Pharmaceutical preparation including pyridylamino acetic acid compound

Abstract

To discover which compounds among the vast number of pyridylamino acetic acid compounds exhibit a markedly superior intraocular pressure-lowering action and can serve as an intraocular pressure-lowering agent or as a therapeutic or prophylactic agent against glaucoma or ocular hypertension, and to discover a manner of administration and / or dosage at which the discovered compounds will provide an effective therapeutic or prophylactic effect when administered to patients (primarily humans).SOLUTION: Provided is a pharmaceutical preparation for lowering intraocular pressure or for preventing or treating glaucoma or ocular hypertension, the pharmaceutical preparation containing 0.0003-0.01% (w / v) of (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino) isopropyl acetate or a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical preparation containing isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof. [Background technology]

[0002] Isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate is represented by the following formula (1): [ka] and is described in Patent Document 1 as one of a vast number of pyridylaminoacetic acid compounds. Furthermore, since these numerous pyridylaminoacetic acid compounds have EP2 agonist activity (Patent Document 2), they are expected to have an intraocular pressure-reducing effect, suggesting their potential as therapeutic agents for glaucoma (Patent Document 1). The entire disclosures of Patent Documents 1 and 2 are incorporated herein by reference.

[0003] However, there is no specific description as to which of the vast number of pyridylaminoacetic acid compounds has a particularly excellent intraocular pressure-reducing effect and can be used as a therapeutic or preventive agent for glaucoma, and there is no description at all as to how the content of these compounds affects the intraocular pressure-reducing effect. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] US Patent Application Publication No. 2012 / 0190852 [Patent Document 2] US Patent Application Publication No. 2011 / 0054172 Summary of the Invention

[0005] The object of the present invention is to find, from among the vast number of pyridylaminoacetic acid compounds, which compounds have particularly excellent intraocular pressure-reducing effects and can be used as therapeutic or preventive agents for glaucoma or ocular hypertension, or as intraocular pressure-reducing agents, and to find in what dosage and / or administration method the discovered compounds can be administered to patients (mainly humans) in order to obtain effective therapeutic or preventive effects.

[0006] As a result of intensive research to solve the above-mentioned problems, the present inventors have found that (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof (hereinafter also referred to as "the compound") has a particularly excellent intraocular pressure-reducing effect and can be used as a therapeutic or preventive agent for glaucoma or ocular hypertension, or as an intraocular pressure-reducing agent. Furthermore, the present inventors have found that a relatively low content of the compound exhibits a more excellent intraocular pressure-reducing effect than a high content of the compound. Furthermore, they have surprisingly found that a compound containing 0.001 to 0.01% (w / v), particularly 0.001 to 0.003% (w / v), when administered as one or two drops once or twice daily to humans, exhibits a particularly excellent intraocular pressure-reducing effect, and that use in such a manner and / or dosage provides effective therapeutic or preventive effects, thereby completing the present invention. Here, "% (w / v)" refers to the mass (g) of the active ingredient (here, the present compound) and additives (surfactants, etc.) contained in 100 mL of the ophthalmic solution. For example, 0.01% (w / v) of the present compound means that the content of the present compound in 100 mL of the ophthalmic solution is 0.01 g. That is, the present invention may relate to the following.

[0007] (1) A pharmaceutical preparation for treating or preventing glaucoma or ocular hypertension, comprising 0.001 to 0.01% (w / v) of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof. (2) The pharmaceutical formulation according to (1), comprising 0.001 to 0.003% (w / v) of (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof. (3) The pharmaceutical formulation according to (1), comprising 0.0011 to 0.0030% (w / v) of (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof. (4) The pharmaceutical formulation according to (1), comprising 0.0011 to 0.0029% (w / v) of (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof. (5) The pharmaceutical formulation according to (1), comprising 0.0013 to 0.0027% (w / v) of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof. (6) The pharmaceutical formulation according to (1), comprising 0.0015 to 0.0025% (w / v) of (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof. (7) Isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or its salt at 0.0010% (w / v), 0.0011% (w / v), 0.0012% (w / v), 0.0013% (w / v), 0.0014% (w / v), 0.0015% (w / v), 0.0016% (w / v), 0.0017% (w / v), 0.0 0.018% (w / v), 0.0019% (w / v), 0.0020% (w / v), 0.0021% (w / v), 0.0022% (w / v), 0.0023% (w / v), 0.0024% (w / v), 0.0025% (w / v), 0.0026% (w / v), 0.0027% (w / v), 0.0028% (w / v), 0.0029% (w / v), or 0.0030% (w / v). (1) The pharmaceutical formulation according to claim 1, (8) (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or its salt at 0.0011% (w / v), 0.0012% (w / v), 0.0013% (w / v), 0.0014% (w / v), 0.0015% (w / v), 0.0016% (w / v), 0.0017% (w / v), and 0.0018% (w / v) 0.0026%(w / v), 0.0027%(w / v), 0.0028%(w / v), 0.0029%(w / v), or 0.0030%(w / v). (9) Isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or its salt at 0.0011% (w / v), 0.0012% (w / v), 0.0013% (w / v), 0.0014% (w / v), 0.0015% (w / v), 0.0016% (w / v), 0.0017% (w / v), 0.0 0.018% (w / v), 0.0019% (w / v), 0.0020% (w / v), 0.0021% (w / v), 0.0022% (w / v), 0.0023% (w / v), 0.0024% (w / v), 0.0025% (w / v), 0.0026% (w / v), 0.0027% (w / v), 0.0028% (w / v), or 0.0029% (w / v). (10) The pharmaceutical preparation according to any one of (1) to (9), which is in the form of eye drops. (11) The pharmaceutical preparation according to any one of (1) to (10), which is for human use. (12) The pharmaceutical preparation according to any one of (1) to (11), which is administered by instillation into the eyes once or twice a day. (13) The pharmaceutical preparation according to any one of (1) to (12), characterized in that it is administered by instillation in the form of one or two drops at a time. (14) The pharmaceutical preparation according to any one of (1) to (13), which is administered by instillation into the eye once a day. (15) The pharmaceutical preparation according to any one of (1) to (14), wherein the pharmaceutical preparation is administered by instillation into the eye, one drop at a time. (16) A method for treating or preventing glaucoma or ocular hypertension, comprising administering the pharmaceutical preparation according to any one of (1) to (11) to a patient in need of such treatment or prevention. (17) The method according to (16), wherein the administration is by eye drop administration. (18) The method for treating or preventing glaucoma or ocular hypertension according to (16) or (17), characterized in that the method is administered by instillation into the eyes once or twice a day. (19) The method for treating or preventing glaucoma or ocular hypertension according to (16) or (17), characterized in that one or two drops are administered as eye drops at a time. (20) The method for treating or preventing glaucoma or ocular hypertension according to (16) or (17), characterized in that the method comprises administering one drop of the compound to the eye once a day.

[0008] The present invention provides a pharmaceutical preparation for treating or preventing glaucoma or ocular hypertension, or for reducing intraocular pressure, which has an excellent intraocular pressure-reducing effect in patients, particularly humans, by administering the compound at the doses described in (1) to (15) above and / or according to the dosage regimen. The present invention also provides a method for treating or preventing glaucoma or ocular hypertension, and a method for reducing intraocular pressure, using the pharmaceutical preparation. The present invention further provides a method of using the present compounds for the manufacture of pharmaceutical preparations for treating or preventing glaucoma or ocular hypertension, or for reducing intraocular pressure. DETAILED DESCRIPTION OF THE INVENTION

[0009] Hereinafter, embodiments of the present invention will be described in detail. The isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof contained in the agent for treating or preventing glaucoma or ocular hypertension, or the agent for reducing intraocular pressure (hereinafter collectively referred to as "medicament") of the present invention can be produced according to the method described in the specification of U.S. Patent Application Publication No. 2012 / 0190852 (Patent Publication 1), a conventional method in the technical field, or the like.

[0010] The salt of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate contained in the agent of the present invention is not particularly limited as long as it is a pharmacologically acceptable salt. Specific examples include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, and phosphate; and organic acid salts such as acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, and aspartate, and preferably includes hydrochloride or trifluoroacetate.

[0011] The content of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof contained in the agent of the present invention is not particularly limited as long as it is within the range of 0.001 to 0.01% (w / v). Specifically, the lower limit is preferably 0.001% (w / v), more preferably 0.0011% (w / v), even more preferably 0.0013% (w / v), and particularly preferably 0.0015% (w / v). The upper limit is preferably 0.01% (w / v), more preferably 0.005% (w / v), even more preferably 0.003% (w / v), even more preferably 0.0029% (w / v), particularly preferably 0.0027% (w / v), and most preferably 0.0025% (w / v). More specifically, the content is preferably 0.001 to 0.005% (w / v), more preferably 0.001 to 0.003% (w / v), even more preferably 0.0011 to 0.0030% (w / v), particularly preferably 0.0011 to 0.0029% (w / v), particularly preferably 0.0013 to 0.0027% (w / v), and most preferably 0.0015 to 0.0025% (w / v). More specifically, 0.0010% (w / v), 0.0011% (w / v), 0.0012% (w / v), 0.0013% (w / v), 0.0014% (w / v), 0.0015% (w / v), 0.0016% (w / v), 0.0017% (w / v), 0.0018% (w / v), 0.0019% (w / v), 0.0020% (w / v), 0.0 021%(w / v), 0.0022%(w / v), 0.0023%(w / v), 0.0024%(w / v), 0.0025%(w / v), 0.0026%(w / v), 0. 0027% (w / v), 0.0028% (w / v), 0.0029% (w / v), 0.0030% (w / v), 0.005% (w / v), and 0.01% (w / v) are preferred.

[0012] In addition, when a salt of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate is contained, this means that the content of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate when the salt is released falls within the above-mentioned range.

[0013] The pharmaceutical preparation of the present invention may contain additives, such as surfactants, buffers, isotonicity agents, stabilizers, preservatives, antioxidants, and high molecular weight polymers, if necessary. The agent of the present invention may be appropriately blended with a surfactant that can be used as an additive in pharmaceuticals. Examples of surfactants include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, vitamin E TPGS, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and the like. More specifically, various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used as the polyoxyethylene castor oil, and the polymerization number of ethylene oxide is preferably 5 to 100, more preferably 20 to 50, particularly preferably 30 to 40, and most preferably 35. Specific examples of polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil, with polyoxyl 35 castor oil being the most preferred.

[0014] As the polyoxyethylene hydrogenated castor oil, various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, particularly preferably 40 to 70, and most preferably 60. Specific examples of polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60, with polyoxyethylene hydrogenated castor oil 60 being the most preferred.

[0015] Examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65, and the like, with polysorbate 80 being the most preferred. Vitamin E TPGS is also known as tocopherol polyethylene glycol 1000 succinate.

[0016] Examples of polyoxyethylene fatty acid esters include polyoxyl 40 stearate. Examples of polyoxyethylene polyoxypropylene glycols include polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol. Examples of sucrose fatty acid esters include sucrose stearate.

[0017] When a surfactant is incorporated into the pharmaceutical preparation of the present invention, its content can be adjusted appropriately depending on the type of surfactant, etc. Specifically, the lower limit is preferably 0.001% (w / v), more preferably 0.01% (w / v), even more preferably 0.1% (w / v), particularly preferably 0.5% (w / v), and most preferably 0.8% (w / v). The upper limit is preferably 10% (w / v), more preferably 5% (w / v), even more preferably 4% (w / v), particularly preferably 3% (w / v), and most preferably 2% (w / v). More specifically, the content is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.1 to 4% (w / v), particularly preferably 0.5 to 3% (w / v), and most preferably 0.8 to 2% (w / v).

[0018] The agent of the present invention may be appropriately blended with a buffering agent that can be used as an additive in pharmaceuticals. Examples of buffering agents include phosphoric acid or a salt thereof, boric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol, etc. More specifically, phosphates include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc.; borates include borax, sodium borate, potassium borate, etc.; citrates include sodium citrate, disodium citrate, trisodium citrate, etc.; acetates include sodium acetate, potassium acetate, etc.; carbonates include sodium carbonate, sodium bicarbonate, etc.; and tartrates include sodium tartrate, potassium tartrate, etc. Among these, boric acid or a salt thereof, or citric acid or a salt thereof, is preferred.

[0019] When a buffering agent is incorporated into the pharmaceutical agent of the present invention, the content can be adjusted as appropriate depending on the type of buffering agent, etc., but is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.1 to 3% (w / v), and most preferably 0.2 to 2% (w / v).

[0020] The drug of the present invention may be appropriately blended with an isotonicity agent that can be used as an additive in pharmaceuticals. Examples of the tonicity adjusting agent include ionic tonicity adjusting agents and non-ionic tonicity adjusting agents. Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., and examples of non-ionic tonicity agents include glycerin, propylene glycol, sorbitol, mannitol, etc. When an isotonicity agent is incorporated into the drug of the present invention, the content thereof can be adjusted appropriately depending on the type of isotonicity agent, etc., but is preferably 0.01 to 10% (w / v), more preferably 0.02 to 7% (w / v), even more preferably 0.1 to 5% (w / v), particularly preferably 0.5 to 4% (w / v), and most preferably 0.8 to 3% (w / v).

[0021] The agent of the present invention may be appropriately blended with a stabilizer that can be used as an additive in pharmaceuticals. Examples of stabilizers include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, and sodium citrate, with disodium edetate being particularly preferred. Sodium edetate may be a hydrate. When a stabilizer is incorporated into the pharmaceutical preparation of the present invention, its content can be adjusted appropriately depending on the type of stabilizer, but is preferably 0.001 to 1% (w / v), more preferably 0.005 to 0.5% (w / v), and most preferably 0.01 to 0.1% (w / v).

[0022] The agent of the present invention may be appropriately blended with a preservative that can be used as an additive in pharmaceuticals. Examples of preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, etc. When a preservative is incorporated into the drug of the present invention, the content can be adjusted appropriately depending on the type of preservative, etc., but is preferably 0.0001 to 1% (w / v), more preferably 0.0005 to 0.1% (w / v), even more preferably 0.001 to 0.05% (w / v), and most preferably 0.005 to 0.010% (w / v).

[0023] The agent of the present invention may be appropriately blended with an antioxidant that can be used as an additive in pharmaceuticals. Examples of antioxidants include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite, etc. When an antioxidant is incorporated into the agent of the present invention, the content can be adjusted appropriately depending on the type of antioxidant, etc., but is preferably 0.0001 to 1% (w / v), more preferably 0.0005 to 0.1% (w / v), and most preferably 0.001 to 0.05% (w / v).

[0024] The drug of the present invention may be appropriately blended with a high molecular weight polymer that can be used as an additive in pharmaceuticals. Examples of high molecular weight polymers include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymers, polyethylene glycol, and the like. When a high molecular weight polymer is incorporated into the drug of the present invention, its content can be adjusted appropriately depending on the type of high molecular weight polymer, etc., but is preferably 0.001 to 5% (w / v), more preferably 0.01 to 1% (w / v), and most preferably 0.1 to 0.5% (w / v). The pH of the agent of the present invention is preferably 4.0 to 8.0, more preferably 4.5 to 7.5, particularly preferably 5.0 to 7.0, and most preferably 5.5 to 6.5. To adjust the pH, a pH adjuster such as hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, or potassium hydroxide may be added to the agent of the present invention.

[0025] The drug of the present invention can be stored in a container made of various materials, such as polyethylene or polypropylene, and is preferably stored in a polyethylene container from the viewpoints of ease of administration (hardness of the container) and stability of the compound. The dosage form of the drug of the present invention is not particularly limited as long as it can be used as a pharmaceutical. Specific examples include eye drops, ophthalmic injections, eye ointments, etc., with eye drops being particularly preferred. These drug dosage forms can be produced according to conventional methods in the art. Furthermore, when the drug of the present invention is a liquid, the solvent or dispersion medium is preferably water.

[0026] In one embodiment, the pharmaceutical agent of the present invention does not contain any other therapeutic agent for glaucoma and is not used in combination with any other therapeutic agent for glaucoma.

[0027] The pharmaceutical agent of the present invention may contain one or more, preferably one to three, more preferably one or two other glaucoma or ocular hypertension therapeutic agents or ocular pressure-reducing agents. The other glaucoma therapeutic agents are not particularly limited. Specifically, commercially available or under development glaucoma therapeutic agents are preferred, commercially available glaucoma therapeutic agents are more preferred, and commercially available glaucoma therapeutic agents having a different mechanism of action from the present compound are particularly preferred. More specific examples include non-selective sympathomimetics, α2 receptor agonists, α1 receptor blockers, β-receptor blockers, parasympathomimetics, carbonic anhydrase inhibitors, prostaglandins, Rho kinase inhibitors, etc. A specific example of a non-selective sympathomimetic agent is dipivefrin, specific examples of α2 receptor agonists include brimonidine and apraclonidine, a specific example of an α1 receptor blocker is bunazosin, specific examples of β receptor blockers include timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, and metipranolol, a specific example of a parasympathomimetic agent is pilocarpine, specific examples of carbonic anhydrase inhibitors include dorzolamide, brinzolamide, and acetazolamide, specific examples of prostaglandins include latanoprost, isopropyl unoprostone, bimatoprost, and travoprost, and a specific example of a Rho kinase inhibitor is ripasudil.

[0028] The method of administration of the drug of the present invention is not particularly limited as long as it is sufficient to achieve the desired efficacy, and can be appropriately selected depending on the symptoms of the disease, the age and weight of the patient, the dosage form of the drug, etc. Specifically, 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and particularly preferably 1 drop can be administered by instillation 1 to 4 times a day, preferably 1 to 3 times a day, more preferably 1 to 2 times a day, and particularly preferably once a day, every day to once a week. It is preferable to administer 1 drop once a day every day. Here, 1 drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, more preferably about 0.02 to about 0.05 mL, and particularly preferably about 0.03 mL. The drug of the present invention means a therapeutic or preventive agent, and more specifically means a therapeutic or preventive agent for glaucoma, a therapeutic or preventive agent for ocular hypertension, or an agent for reducing intraocular pressure. Examples of glaucoma in the present invention include primary open-angle glaucoma, secondary open-angle glaucoma, normal-tension glaucoma, hyperaqueous humor production glaucoma, primary angle-closure glaucoma, secondary angle-closure glaucoma, plateau iris glaucoma, mixed glaucoma, developmental glaucoma, steroid-induced glaucoma, exfoliation glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, lenticular capsular glaucoma, plateau iris syndrome, and the like, preferably primary open-angle glaucoma, normal-tension glaucoma, and primary angle-closure glaucoma, and the pharmaceutical preparation of the present invention is particularly effective for primary open-angle glaucoma. [Example]

[0029] Formulation examples and clinical trial results are shown below, but these are intended to aid in a better understanding of the present invention and are not intended to limit the scope of the present invention. Formulation example Representative formulation examples of the drug of the present invention are shown below. In the formulation examples below, the amount of each ingredient is the content in 100 mL of the formulation. Furthermore, Compound A means isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate.

[0030] [Formulation Example 1] Eye drops (in 100 mL) Compound A 0.002g Boric acid 0.2g Glycerin 2.0g Polysorbate 80 0.5g Disodium edetate 0.05g Benzalkonium chloride 0.005g Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount)

[0031] [Formulation Example 2] Eye drops (in 100 mL) Compound A 0.002g Sodium dihydrogen phosphate 0.2g Glycerin 2.0g Vitamin E TPGS 0.8g Disodium edetate 0.05g Benzalkonium chloride 0.005g Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount)

[0032] [Formulation Example 3] Eye drops (in 100 mL) Compound A 0.002g Trisodium citrate 0.2g Glycerin 2.0g Polyoxyethylene hydrogenated castor oil 60 0.3g Disodium edetate 0.05g Benzalkonium chloride 0.005g Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount)

[0033] In the above Preparation Examples 1 to 3, the desired drug can be obtained by appropriately adjusting the type and / or amount of the present compound A and / or additives.

[0034] 1. Clinical Trials (1) 1-1. Manufacture of eye drops Eye drops 1 and 2 and a placebo eye drop shown in Table 1 were prepared.

[0035] [Table 1]

[0036] 1-2. Test method Patients with primary open-angle glaucoma (26 humans) or ocular hypertension (18 humans) were administered one drop (approximately 0.03 ml) of eye drops 1, 2, or a placebo eye drop once a day in both eyes for four weeks.

[0037] 1-3. Test results and discussion The mean change in intraocular pressure (mmHg) from baseline for eye drops 1 and 2 16 hours after the final instillation was calculated as the difference from the mean change in intraocular pressure for placebo eye drops. The results are shown in Table 2.

[0038] [Table 2]

[0039] As is clear from Table 2, both Eye Drops 1 (0.003%) and Eye Drops 2 (0.01%) exhibited an intraocular pressure-reducing effect, but a more excellent intraocular pressure-reducing effect was observed when the content of Compound A was 0.003% (w / v). Contrary to the expectation of a person skilled in the art, a significantly lower content of Compound A exhibited a more excellent intraocular pressure-reducing effect.

[0040] 2. Clinical Trials (2) 2-1. Manufacturing of eye drops Eye drops 3 to 6 and a placebo eye drop were prepared as shown in Table 3. However, eye drops 3 contains Compound A at 0.0003% (w / v), and is therefore a reference example of the present invention.

[0041] [Table 3]

[0042] 2-2. Test method Patients with primary open-angle glaucoma (37 humans) or ocular hypertension (39 humans) were administered one drop (approximately 0.03 ml) of eye drops 3 to 6 or a placebo eye drop once daily in both eyes for four weeks.

[0043] 2-3. Test results and discussion The mean change in intraocular pressure (mmHg) from before the start of instillation (baseline) for eye drops 3 to 6 16 hours after the final instillation was calculated as the difference from the mean change in intraocular pressure for the placebo eye drops. The results are shown in Table 4.

[0044] [Table 4]

[0045] As is clear from Table 4, all of eye drops 4 to 6 showed a higher intraocular pressure-reducing effect than eye drops 3. Therefore, when the content of compound A was 0.001 to 0.003% (w / v), as in eye drops 4 to 6, they showed a particularly excellent intraocular pressure-reducing effect. In addition, in terms of side effects, they were fully acceptable as pharmaceuticals.

Claims

1. A pharmaceutical preparation for treating or preventing glaucoma or ocular hypertension, comprising 0.0011 to 0.0029% (w / v) of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof, and containing other therapeutic agents for glaucoma.

2. 2. The pharmaceutical formulation according to claim 1, comprising 0.0013 to 0.0027% (w / v) of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof.

3. 2. The pharmaceutical formulation according to claim 1, comprising 0.0015 to 0.0025% (w / v) of isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof.

4. Isopropyl (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate or a salt thereof was added at 0.0011% (w / v), 0.0012% (w / v), 0.0013% (w / v), 0.0014% (w / v), 0.0015% (w / v), 0.0016% (w / v), 0.0017% (w / v), or 0.0 2. The pharmaceutical formulation of claim 1, comprising 0.018% (w / v), 0.0019% (w / v), 0.0020% (w / v), 0.0021% (w / v), 0.0022% (w / v), 0.0023% (w / v), 0.0024% (w / v), 0.0025% (w / v), 0.0026% (w / v), 0.0027% (w / v), 0.0028% (w / v) or 0.0029% (w / v).

5. 2. The pharmaceutical formulation according to claim 1, comprising 0.002% (w / v) of (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)isopropyl acetate or a salt thereof.

6. The pharmaceutical formulation according to any one of claims 1 to 5, wherein the other therapeutic agent for glaucoma is a non-selective sympathomimetic agent, an α2 receptor agonist, an α1 receptor blocker, a β-receptor blocker, a parasympathomimetic agent, a carbonic anhydrase inhibitor, a prostaglandin, or a Rho kinase inhibitor.

7. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the other antiglaucoma drug is dipivefrin, brimonidine, apraclonidine, bunazosin, timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, metipranolol, pilocarpine, dorzolamide, brinzolamide, acetazolamide, latanoprost, isopropyl unoprostone, bimatoprost, travoprost, or ripasudil.

8. The pharmaceutical preparation according to any one of claims 1 to 7, which is in the form of eye drops.

9. 9. The pharmaceutical preparation according to any one of claims 1 to 8, which is administered by instillation into the eyes once or twice a day.

10. The pharmaceutical preparation according to any one of claims 1 to 9, which is administered by instillation into the eye in a dose of 1 or 2 drops at a time.

11. The pharmaceutical preparation according to any one of claims 1 to 10, wherein the preparation is administered by instillation into the eye at a dose of one drop once a day.

12. A method for treating or preventing glaucoma or ocular hypertension, comprising administering the pharmaceutical preparation according to any one of claims 1 to 11 by instillation once or twice a day.

13. A method for treating or preventing glaucoma or ocular hypertension, comprising administering one or two drops of the pharmaceutical preparation according to any one of claims 1 to 11 to the eyes at a time.

14. A method for treating or preventing glaucoma or ocular hypertension, comprising administering one drop of the pharmaceutical preparation according to any one of claims 1 to 11 to the eye once a day.

15. Use of the pharmaceutical formulation according to any one of claims 1 to 11 in the manufacture of a medicament for treating or preventing glaucoma or ocular hypertension.

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