye ointments, ear drops, nasal drops, enema preparations, topical solutions, sprays, ointments, Examples include gels, oral solutions, and syrups. The dosage form is represented by general formula (1). From the perspective of advantageously utilizing the pharmacological effects of the compound, eye disease agents, specifically eye drops, eye Ointments are preferred, and eye drops are particularly preferred.

[0037] 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 Preservatives other than rate-setting agents, stabilizers, pH adjusters, and quaternary ammonium surfactants, and acid-fast agents. Condensing agent, viscosity enhancer, surfactant, solubilizer, suspending agent, cooling agent, dispersant, preservative, oily group Examples include formulations, emulsion bases, and water-soluble bases. 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, tartaric acid, hydroxy acid Sodium phosphate, polyoxyl 45 stearate, purified lanolin, D-sorbitol, sorbate Bitol solution, sorbic acid, potassium sorbate, taurine, sodium bicarbonate, sodium carbonate Thorium hydrate, sodium thiosulfate hydrate, thimerosal, tyroxapole, dehydro Sodium acetate, trometamol, concentrated glycerin, concentrated mixed tocopherols, white petroleum jelly Ingredients: peppermint water, peppermint oil, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, para Propyl oxybenzoate, methyl parahydroxybenzoate, sodium hyaluronate, human serum Albumin, hydroxyethylcellulose, hydroxypropylcellulose, hypromel Glucose, glacial acetic acid, sodium pyrosulfite, phenylethyl alcohol, glucose, propylene Glycol, bergamot oil, benzyl alcohol, borax, boric acid, povidone, poly Oxyethylene (200) polyoxypropylene glycol (70), polystyrene sulfide Sodium phosphate, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyvinyl Nyl alcohol (partially saponified), d-borneol, macrogol 4000, macrog 6000, D-mannitol, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous ri Sodium dihydrogen phosphate, methanesulfonic acid, methylcellulose, l-menthol, monoe Tanolamine, aluminum monostearate, polyethylene glycoside monostearate Ingredients: ethanol, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, lye Uno, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate Examples include thorium, sodium dihydrogen phosphate monohydrate, malic acid, and petrolatum.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] Aqueous compositions are preferably housed in containers from the viewpoint of storage stability and portability. The form of the container is not particularly limited, as long as it is capable of containing the aqueous composition, and depends on the dosage form, etc. You can then select and set it as appropriate. Specifically, examples of such container forms include, Containers for injectables, containers for inhalants, containers for sprays, bottle-shaped containers, tube-shaped containers, eye drops Examples include containers for nasal drops, ear drops, bags, etc. It may be further packaged in a box, bag, or the like.

[0042] The material of the container is not particularly limited and should be selected appropriately according to the shape of the container. Examples of such materials include glass, plastic, cellulose, pulp, rubber, and metal. From the viewpoint of processability, squeezeability, and durability, it is preferable to use plastic. The resin used for the plastic container is preferably a thermoplastic resin, such as low-density polyethylene. Teylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene Polyolefin resins such as polypropylene and cyclic polyolefins; polyethylene tereph Polybutylene terephthalate, polyethylene naphthalate, polybutylene naphth Polyesters such as talate, poly(1,4-cyclohexylenedimethyleneterenaphthalate) Tel-based resins; polyphenylene ether-based resins; polycarbonate-based resins; polysulfone-based resins Examples include resins; polyamide resins; polyvinyl chloride resins; styrene resins, etc. It may also be a mixture (polymer alloy).

[0043] The aqueous composition contains the compound represented by the general formula (1) which has excellent pharmacological effects. Therefore, it can be suitably used as a pharmaceutical product, etc. In this case, the applicable diseases are not particularly limited. The compound represented by the general formula (1) above may be appropriately selected depending on its pharmacological effects and other characteristics.

[0044] 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. 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.

[0045] <<An invention relating to a method for imparting a preservative effect>> Next, we will describe an invention relating to a "method for imparting a preservative effect."

[0046] "Method for imparting preservative effect" refers to a method for imparting a preservative effect to an aqueous composition. In the fruit impregnation method, the preservative effect is evaluated by the preservative power of the target, which is expressed by the general formula (1) above. The compound or its salt or its solvate and both quaternary ammonium-type surfactants If the effect is superior to the case where the ingredients are not included together, it is judged to be effective. The degree is irrelevant. Specifically, for example, according to the "Preservative Efficacy Test Method" in the Reference Information of the Sixteenth Revised Japanese Pharmacopoeia, (For example, Pseudomonas aeruginosa, Staphylococcus aureus) s), Escherichia coli, or fungi (for example, Candida albicans) When using s), the compound represented by the general formula (1) or its salt or so A control (prevention) that does not contain both these solvates and quaternary ammonium surfactants. You can use purified water, which is known to have no spoilage effect, as a control. If it can be confirmed that the number of viable cells is low for any one or more microbial species over any number of days, It is determined to have a preservative effect, and in this case, the imparting of a preservative effect to the aqueous composition is confirmed.

[0047] Furthermore, the meaning of other terms in the method for imparting preservative effects, the amounts of various components, etc., are explained above. This is the same as described in the Invention relating to an aqueous composition. [Examples]

[0048] 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. No. In addition, in the following examples and test examples, ripasudil 1-hydrochloride dihydrate is used in the example. For example, it can be manufactured by the method described in the International Publication No. 2006 / 057397 pamphlet. Yes, it's possible.

[0049] [Test Example 1] Confirmation of the microbial growth inhibitory activity of lipasudil To confirm whether or not ripasudil has growth inhibitory activity against microorganisms (bacteria and fungi), detailed As a bacterium, Pseudomonas aeruginosa; as a fungus, Candida albicans The following tests were conducted using ).

[0050] <Confirmation of inhibitory activity against Pseudomonas aeruginosa> Pseudomonas aeruginosa NBRC 13275 strain, soybean casein daidze Seeds were sown in a medium (Merck) and cultured at 30-35°C for 20-22 hours. After culturing, Dilute with Puton sodium chloride buffer (pH 7.0) to a concentration of 1000 CFU / mL or less, and test A suspension of the test bacteria was obtained. Dissolve 2g of ripasudil 1-hydrochloride dihydrate in 270mL of phosphate buffer (pH 7.2). Then, a sample dilution was obtained. A sample was obtained by mixing 0.5 mL of the test bacterial suspension with 50 mL of the sample diluent. A control solution was prepared by mixing 0.5 mL of the test bacterial suspension with 50 mL of phosphate buffer (pH 7.2). It was simple. After more than 30 minutes have elapsed, the cellulose mixed esters are filtered according to the membrane filtration method. Various samples are filtered using a filter (Millipore) to collect the bacterial cells on the filter. Afterward, the filter was washed with 100 mL of phosphate buffer (pH 7.2). Place the luter on soybean casein digest agar medium (Merck) and 30 The cells were incubated at ~35°C for 3 days. After culturing, the number of colonies formed was counted (the test was performed twice, and the average value was used). (This was obtained.) Also, from the number of colonies obtained, the growth inhibition rate (%) was calculated using the following formula. Ta.

[0051]

number

[0052] <Confirmation of inhibitory activity against Candida growth> Candida albicans NBRC 1594 strain was cultured in Sabouraud glucose liquid medium (Merck). Seeds were sown in ) and cultured at 20-25°C for 44-46 hours. Afterwards, peptone salt buffer (p The test bacterial suspension was obtained by diluting it to a concentration of 1000 CFU / mL or less at H7.0. Using the prepared test bacterial suspension, the same procedure as the above-mentioned test for Pseudomonas aeruginosa was performed to extract the bacterial cells. The mixture was collected on a filter. The resulting filter was placed in Sabouraud glucose agar medium (Mel). (Company K) was placed on top and incubated at 20-25°C for 5 days. After culturing, the number of colonies formed was counted (the test was performed twice, and the average value was used). (This was obtained.) Furthermore, the growth inhibition rate (%) was calculated. The results are shown in Table 1.

[0053] [Table 1]

[0054] As shown in Table 1, lipasudil promotes similar growth against both Pseudomonas aeruginosa and Candida. It was confirmed to possess inhibitory activity. 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 have antiseptic effects against bacteria and fungi. .

[0055] [Test Example 2] Confirmation of enhanced preservative effect by combining ripasudil and benzalkonium Combining ripasudil and benzalkonium provides protection against microorganisms (bacteria and fungi). To confirm whether or not the preservative effect is enhanced, Pseudomonas aeruginosa was used as the bacterium. Using Candida albicans as the fungus, the following tests were conducted. The effective concentration of benzalkonium chloride is 0.002-0.01%, and 0.00 It is known that 1% does not show sufficient bactericidal activity (published by Nanzando Co., Ltd. in 1984). (From "Eye Drops," pp. 76-83). Therefore, in this test, the amount of benzalkonium chloride was used. By using this method, it is possible to confirm whether or not there is a synergistic effect between lipasudil and benzalkonium. I acknowledged it.

[0056] <Confirmation of inhibitory activity against Pseudomonas aeruginosa> Pseudomonas aeruginosa NBRC 13275 strain, soybean casein daidze Seeds were sown on est agar medium (Merck) and incubated at 30-35°C for 18-24 hours. Subsequently, the cultured bacterial cells were suspended in 0.1% peptone salt buffer (Nippon Pharmaceutical Co., Ltd.), and per 1 mL... The bacterial cells number about 10 8 The sample was adjusted to obtain individual bacterial suspensions. To 15 mL of each preparation sample prepared by the method described below, add 0.1 mL of the test bacterial suspension. After inoculation, fill into a sterilized polypropylene eye drop container (capacity: 20 mL), and 20 The samples were stored for 14 days at ~25°C under light-shielding conditions. After storage, various formulation samples were prepared by adding lecithin / polysorbate 80 to soybean / casein. • Prepare a series of dilutions by sequentially diluting the medium 10-fold in digest medium (Nippon Pharmaceutical Co., Ltd.) and then... Following the plate pour method, lecithin polysorbate 80% added soybean casein digester. The mixture was mixed into Stokanten medium (Nippon Seiyakusha) and incubated at 30-35°C for 5 days. After culturing, the number of viable bacteria in 1 mL of each formulation sample is determined from the number of colonies formed and the dilution ratio. The result was calculated.

[0057] <Confirmation of inhibitory activity against Candida growth> Candida albicans NBRC 1594 strain was cultured in Sabouraud glucose agar medium (Mel). Seeds were sown in (Company K) and cultured at 20-25°C for 40-48 hours. Afterwards, the cultured cells were 0.1% When suspended in peptone salt buffer (Nippon Seiyaku Co., Ltd.), approximately 10 bacteria are found per 1 mL. 8 It will become one The mixture was prepared to obtain a test bacterial suspension. Using the obtained test bacterial suspension, the aforementioned Pseudomonas aeruginosa was tested. The same procedure as in the previous test was followed, and various formulation samples inoculated with the test bacterial suspension were stored. After storage, various formulation samples were prepared by adding lecithin / polysorbate 80 to soybean / casein. • Prepare a series of dilutions by sequentially diluting the medium 10-fold in digest medium (Nippon Pharmaceutical Co., Ltd.) and then... Sabouraud glucose agar medium with lecithin polysorbate 80 added, following the plate pour plate method. The mixture was mixed with (Nippon Pharmaceutical Co.) and incubated at 20-25°C for 5 days. After culturing, the number of viable bacteria in 1 mL of each formulation sample is determined from the number of colonies formed and the dilution ratio. The result was calculated.

[0058] The formulation samples include a formulation sample containing lipasudil alone, and a formulation sample containing lipasudil Two types of formulation samples containing ammonium compounds and benzalkonium were used.

[0059] <Sample formulation containing ripasudil alone> Per 100 mL: Lipasudil 1-hydrochloride dihydrate 0.4896 g (lipasudil free (0.4g as a whole), anhydrous sodium dihydrogen phosphate 0.4g, glycerin 2.13 Aqueous solution containing 6g of sodium hydroxide (pH 6.0) and sterile purified water (residue). The composition was prepared and sterilized by filter to obtain a pharmaceutical sample. <Sample formulation containing ripasudil and benzalkonium> Per 100 mL: Lipasudil 1-hydrochloride dihydrate 0.4896 g (lipasudil free (0.4g as a whole), benzalkonium chloride 0.001g (0.001w / v%) , anhydrous sodium dihydrogen phosphate 0.4g, glycerin 2.136g, sodium hydroxide Prepare an aqueous composition containing an appropriate amount (pH 6.0) and sterile purified water (residue), and fill Sterilized and prepared as a pharmaceutical sample.

[0060] The results are shown in Table 2. Note that the number of inoculi was calculated from the number of viable bacteria in the test bacterial suspension at the time of inoculation. The number of viable bacteria was converted to 1 mL.

[0061] [Table 2]

[0062] Based on the results shown in Table 2, the amount of benzalkonium salt that is considered not to exhibit sufficient bactericidal activity is... By combining the compound with lipasudil, the number of viable Pseudomonas aeruginosa bacteria was increased compared to lipasudil alone. The number of viable Candida cells decreased to less than 38,000, a reduction to 1 / 475. Based on the above test results, compounds represented by general formula (1), such as lipasudil, or The salt or solvates thereof, and quaternary ammonium type bonds represented by benzalkonium. By combining it with surfactants, the preservative effect is synergistically enhanced, and quaternary ammonia Even in amounts that would not show preservative effect on its own, the M-type surfactant exhibits excellent preservative properties. It became clear that...

[0063] [Test Example 3] Confirmation of enhanced preservative effect by combining lipasudil and benzalkonium 2 Instead of Pseudomonas aeruginosa as the bacterium, Staphylococcus aureus Except for using *Ccus aureus* (NBRC strain 13276), the same method as in Test Example 2 was used. The test was conducted. The results are shown in Table 3.

[0064] [Table 3]

[0065] Based on the results shown in Table 3, the amount of benzalkonium salt that is considered not to exhibit sufficient bactericidal activity is... By combining the compound with lipasudil, the life of Staphylococcus aureus was improved compared to lipasudil alone. The bacterial count decreased to less than 1 / 20th of its original level.

[0066] [Test Example 4] Confirmation of enhanced preservative effect by combining lipasudil and benzalkonium 3 Instead of Pseudomonas aeruginosa as a bacterium, Escherichia coli: The same method as in Test Example 2 was used, except that NBRC strain 3972 was used and the storage period was 28 days. The test was conducted accordingly. The results are shown in Table 4.

[0067] [Table 4]

[0068] Based on the results shown in Table 4, the amount of benzalkonium salt that is considered not to exhibit sufficient bactericidal activity is... By combining the compound with lipasudil, the number of viable E. coli bacteria was increased compared to lipasudil alone. It decreased to less than 1 / 140,000.

[0069] The results shown in Tables 3 and 4 indicate that the combination of ripasudil and benzalkonium is effective against Pseudomonas aeruginosa and It has been shown that the inhibitory activity against a wide range of microorganisms, not just Candida, is enhanced. It became softer. Based on the above test results, compounds represented by general formula (1), such as lipasudil, or The salt or solvates thereof, and quaternary ammonium type bonds represented by benzalkonium. By combining it with surfactants, the antiseptic effect against a wide range of microorganisms is enhanced. It became clear that this was recognized.

[0070] [Manufacturing Examples 1-27] The following ingredients and quantities (amount per 100 mL of aqueous composition (g)) are included in Tables 5 to 7. The eye drops can be manufactured by conventional methods.

[0071] [Table 5]

[0072] [Table 6]

[0073] [Table 7]

[0074] [Manufacturing Examples 28-54] In production examples 1-27, the same amount of benzethonium salt was used instead of benzalkonium chloride. Products using the compound can be manufactured by conventional methods as eye drops as shown in manufacturing examples 28-54.

[0075] [Manufacturing Examples 55-108] In manufacturing examples 1-54, the same amount of 4-bromo- was used instead of lipasudil 1-hydrochloride dihydrate. 5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoli Products using this ingredient can be manufactured by conventional methods as eye drops, as shown in manufacturing examples 55-108. [Industrial applicability]

[0076] According to the present invention, the present invention contains a compound represented by the general formula (1) having excellent pharmacological effects. Furthermore, it can provide an aqueous composition with excellent preservative effect and good storage stability, suitable for the pharmaceutical industry and other industries. It can be used in a suitable manner.

Claims

[Claim 1] The invention described in the specification.

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