Omidenepag combination

Abstract

To provide a combination of a prophylactic or therapeutic agent for glaucoma or ocular hypertension, which is useful as a prophylactic or therapeutic agent for glaucoma or ocular hypertension.SOLUTION: The present invention provides a combination drug comprising omidenepag or an ester thereof or a salt thereof, and one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil and a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a preventive or therapeutic agent for glaucoma or ocular hypertension, which comprises administering omidenepag, an ester thereof, or a salt thereof in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil, and salts thereof.The present invention also relates to a preventive or therapeutic agent for glaucoma or ocular hypertension, which comprises omidenepag, an ester thereof, or a salt thereof in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil, and salts thereof. [Background technology]

[0002] Glaucoma is an intractable eye disease that can lead to blindness due to increased intraocular pressure caused by various factors, which damages the internal tissues of the eye (retina, optic nerve, etc.). Treatment for glaucoma is generally aimed at lowering intraocular pressure, and representative examples include drug therapy, laser therapy, and surgery.

[0003] Drug therapy includes drugs such as sympathomimetics (non-selective stimulants such as dipivefrin, alpha-2 receptor agonists such as brimonidine), sympatholytics (beta-receptor blockers such as timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, and metipranolol, and alpha-1 receptor blockers such as bunazosin hydrochloride), parasympathomimetics (pilocarpine, etc.), carbonic anhydrase inhibitors (acetazolamide, etc.), prostaglandins (isopropyl unoprostone, latanoprost, travoprost, and bimatoprost, etc.), and Rho-kinase inhibitors (ripasudil).

[0004] In addition, several reports have been made on the use of combinations of drugs with intraocular pressure-lowering effects to achieve a more potent intraocular pressure-lowering effect. For example, Japanese Patent Publication No. 2726672 (Patent Document 2) reports the administration of a combination of a sympatholytic drug and a prostaglandin. International Publication No. 2002 / 38158 (Patent Document 3) discloses a method for treating glaucoma by administering a combination of several drugs with intraocular pressure-lowering effects to the eye. International Publication No. 2004 / 019951 (Patent Document 4) reports the administration of a combination of a Rho kinase inhibitor and a prostaglandin, and International Publication No. 2004 / 045644 (Patent Document 5) reports the administration of a combination of a Rho kinase inhibitor and a β-receptor blocker. Furthermore, combinations of dorzolamide and timolol, latanoprost and timolol, and brimonidine and timolol are commercially available (Non-Patent Document 1).

[0005] Incidentally, Omidenepag is a compound described as one of a vast number of pyridylaminoacetic acid compounds in Patent Documents 6 and 7. It is described that these pyridylaminoacetic acid compounds have EP2 agonist activity, and therefore are expected to have an intraocular pressure-reducing effect, and may serve as therapeutic agents for glaucoma. Furthermore, Patent Document 8 describes that omidenepag exhibits a particularly excellent intraocular pressure-reducing effect when it is present at a specific content, and Patent Document 9 describes that omidenepag is useful as a therapeutic agent for diseases accompanied by highly elevated intraocular pressure. Furthermore, Patent Documents 10 to 12 describe specific preparations containing omidenepag as an active ingredient.

[0006] Patent Documents 13 and 14 describe that the intraocular pressure-lowering effect of omidenepag can be enhanced by combining it with other glaucoma treatment drugs such as timolol, and also describe the combination of omidenepag with a Rho kinase inhibitor. However, there is no specific description of ripasudil or netarsudil as Rho kinase inhibitors, and there is no description at all of the effects that would be shown when omidenepag is used in combination with ripasudil or netarsudil. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2010 / 113957 [Patent Document 2] Patent No. 2726672 [Patent Document 3] International Publication No. 2002 / 38158 [Patent Document 4] International Publication No. 2004 / 019951 [Patent Document 5] International Publication No. 2004 / 045644 [Patent Document 6] US Patent Application Publication No. 2012 / 0190852 [Patent Document 7] US Patent Application Publication No. 2011 / 0054172 [Patent Document 8] US Patent Application Publication No. 2015 / 0196541 [Patent Document 9] International Publication No. 2017 / 006985 Brochure [Patent Document 10] US Patent Application Publication No. 2016 / 0317512 [Patent Document 11] US Patent Application Publication No. 2016 / 0317664 [Patent Document 12] International Publication No. 2017 / 002941 Brochure [Patent Document 13] US Patent Application Publication No. 2014 / 0018396 [Patent Document 14] US Patent Application Publication No. 2014 / 0018350 [Non-patent literature]

[0008] [Non-Patent Document 1] Clinical Ophthalmology,2010,4,1-9 Summary of the Invention [Problem to be solved by the invention]

[0009] It is a very interesting task to find a novel combination of agents for preventing or treating glaucoma or ocular hypertension that is useful as an agent for preventing or treating glaucoma or ocular hypertension. [Means for solving the problem]

[0010] As a result of extensive research into the effects of combining omidenepag with other preventive or therapeutic agents for glaucoma or ocular hypertension, the inventors have found that combining omidenepag with ripasudil or netarsudil enhances the intraocular pressure-lowering effect compared to when each drug is used alone, and have thus completed the present invention.

[0011] That is, the present invention relates to the following.

[0012] (1) A preventive or therapeutic agent for glaucoma or ocular hypertension, characterized by administering omidenepag or its ester, or a salt thereof in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (2) The preventive or therapeutic agent according to (1), which is a combination drug containing omidenepag or its ester or a salt thereof and one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil and salts thereof. (3) The preventive or therapeutic agent according to (1), wherein Omidenepag or its ester or a salt thereof and one or more Rho kinase inhibitors selected from the group consisting of Ripasudil, Netarsudil and salts thereof are administered at different times or simultaneously. (4) A preventive or therapeutic agent for glaucoma or ocular hypertension containing omidenepag or its ester, or a salt thereof, characterized in that it is used in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (5) The preventive or therapeutic agent according to (4) above, which is administered at a different time from or simultaneously with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (6) The preventive or therapeutic agent according to any one of (1) to (5) above, wherein the omidenepag or an ester thereof, or a salt thereof is omidenepag isopropyl. (7) The preventive or therapeutic agent according to any one of (1) to (6) above, wherein the Rho kinase inhibitor is ripasudil monohydrochloride dihydrate. (8) The preventive or therapeutic agent according to any one of (1) to (6) above, wherein the Rho kinase inhibitor is Netarsudil dimesylate or dihydrochloride.

[0013] The present invention also relates to the following:

[0014] (9) An intraocular pressure-reducing agent characterized by combining omidenepag or an ester thereof, or a salt thereof with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (10) An intraocular pressure-reducing agent containing omidenepag or an ester thereof, or a salt thereof, characterized in that it is used in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof.

[0015] Furthermore, the present invention also relates to the following:

[0016] (11) A composition for the prevention or treatment of glaucoma or ocular hypertension, comprising omidenepag or an ester thereof, or a salt thereof, which is administered in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (12) A method for preventing or treating glaucoma or ocular hypertension, comprising administering to a subject in need thereof a therapeutically effective amount of omidenepag or an ester thereof, or a salt thereof, and a therapeutically effective amount of one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (13) Use of a combination of omidenepag or an ester thereof, or a salt thereof with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof, for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension. (14) Use of omidenepag or an ester thereof, or a salt thereof for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension, characterized by being used in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (15) Omidenepag or an ester thereof, or a salt thereof for use in the prevention or treatment of glaucoma or ocular hypertension, characterized by being used in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (16) A combination of omidenepag or an ester thereof, or a salt thereof with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof for use in the prevention or treatment of glaucoma or ocular hypertension.

[0017] Furthermore, the present invention also relates to the following:

[0018] (17) A composition for reducing intraocular pressure containing omidenepag or an ester thereof, or a salt thereof, which is administered in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (18) A method for lowering intraocular pressure, comprising administering a therapeutically effective amount of omidenepag or an ester thereof, or a salt thereof, and a therapeutically effective amount of one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof, to a subject in need thereof. (19) Use of a combination of omidenepag or an ester thereof, or a salt thereof with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof for the manufacture of a medicament for reducing intraocular pressure. (20) Use of omidenepag or an ester thereof, or a salt thereof for the manufacture of a medicament for reducing intraocular pressure, characterized by being used in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (21) Omidenepag or an ester thereof, or a salt thereof for use in reducing intraocular pressure, characterized by being used in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof. (22) A combination of omidenepag or an ester thereof, or a salt thereof with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof for use in reducing intraocular pressure.

[0019] It should be noted that any two or more of the above configurations (1) to (22) can be selected and combined. [Effects of the Invention]

[0020] By administering a combination of Omidenepag and Ripasudil or Netarsudil to the eye, the intraocular pressure-lowering effect is enhanced. Therefore, the present invention is useful as a preventive or therapeutic agent for glaucoma or ocular hypertension. Furthermore, according to the present invention, sufficient safety as a pharmaceutical is ensured. [Brief explanation of the drawings]

[0021] [Figure 1]1 is a graph showing the change in the degree of reduction in intraocular pressure over time in each group administered with omidenepag isopropyl and ripasudil alone and in combination. [Figure 2] 1 is a graph showing the change in the degree of reduction in intraocular pressure over time in each administration group of Omidenepag Isopropyl and Netarsudil alone and in combination. DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention will be described in detail below.

[0023] The present invention relates to a preventive or therapeutic agent for glaucoma or ocular hypertension, characterized in that it comprises omidenepag, an ester thereof, or a salt thereof, administered in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof, and hereinafter these are also simply referred to as "therapeutic agents, etc."

[0024] In the therapeutic agent etc. of the present invention, omidenepag is a compound represented by the following formula (1): [ka] The compound (CAS Registry Number: 1187451-41-7) is also known as (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid.

[0025] In the therapeutic agent etc. of the present invention, the ester of omidenepag is preferably an ester formed by dehydration condensation of the carboxyl group of omidenepag with a monohydric alcohol having 1 to 6 carbon atoms, more preferably an ester formed by dehydration condensation of the carboxyl group of omidenepag with a monohydric alcohol having 2 to 5 carbon atoms, even more preferably a monohydric alcohol having 3 to 4 carbon atoms. Specific examples of the ester include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, n-pentyl ester, and n-hexyl ester, preferably ethyl ester, n-propyl ester, and isopropyl ester, more preferably isopropyl ester. Specific examples of the isopropyl ester of omidenepag include the following formula (2): [ka] The compound (CAS Registry Number: 1187451-19-9) is also known as omidenepag isopropyl or (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino) isopropyl acetate. It has EP2 agonist activity and reduces intraocular pressure, so it is being developed as a treatment for glaucoma and ocular hypertension.

[0026] In the therapeutic agent etc. of the present invention, the salt of omidenepag or the salt of an ester of omidenepag 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; organic acid salts such as acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, and aspartate; metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt; inorganic salts such as ammonium salt; and organic amine salts such as triethylamine salt and guanidine salt, preferably hydrochloride or trifluoroacetate.

[0027] In the therapeutic agent etc. of the present invention, omidenepag or an ester thereof, or a salt thereof can be produced according to the methods described in U.S. Patent Application Publication No. 2012 / 0190852 (Patent Document 6), U.S. Patent Application Publication No. 2011 / 0054172 (Patent Document 7), U.S. Patent Application Publication No. 2017 / 0121288, U.S. Patent Application Publication No. 2017 / 0114043, a conventional method in the technical field, etc. As used herein, the term "omidenepag or an ester thereof, or a salt thereof" includes (1) omidenepag, (2) an ester of omidenepag, (3) a salt of omidenepag, and (4) a salt of an ester of omidenepag.

[0028] When omidenepag or an ester thereof or a salt thereof has geometric isomers and / or optical isomers, these isomers are also included within the scope of the present invention.

[0029] When proton tautomerism exists in omidenepag or its esters or salts thereof, the tautomers (keto form, enol form) are also included in the present invention.

[0030] When omidenepag, its ester, or a salt thereof has a crystalline polymorph and / or a crystalline polymorph system, the crystalline polymorph and / or a crystalline polymorph system (crystalline polymorph system) are also included in the present invention. Here, the crystalline polymorph system (crystalline polymorph system) refers to the crystalline form at each stage and / or the entire crystalline form when the crystalline form changes depending on the conditions and / or state (including the formulated state) of the production, crystallization, storage, etc. of the crystals.

[0031] In the therapeutic agent etc. of the present invention, omidenepag or an ester thereof, or a salt thereof may be in the form of a hydrate or solvate.

[0032] In the therapeutic agent etc. of the present invention, the content of omidenepag or its ester or a salt thereof is not particularly limited and depends on the administration form, but in the case of eye drops, the lower limit of the content of omidenepag or its ester or a salt thereof is preferably 0.0003% (w / v), more preferably 0.001% (w / v), even more preferably 0.0013% (w / v), and particularly preferably 0.0015% (w / v). The upper limit of the content is preferably 0.03% (w / v), more preferably 0.01% (w / v), even more preferably 0.005% (w / v), particularly preferably 0.003% (w / v), and especially preferably 0.0027% (w / v). More specifically, the content may be within a range that combines any of the above lower and upper limits, but is preferably 0.0003 to 0.03% (w / v), more preferably 0.001 to 0.01% (w / v), even more preferably 0.001 to 0.005% (w / v), particularly preferably 0.001 to 0.003% (w / v), even more preferably 0.0013 to 0.003% (w / v), and especially preferably 0.0015 to 0.0027% (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), 0.0021% (w / v), 0.002 2% (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), 0.01% (w / v), 0.03% (w / v), and ranges with these upper or lower limits are preferred. Here, "% (w / v)" refers to the mass (g) of the active ingredient (omidenepag, its ester, or a salt thereof, etc.) and additives (surfactants, etc.) contained in 100 mL of the drug. For example, 0.01% (w / v) of Omidenepag means that the content of Omidenepag contained in 100 mL of the drug is 0.01 g.

[0033] Furthermore, when Omidenepag or its ester is in the form of a salt, hydrate or solvate, the content of Omidenepag or its ester may be calculated based on any of the free form, salt, hydrate or solvate of Omidenepag or its ester.

[0034] In the therapeutic agent etc. of the present invention, Ripasudil is represented by the following formula (3): [ka] The compound (CAS Registry Number: 223645-67-8) is also known as (S)-(-)-1-(4-fluoro-5-isoquinolinesulfonyl)-2-methyl-1,4-homopiperazine. It has Rho kinase inhibitory activity and promotes aqueous humor outflow from the main outflow pathway via the trabecular meshwork and Schlemm's canal. Therefore, it is sold as a treatment for glaucoma and ocular hypertension (Glanatec® Eye Drops 0.4%).

[0035] In the therapeutic agent etc. of the present invention, the salt of Ripasudil 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; organic acid salts such as acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, and aspartate; metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt; inorganic salts such as ammonium salt; and organic amine salts such as triethylamine salt and guanidine salt, preferably hydrochloride, more preferably monohydrochloride.

[0036] When Ripasudil or a salt thereof has geometric isomers and / or optical isomers, these isomers are also included within the scope of the present invention.

[0037] When proton tautomerism exists in Ripasudil or a salt thereof, the tautomers (keto form, enol form) are also included in the present invention.

[0038] When Ripasudil or its salts have crystalline polymorphs and / or crystalline polymorphic systems, these crystalline polymorphs and / or crystalline polymorphic systems (crystalline polymorphic systems) are also included in the present invention. Here, the crystalline polymorphic system (crystalline polymorphic system) refers to the crystalline forms and / or the entire crystalline form at each stage when the crystalline form changes depending on the conditions and / or states of production, crystallization, storage, etc. of the crystals (this state also includes the state of formulation).

[0039] In the therapeutic agent etc. of the present invention, Ripasudil or a salt thereof may be in the form of a hydrate or solvate. As the salt and hydrate of Ripasudil, Ripasudil monohydrochloride dihydrate (CAS Registry Number: 887375-67-9) is the most preferred. In the therapeutic agent etc. of the present invention, Ripasudil or a salt thereof, or a hydrate or solvate thereof, is also simply referred to as "Ripasudil".

[0040] In the therapeutic agent etc. of the present invention, the content of Ripasudil or a salt thereof is not particularly limited and depends on the administration form. In the case of eye drops, the lower limit of the content of Ripasudil or a salt thereof is preferably 0.01% (w / v), more preferably 0.05% (w / v), even more preferably 0.1% (w / v), and particularly preferably 0.2% (w / v). The upper limit of the content is preferably 3% (w / v), more preferably 2% (w / v), even more preferably 1% (w / v), and particularly preferably 0.6% (w / v). More specifically, the content may be within a range that combines any of the above lower and upper limits, but is preferably 0.01 to 3% (w / v), more preferably 0.05 to 2% (w / v), even more preferably 0.1 to 1% (w / v), particularly preferably 0.2 to 0.6% (w / v), and most preferably 0.4% (w / v).

[0041] Furthermore, when Ripasudil is in the form of a salt, hydrate or solvate, the content of Ripasudil or its salt may be calculated based on any of the free form, salt, hydrate or solvate of Ripasudil.

[0042] In the therapeutic agent etc. of the present invention, Netarsudil is represented by the following formula (4): [ka] The compound (CAS Registry Number: 1254032-66-0) is also known as [4-[(1S)-1-(aminomethyl)-2-(isoquinolin-6-ylamino)-2-oxoethyl]phenyl]methyl 2,4-dimethylbenzoate. It has Rho kinase inhibitory activity and norepinephrine transporter (NEP) inhibitory activity, and exhibits intraocular pressure-reducing properties. Therefore, it is sold in the United States as a treatment for glaucoma and ocular hypertension (RHOPRESSA® 0.02%).

[0043] In the therapeutic agent of the present invention, the salt of Netarsudil 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; organic acid salts such as acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, mesylate (methanesulfonate), ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, and aspartate; metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt; inorganic salts such as ammonium salt; and organic amine salts such as triethylamine salt and guanidine salt. Preferably, mesylate (methanesulfonate) or hydrochloride is used, and more preferably, dimesylate (dimethanesulfonate) or dihydrochloride is used.

[0044] When Netarsudil or a salt thereof has geometric isomers and / or optical isomers, these isomers are also included within the scope of the present invention.

[0045] When proton tautomerism exists in Netarsudil or a salt thereof, the tautomers (keto form, enol form) are also included in the present invention.

[0046] When Netarsudil or its salts exist as polymorphs and / or polymorphic systems, these polymorphs and / or polymorphic systems are also included in the present invention. Here, the term "polymorphic system" refers to the crystalline form and / or the entire crystalline form at each stage when the crystalline form changes depending on the conditions and / or state of production, crystallization, storage, etc. (including the formulated state).

[0047] In the therapeutic agent of the present invention, Netarsudil or a salt thereof may be in the form of a hydrate or solvate. The most preferred salt and hydrate of Netarsudil is Netarsudil dimesylate (CAS Registry Number: 1422144-42-0). In the therapeutic agent of the present invention, Netarsudil or a salt thereof, or a hydrate or solvate thereof, is also referred to simply as "Netarsudil."

[0048] The content of Netarsudil or a salt thereof in the therapeutic agent of the present invention is not particularly limited and depends on the administration form. In the case of eye drops, the lower limit of the content of Netarsudil or a salt thereof contained in the pharmaceutical agent of the present invention is preferably 0.001% (w / v), more preferably 0.003% (w / v), even more preferably 0.005% (w / v), and particularly preferably 0.01% (w / v). The upper limit of the content is preferably 0.2% (w / v), more preferably 0.1% (w / v), even more preferably 0.06% (w / v), and particularly preferably 0.04% (w / v). More specifically, the content may be within a range that combines any of the above lower and upper limits, but is preferably 0.001 to 0.2% (w / v), more preferably 0.003 to 0.1% (w / v), even more preferably 0.005 to 0.06% (w / v), particularly preferably 0.01 to 0.04% (w / v), and most preferably 0.02% (w / v).

[0049] Furthermore, when Netarsudil or a salt thereof is in the form of a salt, hydrate, or solvate, the content of Netarsudil or a salt thereof may be calculated based on any of the free form, salt, hydrate, and solvate of Netarsudil.

[0050] In the therapeutic agent etc. of the present invention, in addition to omidenepag or its ester, or a salt thereof, and one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof, one or more other prophylactic or therapeutic agents for glaucoma or ocular hypertension may be used in combination. The other prophylactic or therapeutic agents for glaucoma or ocular hypertension may be any agent that has an intraocular pressure-reducing effect and is useful for the treatment of glaucoma, such as nonselective sympathomimetics, α2 receptor agonists, α1 receptor blockers, β-receptor blockers, parasympathomimetics, carbonic anhydrase inhibitors, and prostaglandins.

[0051] An example of a non-selective sympathomimetic agent is dipivefrin, an example of an α2 receptor agonist is brimonidine or apraclonidine, an example of an α1 receptor blocker is bunazosin, an example of a β receptor blocker is timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, or metipranolol, an example of a parasympathomimetic agent is pilocarpine, an example of a carbonic anhydrase inhibitor is dorzolamide, brinzolamide, or acetazolamide, and an example of a prostaglandin is isopropyl unoprostone, latanoprost, travoprost, or bimatoprost. These also include pharmaceutically acceptable salt forms. Specific examples of salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, and phosphate; organic acid salts such as acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, and aspartate; metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt; inorganic salts such as ammonium salt; and organic amine salts such as triethylamine salt and guanidine salt.

[0052] Furthermore, other prophylactic or therapeutic agents for glaucoma or ocular hypertension may be in the form of a hydrate or solvate.

[0053] When the therapeutic agent of the present invention is used in combination with other prophylactic or therapeutic agents for glaucoma or ocular hypertension, the content thereof is not particularly limited and varies depending on the type of prophylactic or therapeutic agent contained therein and the administration form, but in the case of eye drops, the preferred content is as follows.

[0054] The content of the non-selective sympathomimetic drug varies depending on the type of drug, but in the case of dipivefrin, it is preferably 0.001 to 3% (w / v), more preferably 0.04 to 0.1% (w / v), and particularly preferably 0.04% (w / v) or 0.1% (w / v).

[0055] The content of the α2 receptor agonist varies depending on the type of drug, but in the case of brimonidine, it is preferably 0.01 to 5% (w / v), more preferably 0.1 to 0.5% (w / v), and particularly preferably 0.1%, 0.15%, 0.2%, or 0.5% (w / v). In the case of apraclonidine, it is preferably 0.01 to 5% (w / v), more preferably 0.5 to 1% (w / v), and particularly preferably 0.5% (w / v).

[0056] The content of the α1 receptor blocker varies depending on the type of drug, but in the case of bunazosin, it is preferably 0.001 to 0.3% (w / v), more preferably 0.003 to 0.03% (w / v), and particularly preferably 0.01% (w / v).

[0057] The content of the β-receptor blocker varies depending on the type of drug, but in the case of timolol, it is preferably 0.01 to 5% (w / v), more preferably 0.1 to 0.5% (w / v), and particularly preferably 0.1% (w / v), 0.25% (w / v), or 0.5% (w / v). In the case of befunolol, it is preferably 0.01 to 5% (w / v), more preferably 0.25 to 1% (w / v), and particularly preferably 0.25% (w / v), 0.5% (w / v), or 1% (w / v). In the case of carteolol, it is preferably 0.01 to 5% (w / v), more preferably 1 to 2% (w / v), and particularly preferably 1% (w / v) or 2% (w / v). In the case of nipradilol, the concentration is preferably 0.01 to 5% (w / v), particularly preferably 0.25% (w / v). In the case of betaxolol, the concentration is preferably 0.01 to 5% (w / v), more preferably 0.25 to 0.5% (w / v), particularly preferably 0.25% (w / v) or 0.5% (w / v). In the case of levobunolol, the concentration is preferably 0.01 to 5% (w / v), more preferably 0.25 to 0.5% (w / v), particularly preferably 0.25% (w / v) or 0.5% (w / v). In the case of metipranolol, the concentration is preferably 0.01 to 5% (w / v), particularly preferably 0.3% (w / v).

[0058] The content of the parasympathomimetic drug varies depending on the type of drug, but in the case of pilocarpine, it is preferably 0.01 to 20% (w / v), more preferably 0.1 to 5% (w / v), and particularly preferably 0.5% (w / v), 1% (w / v), 2% (w / v), 3% (w / v), or 4% (w / v).

[0059] The content of the carbonic anhydrase inhibitor varies depending on the type of drug. In the case of dorzolamide, it is preferably 0.01 to 5% (w / v), more preferably 0.5 to 2% (w / v), and particularly preferably 0.5% (w / v), 1% (w / v), or 2% (w / v). In the case of brinzolamide, it is preferably 0.01 to 5% (w / v), more preferably 0.1 to 2% (w / v), and particularly preferably 1% (w / v). In the case of acetazolamide, it is preferably 0.01 to 5% (w / v), more preferably 1 to 5% (w / v). When acetazolamide is orally administered, the daily dose can be 250 to 1000 mg.

[0060] The content of prostaglandins varies depending on the type of drug, but in the case of latanoprost, it is preferably 0.0001 to 5% (w / v), more preferably 0.0005 to 1% (w / v), even more preferably 0.001 to 0.1% (w / v), and particularly preferably 0.005% (w / v).In the case of isopropyl unoprostone, it is preferably 0.001 to 5% (w / v), more preferably 0.01 to 1% (w / v), even more preferably 0.12 to 0.15% (w / v), and particularly preferably 0.12% (w / v) or 0.15% (w / v). In the case of bimatoprost, the concentration is preferably 0.0001 to 5% (w / v), more preferably 0.001 to 1% (w / v), even more preferably 0.01 to 0.03% (w / v), and particularly preferably 0.01% (w / v) or 0.03% (w / v).In the case of travoprost, the concentration is preferably 0.0001 to 5% (w / v), more preferably 0.001 to 1% (w / v), and particularly preferably 0.004% (w / v).

[0061] In addition, when the other prophylactic or therapeutic agent for glaucoma or ocular hypertension is in the form of a salt, hydrate, or solvate, the content of the other prophylactic or therapeutic agent for glaucoma or ocular hypertension may be calculated based on any of the free form, salt, hydrate, or solvate of the other prophylactic or therapeutic agent for glaucoma or ocular hypertension.

[0062] The therapeutic agent etc. of the present invention is characterized in that omidenepag, an ester thereof, or a salt thereof is administered in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof to prevent or treat glaucoma or ocular hypertension. Examples of glaucoma in the therapeutic agent etc. of the present invention include primary open-angle glaucoma, secondary open-angle glaucoma, normal-tension glaucoma, excessive aqueous 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, etc.

[0063] The therapeutic agent etc. of the present invention may be administered in the form of a combination of a formulation containing omidenepag or an ester thereof or a salt thereof and another formulation containing one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil and salts thereof (co-administration), or may be administered in the form of a single formulation (combined drug) containing omidenepag or an ester thereof or a salt thereof and one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil and salts thereof. Furthermore, when a drug contains one or more other prophylactic or therapeutic agents for glaucoma or ocular hypertension in addition to omidenepag or its ester or a salt thereof and one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil, and salts thereof, omidenepag or its ester or a salt thereof, one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil, and salts thereof, and other prophylactic or therapeutic agents for glaucoma or ocular hypertension, the drug may be administered in combination with omidenepag or its ester or a salt thereof, one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil, and salts thereof, and other prophylactic or therapeutic agents for glaucoma or ocular hypertension, or a combination drug containing any of these ingredients may be administered in combination with the remaining ingredients, or a combination drug containing all of the ingredients may be administered.

[0064] The therapeutic agent of the present invention can be administered orally or parenterally, and no special techniques are required for its preparation, which can be carried out using commonly used techniques. Dosage forms include eye drops, eye ointments, injections, tablets, capsules, granules, powders, etc., with eye drops or eye ointments being preferred.

[0065] When omidenepag or its ester or a salt thereof, one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and their salts, and another drug for the prophylaxis or treatment of glaucoma or ocular hypertension are formulated separately, the respective formulations can be prepared according to known methods. For example, a formulation of omidenepag or its ester or a salt thereof can be prepared with reference to the formulation examples described in WO 2009 / 113600 or WO 2010 / 113957. As a formulation of a Rho kinase inhibitor or other drug for the prevention or treatment of glaucoma or ocular hypertension, it is also possible to use commercially available formulations such as ripasudil, netarsudil, dipivefrin, brimonidine, apraclonidine, bunazosin, timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, metipranolol, pilocarpine, dorzolamide, brinzolamide, acetazolamide, isopropyl unoprostone, latanoprost, travoprost, bimatoprost, Cosopt (registered trademark) combination eye drops, Xalacam (registered trademark) combination eye drops, and Duotrava (registered trademark) combination eye drops, or products similar thereto.

[0066] Furthermore, when preparing a single preparation containing each component, it can be prepared in accordance with a known method.

[0067] When preparing eye drops, the desired eye drops can be prepared by adding omidenepag or its esters or salts thereof, or one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof to purified water, a buffer solution, etc., stirring, and then adjusting the pH with a pH adjuster. If necessary, additives commonly used in eye drops can be used, including isotonicity agents, buffering agents, surfactants, stabilizers, and preservatives. Examples of isotonicity agents include sodium chloride and glycerin. Examples of buffering agents include sodium phosphate, sodium acetate, boric acid, borax, citric acid, and sodium citrate. Examples of surfactants include polyoxyethylene sorbitan monooleate, polyoxyl stearate, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil. Examples of stabilizers include sodium citrate and sodium edetate. Examples of preservatives include benzalkonium chloride and parabens.

[0068] The pH of the eye drops may be within the range acceptable for ophthalmic preparations, preferably in the range of pH 4 to 8, more preferably in the range of pH 5 to 7.

[0069] When used as an eye ointment, it can be prepared using a commonly used base, such as white petrolatum or liquid paraffin.

[0070] When oral preparations such as tablets, capsules, granules, and powders are prepared, they can be prepared as needed by adding fillers, lubricants, binders, disintegrants, coating agents, film-forming agents, etc. Examples of fillers include lactose, crystalline cellulose, starch, and vegetable oils, examples of lubricants include magnesium stearate and talc, examples of binders include hydroxypropyl cellulose and polyvinylpyrrolidone, examples of disintegrants include carboxymethylcellulose calcium and low-substituted hydroxypropyl methylcellulose, examples of coating agents include hydroxypropyl methylcellulose, macrogol, and silicone resins, and examples of film-forming agents include gelatin films.

[0071] The administration method of the therapeutic agent of the present invention can be varied as appropriate depending on the dosage form, the severity of the patient's symptoms, age, body weight, administration route, and the physician's judgment, but in the case of a combination drug containing omidenepag or its ester or a salt thereof and one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil, and their salts, it can be administered 1 to 5 times a day, preferably once or twice a day, and most preferably once a day. When a formulation containing omidenepag or its ester or a salt thereof is administered in combination with a formulation containing one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil, and their salts, each formulation can be administered 1 to 3 times a day, at different times or simultaneously, preferably once or twice a day, and most preferably once a day. In addition, when the formulations are administered at different times in the combined administration, there is no limitation on the order in which the formulations are administered, as long as one formulation is administered within 12 hours, preferably within 6 hours, more preferably within 1 hour, even more preferably within 30 minutes, particularly preferably within 5 minutes, and most preferably immediately after the other formulation is administered. In the above administration method, in the case of ophthalmic administration, it is preferable to administer 1 to 3 drops per administration, more preferably 1 or 2 drops, and most preferably 1 drop.

[0072] The above detailed description of the therapeutic agent etc. of the present invention also applies to the agent for preventing or treating glaucoma or ocular hypertension containing omidenepag or its ester or a salt thereof, which is used in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil, and salts thereof of the present invention. The above detailed description of the therapeutic agent etc. of the present invention also applies to the intraocular pressure-reducing agent containing omidenepag or its ester or a salt thereof of the present invention in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil, and salts thereof of the present invention. The above detailed description of the therapeutic agent etc. of the present invention also applies to the intraocular pressure-reducing agent containing omidenepag or its ester or a salt thereof, which is used in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, Netarsudil, and salts thereof of the present invention.

[0073] The above detailed explanation of the therapeutic agent of the present invention also applies to the following aspects of the present invention.

[0074] One aspect of the present invention is a composition for the prevention or treatment of glaucoma or ocular hypertension, which contains omidenepag or an ester thereof, or a salt thereof, and is administered in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof.

[0075] One aspect of the present invention is a method for preventing or treating glaucoma or ocular hypertension, comprising administering to a subject in need thereof a therapeutically effective amount of omidenepag or an ester thereof, or a salt thereof, and a therapeutically effective amount of one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof.

[0076] One aspect of the present invention is use of a combination of omidenepag or an ester thereof, or a salt thereof, and one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof, for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension.

[0077] One aspect of the present invention is use of omidenepag, an ester thereof, or a salt of these for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension, in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof.

[0078] One aspect of the present invention is omidenepag or an ester thereof, or a salt of these for use in the prevention or treatment of glaucoma or ocular hypertension, in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof.

[0079] One aspect of the present invention is a combination of omidenepag or an ester thereof, or a salt thereof with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof for use in the prevention or treatment of glaucoma or ocular hypertension.

[0080] One aspect of the present invention is a composition for reducing intraocular pressure containing omidenepag or an ester thereof, or a salt thereof, which is administered in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof.

[0081] One aspect of the present invention is a method for reducing intraocular pressure, comprising administering to a subject in need thereof a therapeutically effective amount of omidenepag or an ester thereof, or a salt thereof, and a therapeutically effective amount of one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof.

[0082] One aspect of the present invention is use of a combination of omidenepag or an ester thereof, or a salt thereof, and one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof, for the manufacture of a medicament for reducing intraocular pressure.

[0083] One aspect of the present invention is use of omidenepag or an ester thereof, or a salt thereof, for the manufacture of a medicament for reducing intraocular pressure, wherein the medicament is used in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof.

[0084] One aspect of the present invention is omidenepag or an ester thereof, or a salt thereof, for use in reducing intraocular pressure, in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof.

[0085] One aspect of the present invention is a combination of omidenepag or an ester thereof, or a salt thereof with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof for use in reducing intraocular pressure. [Example]

[0086] The following formulation examples and pharmacological tests are provided for better understanding of the present invention and are not intended to limit the scope of the present invention.

[0087] [Formulation example] Specific examples of formulations of eye drops and eye ointment containing omidenepag or its ester, or a salt thereof according to the present invention, combined with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof are shown below.

[0088] [Formulation Example 1] Eye drops (in 100 mL) Omidenepag Isopropyl 0.002g Ripasudil monohydrochloride dihydrate 0.4896g Sodium dihydrogen phosphate 0.15g Glycerin (appropriate amount) Polyoxyl 35 Castor Oil 1.7g Sodium edetate 0.05g Benzalkonium chloride 0.005g Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount)

[0089] [Formulation Example 2] Eye drops (in 100 mL) Omidenepag Isopropyl 0.002g Netarsudil 0.02g Sodium dihydrogen phosphate 0.15g Glycerin (appropriate amount) Polyoxyl 35 Castor Oil 1.7g Sodium edetate 0.05g Benzalkonium chloride 0.005g Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount)

[0090] [Formulation Example 3] Eye drops (in 100 mL) Omidenepag Isopropyl 0.002g Netarsudil dimesylate 0.02g Sodium dihydrogen phosphate 0.15g Glycerin (appropriate amount) Polyoxyl 35 Castor Oil 1.7g Sodium edetate 0.05g Benzalkonium chloride 0.005g Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount)

[0091] [Formulation Example 4] Eye ointment (in 100g) Omidenepag Isopropyl 0.01g Ripasudil monohydrochloride dihydrate 0.5g Liquid paraffin 10.0g White petrolatum (appropriate amount)

[0092] [Formulation Example 5] Eye ointment (in 100g) Omidenepag Isopropyl 0.01g Netarsudil 0.5g Liquid paraffin 10.0g White petrolatum (appropriate amount)

[0093] In the above formulation, by changing the types and amounts of omidenepag or its ester or a salt thereof, one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil and salts thereof, and additives, eye drops and eye ointments of the desired combination and concentration can be prepared.

[0094] [Pharmacological testing] [Example 1] In order to investigate the usefulness of a combination of omidenepag or its esters or salts thereof with ripasudil, the intraocular pressure-lowering effect was examined when omidenepag isopropyl and ripasudil were administered in combination to experimental animals (normotensive monkeys).

[0095] (Preparation of test compound solution) (1) Preparation of the base Polyoxyl 35 castor oil, glycerin, sodium citrate, sodium edetate, and benzalkonium chloride were added to purified water and dissolved, and after adjusting the pH, purified water was added to adjust the total volume.

[0096] (2) Preparation of Omidenepag Isopropyl Solution Omidenepag isopropyl, polyoxyl 35 castor oil, glycerin, sodium citrate, sodium edetate, and benzalkonium chloride were added to purified water and dissolved. After adjusting the pH, purified water was added to adjust the total volume to prepare a 0.0006 w / v% Omidenepag isopropyl solution.

[0097] (3) Preparation of saline solution Commercially available physiological saline solution (trade name: Otsuka Saline Injection, obtained from Otsuka Pharmaceutical Factory, Inc.) was used as is.

[0098] (4) Preparation of Ripasudil solution Commercially available Ripasudil eye drops were used as is.

[0099] (Test Method) The intraocular pressure-lowering effect of coadministering omidenepag isopropyl and ripasudil was investigated. For comparison, the intraocular pressure-lowering effect of administering omidenepag isopropyl alone or ripasudil alone was also investigated. Vehicle and saline were administered as controls.

[0100] (Drugs and animals used in the test) Omidenepag isopropyl solution: 0.0006 w / v% Omidenepag isopropyl solution (ophthalmic dose: 20 μL) Ripasudil solution: Ripasudil eye drops (trade name: Glanatec (registered trademark) eye drops 0.4%, amount to be instilled: 20 μL) Experimental animals: Cynomolgus monkeys (sex: male, 7 animals per group)

[0101] (Administration method and measurement method) [1] Combination administration of Omidenepag Isopropyl and Ripasudil (1) One drop of 0.4% oxybuprocaine hydrochloride eye drops (trade name: Benoxil (registered trademark) eye drops 0.4%) was instilled into one eye of the experimental animals to induce local anesthesia.

[0102] (2) The intraocular pressure was measured immediately before administration of the test compound solution and used as the initial intraocular pressure.

[0103] (3) Omidenepag isopropyl solution was instilled into one eye of the experimental animals (the contralateral eye was left untreated). After a short time (approximately 5 minutes), Ripasudil solution was instilled into the same eye.

[0104] (4) After instillation of Omidenepag isopropyl solution, one drop of 0.4% oxybuprocaine hydrochloride ophthalmic solution was instilled into each eye under local anesthesia at 2, 4, 6, 8, and 24 hours to measure intraocular pressure. Intraocular pressure was measured three times, and the average value is shown in the results.

[0105] [2] Omidenepag isopropyl monotherapy The test was carried out in the same manner as in the above combined administration test, except that the ripasudil solution was replaced with physiological saline.

[0106] [3] Ripasudil monotherapy The test was conducted in the same manner as in the above combined administration test, except that Omidenepag isopropyl solution was used instead of the vehicle.

[0107] [4] Control The test was conducted in the same manner as in the above combined administration test, except that the Omidenepag isopropyl solution was used as the vehicle and the Ripasudil solution was used as the physiological saline solution.

[0108] (Results and Discussion) The change in intraocular pressure over time for each treatment group is shown in Figure 1 and Table 1. The change in intraocular pressure for each individual is the difference from the pre-treatment value (0 hours) at each measurement time point, and is shown as the mean ± SEM for seven animals in each group. Significance was evaluated using the Dunnett-Hsu test. Significance levels relative to the control group are indicated as *: p<0.05, **: p<0.01, and ***: p<0.001. Significance levels relative to the omidenepag isopropyl treatment group are indicated as ††: p<0.01 and †††: p<0.001. Significance levels relative to the ripasudil treatment group are indicated as ♯: p<0.05, ♯♯: p<0.01, and ♯♯♯: p<0.001.

[0109] [Table 1]

[0110] As is clear from Figure 1 and Table 1, the group administered the combination of omidenepag isopropyl and ripasudil demonstrated a superior intraocular pressure-lowering effect and sustained effect compared to the groups administered the drugs alone, i.e., the omidenepag isopropyl and ripasudil groups. At all measurement times, the change in intraocular pressure in the group administered the combination of omidenepag isopropyl and ripasudil was greater than the sum of the change in intraocular pressure in the omidenepag isopropyl and ripasudil groups, confirming a synergistic effect in reducing intraocular pressure.

[0111] From the above, it was found that by combining omidenepag or its ester, or a salt thereof with ripasudil, a synergistic intraocular pressure-reducing effect and a sustained effect of this effect can be obtained.

[0112] [Example 2] To investigate the usefulness of combining Omidenepag or its esters, or salts thereof with Netarsudil, the intraocular pressure-lowering effect was examined when Omidenepag isopropyl and Netarsudil were administered concomitantly to experimental animals (normotensive monkeys).

[0113] (Preparation of test compound solution) (1) Preparation of the base for Omidenepag isopropyl solution Polyoxyl 35 castor oil, glycerin, sodium citrate, sodium edetate, and benzalkonium chloride were added to purified water and dissolved, and after adjusting the pH, purified water was added to adjust the total volume.

[0114] (2) Preparation of Omidenepag Isopropyl Solution Omidenepag isopropyl, polyoxyl 35 castor oil, glycerin, sodium citrate, sodium edetate, and benzalkonium chloride were added to purified water and dissolved. After adjusting the pH, purified water was added to adjust the total volume to prepare a 0.0006 w / v% Omidenepag isopropyl solution.

[0115] (3) Preparation of Netarsudil solution Netarsudil dimesylate was dissolved in physiological saline containing a solubilizer, and then a Netarsudil solution of the desired concentration was prepared using a commonly used method.

[0116] (Test Method) The intraocular pressure-lowering effect of coadministering Omidenepag isopropyl and Netarsudil was examined. For comparison, the intraocular pressure-lowering effect of administering Omidenepag isopropyl alone or Netarsudil alone was also examined. As controls, Omidenepag isopropyl solution base and Netarsudil solution base were administered.

[0117] (Drugs and animals used in the test) Omidenepag isopropyl solution: 0.0006 w / v% Omidenepag isopropyl solution (ophthalmic dose: 20 μL) Netarsudil solution: 0.01 w / v% Netarsudil solution (ophthalmic dose: 20 μL) Experimental animals: Cynomolgus monkeys (sex: male, 8 animals per group)

[0118] (Administration method and measurement method) [1] Combination administration of Omidenepag Isopropyl and Netarsudil (1) One drop of 0.4% oxybuprocaine hydrochloride eye drops (trade name: Benoxil (registered trademark) eye drops 0.4%) was instilled into one eye of the experimental animals to induce local anesthesia.

[0119] (2) The intraocular pressure was measured immediately before administration of the test compound solution and used as the initial intraocular pressure.

[0120] (3) Omidenepag isopropyl solution was instilled into one eye of the experimental animals (the contralateral eye was left untreated). After a short time (approximately 5 minutes), Netarsudil solution was instilled into the same eye.

[0121] (4) After instillation of Omidenepag isopropyl solution, one drop of 0.4% oxybuprocaine hydrochloride ophthalmic solution was instilled into each eye under local anesthesia at 2, 4, 6, 8, and 24 hours to measure intraocular pressure. Intraocular pressure was measured three times, and the average value is shown in the results.

[0122] [2] Omidenepag isopropyl monotherapy The test was conducted in the same manner as the above combined administration test, except that the Netarsudil solution was substituted for the vehicle of the Netarsudil solution.

[0123] [3] Administration of Netarsudil alone The test was conducted in the same manner as in the above combined administration test, except that Omidenepag isopropyl solution was used instead of the vehicle of Omidenepag isopropyl solution.

[0124] [4] Control The test was conducted in the same manner as the above combined administration test, except that Omidenepag isopropyl solution was substituted for the vehicle of Omidenepag isopropyl solution, and Netarsudil solution was substituted for the vehicle of Netarsudil solution.

[0125] (Results and Discussion) The change in intraocular pressure over time for each treatment group is shown in Figure 2 and Table 2. The change in intraocular pressure for each individual is the difference from the pre-treatment value (0 hours) at each measurement time point, and is shown as the mean ± SEM for eight animals in each group. Significance was evaluated using the Dunnett-Hsu test. Significance levels relative to the control group are indicated as *: p<0.05, **: p<0.01, and ***: p<0.001. Significance levels relative to the Omidenepag Isopropyl treatment group are indicated as †: p<0.05, ††: p<0.01, and †††: p<0.001. Significance levels relative to the Netarsudil treatment group are indicated as ♯♯: p<0.01 and ♯♯♯: p<0.001.

[0126] [Table 2]

[0127] As is clear from Figure 2 and Table 2, the group administered the combination of Omidenepag isopropyl and Netarsudil demonstrated a superior intraocular pressure-lowering effect and sustained effect compared to the groups administered the drugs alone, i.e., the Omidenepag isopropyl and Netarsudil groups. At all measurement times, the change in intraocular pressure in the Omidenepag isopropyl and Netarsudil combination group was greater than the sum of the change in intraocular pressure in the Omidenepag isopropyl and Netarsudil groups, confirming a synergistic effect in reducing intraocular pressure.

[0128] From the above, it was found that by combining Omidenepag or its ester, or a salt thereof with Netarsudil, a synergistic intraocular pressure-reducing effect and a sustained effect of this effect can be obtained. [Industrial Applicability]

[0129] By administering omidenepag, its ester, or a salt thereof in combination with one or more Rho kinase inhibitors selected from the group consisting of ripasudil, netarsudil, and salts thereof to the eye, the intraocular pressure-reducing effect is enhanced. Therefore, the present invention is useful as an agent for the prevention or treatment of glaucoma or ocular hypertension.

Claims

1. A preventive or therapeutic agent for glaucoma or ocular hypertension, characterized in that it comprises administering a combination of Omidenepag or its ester, or a salt thereof, and one or more Rho kinase inhibitors selected from the group consisting of Netarsudil and its salts.

2. 2. The preventive or therapeutic agent according to claim 1, which is a combination drug containing Omidenepag or an ester thereof, or a salt thereof, and one or more Rho kinase inhibitors selected from the group consisting of Netarsudil and salts thereof.

3. 2. The preventive or therapeutic agent according to claim 1, wherein Omidenepag or an ester thereof, or a salt thereof and one or more Rho kinase inhibitors selected from the group consisting of Netarsudil and a salt thereof are administered at different times or simultaneously.

4. A preventive or therapeutic agent for glaucoma or ocular hypertension containing omidenepag or its ester or a salt thereof, characterized in that it is used in combination with one or more Rho kinase inhibitors selected from the group consisting of netarsudil and salts thereof.

5. The preventive or therapeutic agent according to claim 4, which is administered at a different time from or simultaneously with one or more Rho kinase inhibitors selected from the group consisting of Netarsudil and salts thereof.

6. The preventive or therapeutic agent according to any one of claims 1 to 5, wherein the omidenepag or an ester thereof, or a salt thereof is omidenepag isopropyl.

7. The preventive or therapeutic agent according to any one of claims 1 to 6, wherein the Rho kinase inhibitor is Netarsudil dimesylate or dihydrochloride.

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