A combination drug of cepetaprost and a Rho kinase inhibitor.

Abstract

To provide a combination of agents useful for the prevention or treatment of glaucoma or ocular hypertension. [Solution] Combining sepetaprost with a Rho kinase inhibitor enhances the intraocular pressure-lowering effect compared to using each drug alone. The drugs can be administered either as a single agent or as a combination product.

Description

Technical Field

[0001] The present invention relates to a preventive or therapeutic agent for glaucoma or ocular hypertension, which is characterized in that sepetaprost and a Rho kinase inhibitor are administered in combination. The present invention also relates to a preventive or therapeutic agent for glaucoma or ocular hypertension containing sepetaprost, which is characterized by being used in combination with a Rho kinase inhibitor.

Background Art

[0002] Glaucoma is a refractory eye disease in which intraocular pressure rises due to various etiologies, and there is a risk of blindness due to damage to internal tissues of the eyeball (such as the retina and optic nerve). As a treatment method for glaucoma, intraocular pressure reduction therapy is common, and typical examples include drug therapy, laser therapy, and surgical therapy.

[0003] For drug therapy, drugs such as sympathomimetic agents (non-selective stimulants such as dipivefrin, α2 receptor agonists such as brimonidine), sympatholytic agents (β receptor blockers such as timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, metipranolol, α1 receptor blockers such as bunazosin hydrochloride), parasympathomimetic agents (such as pilocarpine), carbonic anhydrase inhibitors (such as acetazolamide), prostaglandins (such as isopropyl unoprostone, latanoprost, travoprost, bimatoprost), and Rho kinase inhibitors (such as ripasudil) are used.

[0004] Furthermore, several studies have reported the use of combinations of drugs with intraocular pressure-lowering effects to obtain a stronger intraocular pressure-lowering effect. For example, Japanese Patent Publication No. 2726672 (Patent Document 2) reports the administration of a combination of a sympathetic nerve blocker and prostaglandins. 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. In addition, International Publication No. 2004 / 019951 (Patent Document 4) reports the administration of a combination of a Rho kinase inhibitor and prostaglandins, 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. Combinations of dorzolamide and timolol, latanoprost and timolol, and brimonidine and timolol are commercially available (Non-Patent Document 1).

[0005] By the way, Sepetaprost is given by equation (1) [ka] These compounds are represented by [formula] and are described in Patent Document 6 as one of a vast number of compounds. It is stated that these compounds have a potent and sustained intraocular pressure-lowering effect and therefore could be used as glaucoma treatments. [Prior art documents] [Patent Documents]

[0006] [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] International Publication No. 2011 / 013651 [Non-patent literature]

[0007] [Non-Patent Document 1] Clinical Ophthalmology,2010,4,1-9 [Overview of the project] [Problems that the invention aims to solve]

[0008] Finding combinations of preventive or therapeutic agents for glaucoma or ocular hypertension that are useful as preventive or therapeutic agents for glaucoma or ocular hypertension is a very interesting challenge. [Means for solving the problem]

[0009] The inventors diligently researched the effects of combining sepetaprost with a Rho kinase inhibitor to prevent or treat glaucoma or ocular hypertension, and as a result found that combining sepetaprost with a Rho kinase inhibitor enhances the intraocular pressure-lowering effect compared to the use of each drug alone, thus completing the present invention.

[0010] In other words, the present invention relates to the following.

[0011] (1) A preventive or therapeutic agent for glaucoma or ocular hypertension, characterized by being administered in combination with sepetaprost and a Rho kinase inhibitor. (2) The prophylactic or therapeutic agent described in (1) above, which is a combination agent containing sepetaprost and a Rho kinase inhibitor. (3) The prophylactic or therapeutic agent described in (1) above, wherein the sepetaprost and the Rho kinase inhibitor are administered at different times or simultaneously. (4) A prophylactic or therapeutic agent for glaucoma or ocular hypertension containing sepetaprost, characterized by being used in combination with a Rho kinase inhibitor. (5) The prophylactic or therapeutic agent described in (4) above, which is administered at a different time from or concurrently with the Rho kinase inhibitor. (6) The prophylactic or therapeutic agent according to any one of (1) to (5) above, wherein the Rho kinase inhibitor is at least one selected from the group consisting of ripasudil, netarsudil and salts thereof. (7) The prophylactic or therapeutic agent according to any one of (1) to (6) above, wherein the Rho kinase inhibitor is ripasudil monohydrochloride dihydrate. (8) The prophylactic or therapeutic agent according to any one of (1) to (6) above, wherein the Rho kinase inhibitor is the mesylate or hydrochloride of netarsudil.

[0012] The present invention also relates to the following.

[0013] (9) An intraocular pressure-lowering agent characterized by combining sepetaprost and a Rho kinase inhibitor. (10) An intraocular pressure-lowering agent containing sepetaprost, characterized by being used in combination with a Rho kinase inhibitor.

[0014] Furthermore, the present invention also relates to the following.

[0015] (11) A prophylactic or therapeutic composition for glaucoma or ocular hypertension containing sepetaprost, characterized by being administered in combination with a Rho kinase inhibitor. (12) A method for preventing or treating glaucoma or ocular hypertension, comprising administering a therapeutically effective amount of sepetaprost and a therapeutically effective amount of a Rho kinase inhibitor to a subject who needs it. (13) Use of a combination of sepetaprost and a Rho kinase inhibitor for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension. (14) Use of sepetaprost for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension, characterized by being used in combination with a Rho kinase inhibitor. (15) Sepetaprost for use in the prevention or treatment of glaucoma or ocular hypertension, characterized by being used in combination with a Rho kinase inhibitor. A combination of sepetaprost and a Rho kinase inhibitor for use in the prevention or treatment of glaucoma or ocular hypertension.

[0016] Furthermore, the present invention also relates to the following.

[0017] (17) An intraocular pressure-lowering composition containing sepetaprost, which is characterized by being administered in combination with a Rho kinase inhibitor. (18) A method for lowering intraocular pressure, which includes administering a therapeutically effective amount of sepetaprost and a therapeutically effective amount of a Rho kinase inhibitor to a subject who needs it. (19) Use of a combination of sepetaprost and a Rho kinase inhibitor for the manufacture of a medicament for lowering intraocular pressure. (20) Use of sepetaprost for the manufacture of a medicament for lowering intraocular pressure, which is characterized by being used in combination with a Rho kinase inhibitor. (21) Sepetaprost for use in lowering intraocular pressure, which is characterized by being used in combination with a Rho kinase inhibitor. (22) A combination of sepetaprost and a Rho kinase inhibitor for use in lowering intraocular pressure.

[0018] In addition, any two or more of the above (1) to (22) configurations can be arbitrarily selected and combined.

Advantages of the Invention

[0019] By combining sepetaprost and a Rho kinase inhibitor and administering them 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 medicament is ensured.

Brief Description of the Drawings

[0020] [Figure 1] It is a graph showing changes in the intraocular pressure-lowering width over time for each administration group of sepetaprost and ripasudil alone and in combination. [Figure 2]This graph shows the changes in intraocular pressure reduction over time in each group of patients receiving sepetaprost and netarsudil alone and in combination. [Modes for carrying out the invention]

[0021] The present invention will be described in detail below.

[0022] The present invention relates to a preventive or therapeutic agent for glaucoma or ocular hypertension, characterized by administration of a combination of sepetaprost and a Rho kinase inhibitor, and hereinafter these will also be simply referred to as "therapeutic agents, etc."

[0023] In the therapeutic agent of the present invention, sepetaprost is represented by the following formula (1) [ka] This compound is represented by (CAS Registry Number: 1262873-06-2) and is also known as 2-propanyl 4-{(3S,5aR,6R,7R,8aS)-6-[(1E,3R)-4-(2,5-difluorophenoxy)-3-hydroxy-1-buten-1-yl]-7-hydroxyoctahydro-2H-cyclopenta[b]oxepin-3-yl}butanoate.

[0024] Sepetaprost can be manufactured according to the method described in International Publication No. 2011 / 013651 (Patent Document 6), conventional methods in the art, etc.

[0025] If geometric and / or optical isomers of sepetaprost exist, those isomers are also included in the scope of the present invention.

[0026] If cepetaprost exhibits proton tautomerism, its tautomers (keto and enol forms) are also included in the present invention.

[0027] If crystalline polymorphisms and / or groups of crystalline polymorphisms (crystalline polymorphic systems) exist in sepetaprost, these crystalline polymorphs and / or groups of crystalline polymorphisms (crystalline polymorphic systems) are also included in the present invention. Here, a group of crystalline polymorphisms (crystalline polymorphic systems) means the crystalline forms and / or the entirety thereof at each stage when the crystalline form changes in various ways depending on the conditions and / or state of the crystals, such as the manufacturing, crystallization, and storage conditions (this state also includes the formulated state).

[0028] Sepetaprost may be available in the form of a hydrate or solvate.

[0029] In the therapeutic agent of the present invention, the content of sepetaprost is not particularly limited and depends on the form of administration, but in the case of eye drops, the content of sepetaprost is preferably 0.000001 to 5% (w / v), and more preferably 0.00001 to 0.05% (w / v). Here, "% (w / v)" means the mass (g) of the active ingredient or additive contained in 100 mL of the drug. For example, 0.01% (w / v) of sepetaprost means that the content of sepetaprost contained in 100 mL of the drug is 0.01 g.

[0030] Furthermore, the sepetaprost content may be calculated based on the free form, hydrate, or solvate of sepetaprost, if sepetaprost is in the form of a hydrate or solvate.

[0031] In the present invention, a Rho kinase inhibitor refers to a compound that inhibits serine / threonine kinases that are activated in conjunction with Rho activation. Examples include compounds that inhibit ROKα (ROCK-II), p160ROCK (ROKβ, ROCK-I), and other proteins having serine / threonine kinase activity.

[0032] Specific examples of Rho kinase inhibitors include (R)-trans-N-(pyridine-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-aminoethyl)benzamide, disclosed in International Publication No. 98 / 06433 and International Publication No. 00 / 09162, respectively; International Publication No. 97 / 23222, Nature, 389. Rho kinase inhibitors such as 1-(5-isoquinoline sulfonyl)homopiperazine and 1-(5-isoquinoline sulfonyl)-2-methylpiperazine disclosed in 990-994 (1997); Rho kinase inhibitors such as (1-benzylpyrrolidine-3-yl)-(1H-indazole-5-yl)amine disclosed in International Publication 01 / 56988; Rho kinase inhibitors such as (1-benzylpiperidine-4-yl)-(1H-indazole-5-yl)amine disclosed in International Publication 02 / 100833; Rho kinase inhibitors such as N-[2-(4-fluorophenyl)-6,7-dimethoxy-4-quinazolinyl]-N-(1H-indazole-5-yl)amine disclosed in International Publication 02 / 076976; Rho kinase inhibitors such as N-4-(1H-indazole-5-yl)-6,7-dimethoxy-N-2-pyridine-4-ylquinazoline-2,4-diamine disclosed in International Publication No. 02 / 076977; Rho kinase inhibitors such as 4-methyl-5-(2-methyl-[1,4]diazepan-1-sulfonyl)isoquinoline disclosed in International Publication No. 99 / 64011; Rho kinase inhibitors such as (S)-(-)-1-(4-fluoro-5-isoquinoline sulfonyl)-2-methyl-1,4-homopiperazine disclosed in International Publication No. 2006 / 068208; and 4-(3-amino-1-(isoquinoline-6-ylamino)-1-oxopropan-2-yl)benzyl disclosed in International Publication No. 2010 / 126626 Examples include Rho kinase inhibitors such as 2,4-dimethylbenzoate.In particular, (S)-(-)-1-(4-fluoro-5-isoquinoline sulfonyl)-2-methyl-1,4-homopiperazine, 4-(3-amino-1-(isoquinoline-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate, and [4-[(1S)-1-(aminomethyl)-2-(isoquinoline-6-ylamino)-2-oxoethyl]phenyl]methyl 2,4-dimethylbenzoate are preferred.

[0033] In the therapeutic agent of the present invention, the content of the Rho kinase inhibitor is not particularly limited and depends on the form of administration, but in the case of eye drops, the content of the Rho kinase inhibitor is preferably 0.0001 to 5% (w / v), and more preferably 0.001 to 1% (w / v).

[0034] Furthermore, the content of these Rho kinase inhibitors may be calculated based on the free form, salt, hydrate, or solvate of the Rho kinase inhibitor, if the Rho kinase inhibitor is in the form of a salt, hydrate, or solvate.

[0035] In the therapeutic agent of the present invention, lipasudil is represented by the following formula (2) [ka] This compound (CAS registry number: 223645-67-8), also known as (S)-(-)-1-(4-fluoro-5-isoquinoline sulfonyl)-2-methyl-1,4-homopiperazine, has Rho kinase inhibitory activity and promotes aqueous humor outflow from the main outflow pathway via the trabecular meshwork-Schlemm's canal. It is marketed as a treatment for glaucoma and ocular hypertension (Granatec® eye drops 0.4%).

[0036] In the therapeutic agent of the present invention, the salt of lipasudil is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, examples include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, or phosphate; organic salts such as acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, or aspartate; metal salts such as sodium salt, potassium salt, calcium salt, or magnesium salt; inorganic salts such as ammonium salt; or organic amine salts such as triethylamine salt or guanidine salt. Preferably, hydrochloride is used, and more preferably, monohydrochloride is used.

[0037] If geometric isomers and / or optical isomers exist for lipasudil or its salts, those isomers are also included in the scope of the present invention.

[0038] If lipasudil or its salts exhibit proton tautomerism, their tautomers (keto and enol forms) are also included in the present invention.

[0039] If polymorphisms and / or groups of polymorphisms (polymorphic systems) exist in lipasudil or its salts, these polymorphs and / or groups of polymorphisms (polymorphic systems) are also included in the present invention. Here, a group of polymorphisms (polymorphic systems) refers to the crystalline forms and / or the entirety thereof at each stage when the crystalline form changes in various ways depending on the conditions and / or state of the crystals, such as the manufacturing, crystallization, and storage conditions (this state also includes the formulated state).

[0040] In the therapeutic agent of the present invention, lipasudil or a salt thereof may take the form of a hydrate or solvate. Lipasudil monohydrochloride dihydrate (CAS registry number: 887375-67-9) is most preferred as the salt and hydrate of lipasudil. In the therapeutic agent of the present invention, lipasudil or a salt thereof, or their hydrate or solvate, is also simply referred to as "lipasudil".

[0041] In the therapeutic agent of the present invention, the content of lipasudil or its salt is not particularly limited and depends on the form of administration. However, in the case of eye drops, the lower limit of the content of lipasudil or its salt 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 above 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 above content may be within a range that combines either the lower limit or the upper limit, 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).

[0042] Furthermore, the content of lipasudil or its salts may be calculated based on the free form, salt, hydrate, or solvate of lipasudil or its salts, if lipasudil or its salts are in the form of salts, hydrates, or solvates.

[0043] In the therapeutic agent of the present invention, Netarsudil is represented by the following formula (3) [ka] This compound (CAS Registry Number: 1254032-66-0), also known as [4-[(1S)-1-(aminomethyl)-2-(isoquinoline-6-ylamino)-2-oxoethyl]phenyl]methyl 2,4-dimethylbenzoate. It has Rho kinase inhibitory and norepinephrine transporter (NEP) inhibitory effects, and exhibits intraocular pressure-lowering effects, and is marketed in the United States as a treatment for glaucoma and ocular hypertension (RHOPRESSA® 0.02%).

[0044] In the therapeutic agents of the present invention, the salt of Netarsudil is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, examples include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, or phosphate; organic salts such as acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, mesylate (methanesulfonate), ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, or aspartate; metal salts such as sodium salt, potassium salt, calcium salt, or magnesium salt; inorganic salts such as ammonium salt; or organic amine salts such as triethylamine salt or guanidine salt. Preferably, mesylate (methanesulfonate) or hydrochloride is used, and more preferably, dimesylate (dimethanesulfonate) or dihydrochloride is used.

[0045] If geometric isomers and / or optical isomers exist for Netarsudil or its salts, those isomers are also included in the scope of the present invention.

[0046] If Netarsudil or its salts exhibit proton tautomerism, their tautomers (keto and enol forms) are also included in the present invention.

[0047] If Netarsudil or its salts have crystalline polymorphs and / or groups of crystalline polymorphs (crystalline polymorph systems), then those crystalline polymorphs and / or groups of crystalline polymorphs (crystalline polymorph systems) are also included in the present invention. Here, a group of crystalline polymorphs (crystalline polymorph systems) means the crystalline forms and / or the entirety thereof at each stage when the crystalline form changes in various ways depending on the conditions and / or state of the crystals, such as the manufacturing, crystallization, and storage conditions (this state includes the formulated state).

[0048] In the therapeutic agents of the present invention, Netarsudil or a salt thereof may take the form of a hydrate or solvate. Netarsudil dimesylate (CAS registry number: 1422144-42-0) is most preferred as a salt or hydrate of Netarsudil. In the therapeutic agents of the present invention, Netarsudil or a salt thereof, or their hydrate or solvate, is also simply referred to as "Netarsudil".

[0049] In the therapeutic agent of the present invention, the content of Netarsudil or its salt is not particularly limited and depends on the form of administration. However, in the case of eye drops, the lower limit of the content of Netarsudil or its salt 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 above 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 above content may be within a range that combines either the lower limit or the upper limit, 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).

[0050] Furthermore, the content of Netarsudil or its salts may be calculated based on the free form, salt, hydrate, or solvate of Netarsudil or its salts, if Netarsudil or its salts are in the form of salts, hydrates, or solvates.

[0051] In the therapeutic agent of the present invention, in addition to sepetaprost and a Rho kinase inhibitor, one or more other preventive or therapeutic agents for glaucoma or ocular hypertension may be used in combination. The other preventive or therapeutic agents for glaucoma or ocular hypertension may be any agent that has an intraocular pressure-lowering effect and is useful for treating glaucoma, and examples include non-selective sympathomimetic agents, α2 receptor agonists, α1 receptor blockers, β receptor blockers, parasympathomimetic agents, carbonic anhydrase inhibitors, and prostaglandins.

[0052] Examples of non-selective sympathomimetic drugs include dipivefrin; examples of α2 receptor agonists include brimonidine and apraclonidine; examples of α1 receptor blockers include bunazosin; examples of β receptor blockers include timolol, befnolol, carteolol, nipradilol, betaxolol, levovunolol, and metipranolol; examples of parasympathomimetic drugs include pilocarpine; examples of carbonic anhydrase inhibitors include dorzolamide, brinzolamide, and acetazolamide; and examples of prostaglandins include isopropyl unoprostone, latanoprost, travoprost, and bimatoprost. These also include pharmaceutically acceptable salt forms. Specific examples of salts include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, or phosphate; organic salts such as acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, or aspartate; metal salts such as sodium salt, potassium salt, calcium salt, or magnesium salt; inorganic salts such as ammonium salt; or organic amine salts such as triethylamine salt or guanidine salt.

[0053] Furthermore, other preventive or therapeutic agents for glaucoma or ocular hypertension may be available in the form of hydrates or solvates.

[0054] When the therapeutic agent of the present invention is used in combination with other preventive or therapeutic agents for glaucoma or ocular hypertension, the content is not particularly limited and depends on the type and form of administration of the preventive or therapeutic agent contained, but the preferred content in the case of eye drops is as follows.

[0055] The amount of non-selective sympathomimetic agent present varies depending on the type of drug, but in the case of dipivefrin, 0.001 to 3% (w / v) is preferred, 0.04 to 0.1% (w / v) is more preferred, and 0.04% (w / v) or 0.1% (w / v) is particularly preferred.

[0056] The amount of α2 receptor agonist varies depending on the type of drug, but in the case of brimonidine, 0.01 to 5% (w / v) is preferred, 0.1 to 0.5% (w / v) is more preferred, and 0.1% (w / v), 0.15% (w / v), 0.2% (w / v), or 0.5% (w / v) is particularly preferred. In the case of apraclonidine, 0.01 to 5% (w / v) is preferred, 0.5 to 1% (w / v) is more preferred, and 0.5% (w / v) is particularly preferred.

[0057] The amount of α1 receptor blocker present varies depending on the type of drug, but in the case of bunazosin, 0.001-0.3% (w / v) is preferred, 0.003-0.03% (w / v) is more preferred, and 0.01% (w / v) is particularly preferred.

[0058] The amount of β-receptor blocker varies depending on the type of drug, but in the case of timolol, 0.01 to 5% (w / v) is preferred, 0.1 to 0.5% (w / v) is more preferred, and 0.1% (w / v), 0.25% (w / v), or 0.5% (w / v) is particularly preferred. In the case of befnolol, 0.01 to 5% (w / v) is preferred, 0.25 to 1% (w / v) is more preferred, and 0.25% (w / v), 0.5% (w / v), or 1% (w / v) is particularly preferred. In the case of carteolol, 0.01 to 5% (w / v) is preferred, 1 to 2% (w / v) is more preferred, and 1% (w / v) or 2% (w / v) is particularly preferred. For nipradilol, 0.01-5% (w / v) is preferred, and 0.25% (w / v) is particularly preferred. For betaxolol, 0.01-5% (w / v) is preferred, 0.25-0.5% (w / v) is more preferred, and 0.25% (w / v) or 0.5% (w / v) is particularly preferred. For levovunol, 0.01-5% (w / v) is preferred, 0.25-0.5% (w / v) is more preferred, and 0.25% (w / v) or 0.5% (w / v) is particularly preferred. For metipranolol, 0.01-5% (w / v) is preferred, and 0.3% (w / v) is particularly preferred.

[0059] The amount of parasympathetic agonist present varies depending on the type of drug, but in the case of pilocarpine, 0.01 to 20% (w / v) is preferred, 0.1 to 5% (w / v) is more preferred, and 0.5% (w / v), 1% (w / v), 2% (w / v), 3% (w / v), or 4% (w / v) is particularly preferred.

[0060] The carbonic anhydrase inhibitor content varies depending on the type of drug. For dorzolamide, 0.01-5% (w / v) is preferred, 0.5-2% (w / v) is more preferred, and 0.5% (w / v), 1% (w / v), or 2% (w / v) is particularly preferred. For brinzolamide, 0.01-5% (w / v) is preferred, 0.1-2% (w / v) is more preferred, and 1% (w / v) is particularly preferred. For acetazolamide, 0.01-5% (w / v) is preferred, and 1-5% (w / v) is more preferred. When acetazolamide is administered orally, a daily dose of 250-1000 mg can be used.

[0061] The prostaglandin content varies depending on the type of drug, but in the case of latanoprost, 0.0001 to 5% (w / v) is preferred, 0.0005 to 1% (w / v) is more preferred, 0.001 to 0.1% (w / v) is even more preferred, and 0.005% (w / v) is particularly preferred. In the case of isopropyl unoprostone, 0.001 to 5% (w / v) is preferred, 0.01 to 1% (w / v) is more preferred, 0.12 to 0.15% (w / v) is even more preferred, and 0.12% (w / v) or 0.15% (w / v) is particularly preferred. For bimatoprost, 0.0001 to 5% (w / v) is preferred, 0.001 to 1% (w / v) is more preferred, 0.01 to 0.03% (w / v) is even more preferred, and 0.01% (w / v) or 0.03% (w / v) is particularly preferred. For travoprost, 0.0001 to 5% (w / v) is preferred, 0.001 to 1% (w / v) is more preferred, and 0.004% (w / v) is particularly preferred.

[0062] Furthermore, the content of these other preventive or therapeutic agents for glaucoma or ocular hypertension may be calculated based on the free form, salt, hydrate, or solvate of the other preventive or therapeutic agents for glaucoma or ocular hypertension, if the other preventive or therapeutic agents for glaucoma or ocular hypertension are in the form of salts, hydrates, or solvates.

[0063] In the therapeutic agent of the present invention, one or more other preventive or therapeutic agents for glaucoma or ocular hypertension may be used in combination with sepetaprost instead of a Rho kinase inhibitor. Other preventive or therapeutic agents for glaucoma or ocular hypertension may be any agent that is useful for treating glaucoma and has an intraocular pressure-lowering effect or neuroprotective effect, and include non-selective sympathomimetic agents, α2 receptor agonists, α1 receptor blockers, parasympathomimetic agents, carbonic anhydrase inhibitors, prostaglandins, NMDA antagonists, etc. Specific examples of these and their content will be as described above. More specific examples of combinations include: cepetaprost and dipivefrine, cepetaprost and brimonidine, cepetaprost and apraclonidine, cepetaprost and bunazosin, cepetaprost and pilocarpine, cepetaprost and carbachol, cepetaprost and demepotassium, cepetaprost and ecothiophe, cepetaprost and distigmine bromide, cepetaprost and dorzolamide, cepetaprost and brinzolamide, cepetaprost and acetazolamide, cepetaprost and diclofenamide, cepetaprost and metazolamide, cepetaprost and isopropyl unoprostone, cepetaprost and latanoprost, cepetaprost and travoprost, and cepetaprost and bimatoprost.

[0064] The therapeutic agents of the present invention are characterized by their ability to prevent or treat glaucoma or ocular hypertension by administering a combination of sepetaprost and a Rho kinase inhibitor. Examples of glaucoma treated with the therapeutic agents of the present invention include primary open-angle glaucoma, secondary open-angle glaucoma, normal-tension glaucoma, aqueous humor hyperproductive glaucoma, primary closed-angle glaucoma, secondary closed-angle glaucoma, plateau iris glaucoma, mixed glaucoma, developmental glaucoma, steroid glaucoma, exfoliation glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, lens capsule glaucoma, and plateau iris syndrome.

[0065] In the therapeutic agent of the present invention, the administration method may be to administer a preparation containing cepetaprost and another preparation containing a Rho kinase inhibitor (combined administration), or to administer a single preparation (combination preparation) containing cepetaprost and a Rho kinase inhibitor. Furthermore, if, in addition to cepetaprost and a Rho kinase inhibitor, one or more other preventive or therapeutic agents for glaucoma or ocular hypertension are used in combination, cepetaprost and a Rho kinase inhibitor may be administered in combination with the other preventive or therapeutic agents for glaucoma or ocular hypertension, or a combination preparation containing any of these components may be administered in combination with the remaining components, or a combination preparation containing all components may be used.

[0066] The therapeutic agents of the present invention can be administered orally or parenterally, and no special techniques are required for their formulation; they can be formulated using commonly used techniques. Examples of dosage forms include eye drops, eye ointments, injections, tablets, capsules, granules, and powders, with eye drops or eye ointments being preferred.

[0067] When preparing separate formulations of cepetaprost, a Rho kinase inhibitor, and other preventive or therapeutic agents for glaucoma or ocular hypertension, the formulations can be prepared according to known methods. As formulations of Rho kinase inhibitors and other preventive or therapeutic agents for glaucoma or ocular hypertension, commercially available formulations such as ripasudil, netarsudil, dipivefrin, brimonidine, apraclonidine, bunazosin, timolol, befnolol, carteolol, nipradilol, betaxolol, levobunolol, metipranolol, pilocarpine, dorzolamide, brinzolamide, acetazolamide, isopropylunoprostone, latanoprost, travoprost, bimatoprost, Cosopt® eye drops, Xalacom® eye drops, Duotrav® eye drops, or similar formulations can be used.

[0068] Furthermore, when preparing a single formulation containing each of the components, it can be prepared in accordance with known methods.

[0069] When preparing eye drops, the desired eye drops can be prepared by adding sepetaprost or a Rho kinase inhibitor to purified water or a buffer solution, stirring, and then adjusting the pH with a pH adjuster. In addition, commonly used additives for eye drops can be used as needed, and examples of such additives include isotonic agents, buffering agents, surfactants, stabilizers, preservatives, and solubilizers.

[0070] The pH of the eye drops should be within the range acceptable for ophthalmic preparations, preferably in the range of pH 4 to 8, and more preferably in the range of pH 5 to 7.

[0071] When used as an eye ointment, it can be prepared using commonly used bases, such as white petrolatum and liquid paraffin.

[0072] When preparing oral preparations such as tablets, capsules, granules, or powders, bulking agents, lubricants, binders, disintegrants, coating agents, and film-forming agents may be added as needed. Examples of bulking agents include lactose, crystalline cellulose, starch, and vegetable oil; 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 resin; and examples of film-forming agents include gelatin films.

[0073] The method of administering the therapeutic agent of the present invention can be appropriately changed depending on the dosage form, the severity of the patient's symptoms, age, weight, route of administration, and the physician's judgment. However, in the case of a combination preparation containing cepetaprost and a Rho kinase inhibitor, it can be administered 1 to 5 times a day, preferably once or twice a day, and most preferably once a day. When administering a preparation containing cepetaprost and a preparation containing a Rho kinase inhibitor in combination, each preparation 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 the case of combination administration, when the preparations are administered at different times, there is no restriction on the order in which the preparations are administered. After one preparation is administered, the other preparation should be 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 as soon as possible. In the above administration method, when administering by eye drops, it is preferable to administer 1 to 3 drops per dose, more preferably 1 or 2 drops, and most preferably 1 drop.

[0074] The above detailed description of the therapeutic agents of the present invention also applies to glaucoma or ocular hypertension prevention or treatment agents containing cepetaprost, characterized by being used in combination with the Rho kinase inhibitor of the present invention. The above detailed description of the therapeutic agents of the present invention also applies to intraocular pressure lowering agents characterized by being a combination of cepetaprost and the Rho kinase inhibitor of the present invention. The above detailed description of the therapeutic agents of the present invention also applies to intraocular pressure lowering agents containing cepetaprost, characterized by being used in combination with the Rho kinase inhibitor of the present invention.

[0075] Furthermore, the detailed description of the therapeutic agent, etc. of the present invention described above also applies to the embodiments of the present invention shown below.

[0076] One aspect of the present invention is a composition for the prevention or treatment of glaucoma or ocular hypertension, containing sepetaprost, characterized by being administered in combination with a Rho kinase inhibitor.

[0077] One aspect of the present invention is a method for preventing or treating glaucoma or ocular hypertension, comprising administering a therapeutically effective amount of sepetaprost and a therapeutically effective amount of a Rho kinase inhibitor to a subject in need thereof.

[0078] One aspect of the present invention is the use of a combination of sepetaprost and a Rho kinase inhibitor for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension.

[0079] One aspect of the present invention is the use of sepetaprost for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension, characterized in that it is used in combination with a Rho kinase inhibitor.

[0080] One aspect of the present invention is sepetaprost for use in the prevention or treatment of glaucoma or ocular hypertension, characterized by being used in combination with a Rho kinase inhibitor.

[0081] One aspect of the present invention is a combination of sepetaprost and a Rho kinase inhibitor for use in the prevention or treatment of glaucoma or ocular hypertension.

[0082] One aspect of the present invention is an intraocular pressure-lowering composition containing sepetaprost, characterized by being administered in combination with a Rho kinase inhibitor.

[0083] One aspect of the present invention is a method for lowering intraocular pressure, comprising administering a therapeutically effective amount of sepetaprost and a therapeutically effective amount of a Rho kinase inhibitor to a subject in need thereof.

[0084] One aspect of the present invention is the use of a combination of sepetaprost and a Rho kinase inhibitor for the manufacture of a pharmaceutical product for lowering intraocular pressure.

[0085] One aspect of the present invention is the use of sepetaprost for the manufacture of a pharmaceutical product for lowering intraocular pressure, characterized by its use in combination with a Rho kinase inhibitor.

[0086] One aspect of the present invention is sepetaprost for use in lowering intraocular pressure, characterized by being used in combination with a Rho kinase inhibitor.

[0087] One aspect of the present invention is a combination of sepetaprost and a Rho kinase inhibitor for use in lowering intraocular pressure. [Examples]

[0088] The results of the pharmacological tests are shown below, but these are for the purpose of better understanding the present invention and do not limit the scope of the invention.

[0089] [Pharmacology Exam] [Example 1] To investigate the usefulness of the combination of cepetaprost and a Rho kinase inhibitor, we examined the intraocular pressure-lowering effect of co-administration of cepetaprost and ripasudil, a Rho kinase inhibitor, in experimental animals (monkeys with normal intraocular pressure).

[0090] (Preparation of the test compound solution) (1) Preparation of sepetaprost solution Cepetaprost was dissolved in purified water containing a solubilizer, and then a sepetaprost solution of the desired concentration was prepared using a commonly used method.

[0091] (2) Preparation of lipasudil solution I used commercially available lipasudil eye drops (Kowa Co., Ltd., Granatec® eye drops 0.4%) as is.

[0092] (Test method) The intraocular pressure-lowering effect of co-administration of cepetaprost and ripasudil was investigated. For comparison, the intraocular pressure-lowering effects of cepetaprost alone or ripasudil alone were also examined. For control groups, cepetaprost solution base and physiological saline were administered.

[0093] (Drugs and animals used in the test) Cepetaprost solution: 0.0003% (w / v) cepetaprost solution (eye drop dose: 20 μL / eye) Ripasudil solution: 0.4% (w / v) ripasudil solution (product name: Granatec® ophthalmic solution 0.4%, instillation amount: 20 μL / eye) Experimental animals: Cryptomolgus macaques (Sex: Male, 8 individuals per group)

[0094] (Method of administration and method of measurement) [1] Concomitant administration of sepetaprost and ripasudil (1) One drop of 0.4% oxybuprocaine hydrochloride eye drops (trade name: Benoxil® eye drops 0.4%) was administered to one eye of an experimental animal to induce local anesthesia.

[0095] (2) Intraocular pressure was measured immediately before administration of the test compound solution and was recorded as the pre-administration intraocular pressure value (0 hours).

[0096] (3) Sepetaprost solution was instilled into one eye of the experimental animal (the other eye was left untreated). After a short time (about 5 minutes), ripasudil solution was instilled into the same eye.

[0097] (4) Sepetaprost solution was instilled into the eye to be measured, one drop at a time, 2, 4, 6, 8, and 24 hours after administration. After local anesthesia, intraocular pressure was measured. Intraocular pressure was measured three times for each eye, and the average value was calculated. The change in intraocular pressure (mmHg) was calculated as the difference from the intraocular pressure value before administration at each measurement point.

[0098] [2] Sepetaprost monotherapy The ripasudil solution was replaced with physiological saline, and the rest of the test was conducted using the same method as in the above-mentioned combined administration study.

[0099] [3] Administration of ripasudil alone The sepetaprost solution was replaced with a different base, and the rest of the test was conducted using the same method as in the above-mentioned combined administration study.

[0100] [4] Control The procedure was the same as the above-mentioned combined administration study, but with the base of the sepetaprost solution replaced with physiological saline in the ripasudil solution.

[0101] (result) Figure 1 and Table 1 show the changes in intraocular pressure (IOP) reduction over time for each treatment group. The change in IOP is shown as the difference from the pre-administration value (0 hours) for each individual at each measurement time point, expressed as the mean value of 8 individuals ± SEM for each group. Comparisons between the control group and the sepetaprost group, ripasudil group, or sepetaprost / ripasudil combination group, and comparisons between the sepetaprost / ripasudil combination group and the sepetaprost group or ripasudil group were performed using the Bartlett test, followed by the Dunnett test if the variances were homogeneous, and the Steel test if the variances were heterogeneous. The significance level for the control group was indicated as ##: p<0.01 in the Dunnett test, and as *: p<0.05 and **: p<0.01 in the Steel test. The significance level for the sepetaprost / ripasudil combination group compared to the other group was shown as †: p<0.05 and ††: p<0.01 in Dunnett's test, and as $$: p<0.01 in Steel's test.

[0102] [Table 1]

[0103] As is clear from Figure 1 and Table 1, the group receiving combination therapy with sepetaprost and ripasudil showed superior intraocular pressure-lowering effects and sustained effects compared to the drug monotherapy groups, i.e., the sepetaprost-only group and the ripasudil-only group. In particular, at 2, 4, and 8 hours post-administration, the change in intraocular pressure in the sepetaprost and ripasudil combination therapy group was greater than the sum of the changes in intraocular pressure in the sepetaprost-only group and the ripasudil-only group, confirming a synergistic effect of intraocular pressure lowering.

[0104] Based on the above findings, it was found that combining sepetaprost with a Rho kinase inhibitor results in a stronger intraocular pressure-lowering effect and a sustained effect.

[0105] [Example 2] To investigate the usefulness of the combination of cepetaprost and a Rho kinase inhibitor, we examined the intraocular pressure-lowering effect of co-administration of cepetaprost and the Rho kinase inhibitor Netarsudil in experimental animals (monkeys with normal intraocular pressure).

[0106] (Preparation of the test compound solution) (1) Preparation of sepetaprost solution Cepetaprost was dissolved in purified water containing a solubilizer, and then a sepetaprost solution of the desired concentration was prepared using a commonly used method.

[0107] (2) 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.

[0108] (Test method) The intraocular pressure-lowering effect of co-administration of cepetaprost and netarsudil was investigated. For comparison, the intraocular pressure-lowering effects of cepetaprost alone or netarsudil alone were also examined. Controls included administration of the base for cepetaprost solution and the base for netarsudil solution.

[0109] (Drugs and animals used in the test) Cepetaprost solution: 0.0003% (w / v) cepetaprost solution (eye drop dose: 20 μL / eye) Netarsudil solution: 0.01% (w / v) Netarsudil solution (eye drop dose: 20 μL / eye) Experimental animals: Cryptomolgus macaques (Sex: Male, 8 individuals per group)

[0110] (Method of administration and method of measurement) [1] Concomitant administration of sepetaprost and netarsudil (1) One drop of 0.4% oxybuprocaine hydrochloride eye drops (trade name: Benoxil® eye drops 0.4%) was administered to one eye of an experimental animal to induce local anesthesia.

[0111] (2) Intraocular pressure was measured immediately before administration of the test compound solution and was recorded as the pre-administration intraocular pressure value (0 hours).

[0112] (3) Sepetaprost solution was instilled into one eye of the experimental animal (the other eye was left untreated). After a short time (about 5 minutes), Netarsudil solution was instilled into the same eye.

[0113] (4) Sepetaprost solution was instilled into the eye to be measured, one drop at a time, 2, 4, 6, 8, and 24 hours after administration. After local anesthesia, intraocular pressure was measured. Intraocular pressure was measured three times for each eye, and the average value was calculated. The change in intraocular pressure (mmHg) was calculated as the difference from the intraocular pressure value before administration at each measurement point.

[0114] [2] Sepetaprost monotherapy The Netarsudil solution was replaced with a different base, and the rest of the test was conducted using the same method as in the above-mentioned combined administration study.

[0115] [3] Netarsudil monotherapy The sepetaprost solution was replaced with a different base, and the rest of the test was conducted using the same method as in the above-mentioned combined administration study.

[0116] [4] Control The sepetaprost solution was replaced with the sepetaprost solution base, and the netarsudil solution was replaced with the netarsudil solution base, while the rest of the test was conducted using the same method as in the above-mentioned combined administration test.

[0117] (result) Figure 2 and Table 2 show the changes in intraocular pressure (IOP) reduction over time for each treatment group. The change in IOP is shown as the difference from the pre-administration value (0 hours) for each individual at each measurement time point, expressed as the mean value of 8 individuals ± SEM for each group. For comparisons between the control group and the cepetaprost group, netarsudil group, or cepetaprost / netarsudil combination group, and for comparisons between the cepetaprost / netarsudil combination group and the cepetaprost group or netarsudil group, Bartlett's test was performed, followed by Dunnett's test if the variances were homogeneous, and Steel's test if they were heterogeneous. The significance level relative to the control group is indicated as *: p<0.05, **: p<0.01 in Steel's test, and as #: p<0.05, ###: p<0.001 in Dunnett's test. The significance level for the sepetaprost / netarsudil combination group compared to the other group was shown as †: p<0.05 in Dunnett's test.

[0118] [Table 2]

[0119] As is clear from Figure 2 and Table 2, the group receiving cepetaprost and netarsudil in combination demonstrated superior intraocular pressure-lowering effects and sustained effects compared to the groups receiving each drug alone, i.e., the cepetaprost-only group and the netarsudil-only group.

[0120] Based on the above findings, it was found that combining sepetaprost with a Rho kinase inhibitor results in a stronger intraocular pressure-lowering effect and a sustained effect. [Industrial applicability]

[0121] Administering sepetaprost and a Rho kinase inhibitor in combination to the eye enhances the intraocular pressure-lowering effect. Therefore, the present invention is useful as a preventive or therapeutic agent for glaucoma or ocular hypertension.

Claims

1. An eye drop for the prevention or treatment of glaucoma or ocular hypertension, characterized by being administered in combination with 0.00001 to 0.05% (w / v) sepetaprost and netarsudil or a pharmacoagulably acceptable salt thereof.

2. The eye drop according to claim 1, which is a combination preparation containing sepetaprost and netarsudil or a pharmaceutically acceptable salt thereof.

3. The eye drops according to claim 1, wherein sepetaprost and netarsudil or a pharmaceutically acceptable salt thereof are administered at different times or simultaneously.

4. The eye drops according to claim 3, wherein, when administered at different times, the other is administered within 30 minutes after the first administration.

5. The eye drops according to claim 3, wherein, when administered at different times, the other is administered within 5 minutes after the first administration.

6. An eye drop according to claim 1 or 2, which is administered once a day.

7. The eye drop according to any one of claims 1 to 6, wherein Netarsudil or a pharmaceutically acceptable salt thereof is a dimesylate or dihydrochloride of Netarsudil.

8. An eye drop for the prevention or treatment of glaucoma or ocular hypertension, containing 0.00001 to 0.05% (w / v) sepetaprost, characterized by being used in combination with Netarsudil or a pharmaceutically acceptable salt thereof.

9. The eye drops according to claim 8, administered at a different time from, or concurrently with, Netarsudil or a pharmaceutically acceptable salt thereof.

10. The eye drops according to claim 9, wherein, when administered at different times, the other is administered within 30 minutes after the first administration.

11. The eye drops according to claim 9, wherein, when administered at different times, the other is administered within 5 minutes after the first administration.

12. An eye drop according to claim 8 or 9, which is administered once a day.

13. The eye drop according to any one of claims 8 to 12, wherein Netarsudil or a pharmaceutically acceptable salt thereof is a dimesylate or dihydrochloride of Netarsudil.

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