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WO2019124489A1 - Medicament comprising combination of sepetaprost and ep2 agonist - Google Patents

Medicament comprising combination of sepetaprost and ep2 agonist Download PDF

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Publication number
WO2019124489A1
WO2019124489A1 PCT/JP2018/046971 JP2018046971W WO2019124489A1 WO 2019124489 A1 WO2019124489 A1 WO 2019124489A1 JP 2018046971 W JP2018046971 W JP 2018046971W WO 2019124489 A1 WO2019124489 A1 WO 2019124489A1
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Prior art keywords
agonist
combination
glaucoma
cepetaprost
sepetaprost
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French (fr)
Japanese (ja)
Inventor
誉子 山元
孝純 谷口
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Santen Pharmaceutical Co Ltd
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Santen Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an agent for the prophylaxis or treatment of glaucoma or ocular hypertension characterized in that cepetaprost and an EP2 agonist are administered in combination.
  • the present invention also relates to an agent for the prophylaxis or treatment of glaucoma or ocular hypertension containing cepetaprost, which is characterized in that it is used in combination with an EP2 agonist.
  • Patent Document 2 discloses a method for treating glaucoma by administering to the eye a combination of several drugs having an intraocular pressure lowering action.
  • Patent Document 3 discloses a method for treating glaucoma by administering to the eye a combination of several drugs having an intraocular pressure lowering action.
  • WO 2004/019951 includes administration of a combination of a Rho kinase inhibitor and a prostaglandin, and WO 2004/045644 (patent document 5) a Rho kinase inhibitor.
  • Sepetaprost is an equation (1) And is described in Patent Document 6 as one of a vast number of compounds. It is described that these compounds can be a therapeutic agent for glaucoma because they have strong and sustained ocular hypotensive action.
  • the present invention relates to the following.
  • the prophylactic or therapeutic agent according to (1) which is a combination containing cepetaprost and an EP2 agonist.
  • An agent for the prophylaxis or treatment of glaucoma or ocular hypertension comprising cepetaprost, which is used in combination with an EP2 agonist.
  • the prophylactic or therapeutic agent according to (4) which is administered at different times or simultaneously with the EP2 agonist.
  • the present invention also relates to the following.
  • An intraocular pressure-lowering agent comprising a combination of sepetaprost and an EP2 agonist.
  • the present invention also relates to the following.
  • a composition for preventing or treating glaucoma or ocular hypertension comprising cepetaprost, which is administered in combination with an EP2 agonist.
  • a method for the prophylaxis or treatment of glaucoma or ocular hypertension comprising administering a therapeutically effective amount of cepetaprost and a therapeutically effective amount of an EP2 agonist to a subject in need thereof.
  • sepetaprost for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension characterized by being combined with an EP2 agonist.
  • Sepetaprost for use in the prevention or treatment of glaucoma or ocular hypertension, characterized in that it is used in combination with an EP2 agonist.
  • the present invention also relates to the following.
  • a method for reducing intraocular pressure comprising administering a therapeutically effective amount of Sepetaprost and a therapeutically effective amount of an EP2 agonist to a subject in need thereof.
  • Use of sepetaprost for the preparation of a medicament for lowering intraocular pressure characterized in that it is used in combination with an EP2 agonist.
  • Sepetaprost, for use in lowering intraocular pressure characterized in that it is used in combination with an EP2 agonist.
  • each structure of said (1) to (20) can select 2 or more arbitrarily, and can combine them.
  • the present invention is useful as an agent for the prophylaxis or treatment of glaucoma or ocular hypertension. Furthermore, according to the present invention, sufficient safety as a medicine is secured.
  • the present invention is an agent for the prophylaxis or treatment of glaucoma or ocular hypertension characterized in that cepetaprost and an EP2 agonist are administered in combination, and hereinafter, these are also simply referred to as "therapeutic agents etc.”
  • sepetaprost has the following formula (1) And 2-propanyl 4- ⁇ (3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2). It is also called 5, 5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl ⁇ butanolo.
  • Sepetaprost can be produced according to the method described in International Publication WO2011 / 013 051 (Patent Document 6), the ordinary method in the art, and the like.
  • crystalline polymorphic group refers to a crystalline form depending on the conditions and / or conditions (also including the formulated condition in this condition) such as production, crystallization, storage, etc. of those crystals. Means the crystal form and / or the whole in each step when various changes occur.
  • the content of cepetaprost is not particularly limited, and although it depends on the administration form, in the case of eye drops, the content of cepetaprost is 0.000001 to 5% (w / v) Preferably, 0.00001 to 0.05% (w / v) is more preferable.
  • “% (w / v)” means the mass (g) of the active ingredient and the additive contained in 100 mL of the drug.
  • Sepetaprost 0.01% (w / v) means that the content of Sepetaprost contained in 100 mL of the drug is 0.01 g.
  • cepetaprost when the cepetaprost is in the form of a hydrate or a solvate, the content of cepetaprost may be calculated based on any of the free form, the hydrate and the solvate of cepetaprost.
  • EP2 agonists such as isopropyl (-ylamino) acetic acid or (6- ⁇ [4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl ⁇ pyridin-2-ylamino) acetate, WO 2008 / 2- [3- [N- [4- (1H-pyrazol-1-yl) benzyl] -N- (pyridin-3-ylsulfonyl) aminomethyl] phenoxy] acetic acid isopropyl ester disclosed in 015517 (Taprenepag EP2 agonists such as isopropyl), WO 2006/098 Propan-2-yl 5-[[(2R) -1- [4-[(1S) -1-hydroxyhexyl] phenyl] -5-oxopyrrolidin-2-yl] methoxymethyl disclosed in No.
  • the content of EP2 agonist is not particularly limited, and although it depends on the administration form, in the case of eye drops, the content of EP2 agonist is 0.0001 to 5% (w / v) Is preferred, and 0.001 to 1% (w / v) is more preferred.
  • the content of these EP2 agonists is calculated based on any of the free body, the salt, the hydrate and the solvate of the EP2 agonist. It may be
  • Omidenepag is represented by the following formula (2) (CAS registration number: 1187451-41-7), (6- ⁇ [4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl ⁇ pyridine-2- Also known as ylamino) acetic acid. It is developed as a therapeutic agent for glaucoma because it has an EP2 agonistic action and exhibits an intraocular pressure lowering action.
  • 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, and more preferably, the carboxyl group of omidenepag is carbon
  • An ester formed by dehydration condensation with a monohydric alcohol having a number of 2 to 5, more preferably 3 to 4 carbon atoms is preferable.
  • esters include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, n-pentyl ester or n-hexyl ester
  • ethyl ester, n-propyl ester and isopropyl ester are mentioned, and more preferably isopropyl ester is mentioned.
  • the salt of omidenepag or the salt of ester of omidenepag is not particularly limited as long as it is a pharmacologically acceptable salt.
  • inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or phosphate; acetate, trifluoroacetate, benzoate, oxalate, Malonate, Succinate, Maleate, Fumarate, Tartrate, Citrate, Methanesulfonate, Ethanesulfonate, Trifluoromethanesulfonate, Benzenesulfonate, p-Toluenesulfonate
  • Organic salts such as glutamate or asparaginate; 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
  • Omidenepag or an ester thereof or a salt thereof is disclosed in US Patent Application Publication No. 2012/0190852, US Patent Application Publication No. 2011/0054172, US Patent Application Publication No. 2017/0121288. No. 201, U.S. Patent Application Publication No. 2017/0114043, and the usual methods in the art.
  • the term "omidenepag or ester thereof or a salt thereof" used in the present application includes (1) Omidenepag, (2) ester of omidenepag, (3) salt of omidenepag, and (4) salt of ester of omidenepag It is an included meaning.
  • the crystalline polymorphic group refers to a crystalline form depending on the conditions and / or conditions (also including the formulated condition in this condition) such as production, crystallization, storage, etc. of those crystals. Means the crystal form and / or the whole in each step when various changes occur.
  • Omidenepag or an ester thereof or a salt thereof may be in the form of a hydrate or a solvate.
  • the upper limit of the content is preferably 0.03% (w / v), more preferably 0.01% (w / v), still more preferably 0.005% (w / v), and 0.003 % (W / v) is particularly preferred and 0.0027% (w / v) is particularly preferred. More specifically, although the content may be a range combining any of the above lower limit and the upper limit, 0.0003 to 0.03% (w / v) is preferable, and 0.001 to 0.01 is preferable. % (W / v) is more preferable, 0.001 to 0.005% (w / v) is more preferable, and 0.001 to 0.003% (w / v) is particularly preferable, and 0.0013 to 0.
  • 003% (w / v) is particularly preferred and 0.0015 to 0.0027% (w / v) is particularly preferred. 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), 0.0022% (w / v), 0.0023% (w / v), 0.0024% (W / v), 0.0025% (w / v), 0.0026% (w / v), 0.0027% (w / v), 0.0028% (w / v), 0.0029% (W / v
  • Omidenepag or an ester thereof or a salt thereof When the content of Omidenepag or an ester thereof or a salt thereof is in the form of a salt, a hydrate or a solvate, the Omidenepag or an ester thereof or a salt thereof, the Omidenepag or an ester thereof or a salt thereof It may be calculated based on any of the free form, salt, hydrate and solvate.
  • one or more other glaucoma or ocular hypertension preventive or therapeutic agents may be used in combination.
  • Other agents for preventing or treating glaucoma or ocular hypertension may be those which have an intraocular pressure lowering action and are useful for glaucoma treatment, and are nonselective sympathetic agonists, alpha 2 receptor agonists, alpha 1 Receptor blockers, beta receptor blockers, parasympathetic agonists, carbonic anhydrase inhibitors, prostaglandins and the like can be mentioned.
  • nonselective sympathetic agonists include dipivefrine
  • specific examples of ⁇ 2 receptor agonists include brimonidine and apraclonidine
  • specific examples of ⁇ 1 receptor blockers include bunazosin
  • beta receptor blockers include timolol, befnolol, carteolol, niprazilol, betaxolol, levobnolol, and methipranol
  • specific examples of parasympathomimetics include pilocarpine
  • carbonate Specific examples of the dehydrating enzyme inhibitor include dorzolamide, brinzolamide and acetazolamide
  • specific examples of the prostaglandins include isopropyl unoprostone, latanoprost, travoprost and bimatoprost.
  • salts include hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates or phosphates and other inorganic acid salts; acetates, trifluoroacetates, benzoates, oxalic acid Salt, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfone Acid salts, organic acid salts such as glutamate or aspartate; metal salts such as sodium salts, potassium salts, calcium salts or magnesium salts; inorganic salts such as ammonium salts; or organic amine salts such as triethylamine salts or guanidine salts Can be mentioned.
  • glaucoma or ocular hypertensive prophylactic or therapeutic agents may be in the form of hydrates or solvates.
  • the content thereof is not particularly limited, depending on the type and administration form of the preventive or therapeutic agents contained.
  • the preferable content in the case of eye drops is as follows.
  • the content of the nonselective sympathetic agonist varies depending on the type of drug, but in the case of dipivefrine, 0.001 to 3% (w / v) is preferable, and 0.04 to 0.1% (w / v). v) is more preferred, 0.04% (w / v) or 0.1% (w / v) is particularly preferred.
  • the content of the ⁇ 2 receptor agonist varies depending on the type of drug, but in the case of brimonidine, 0.01 to 5% (w / v) is preferable, and 0.1 to 0.5% (w / v) Is more preferred, 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 preferable, 0.5 to 1% (w / v) is more preferable, and 0.5% (w / v) is particularly preferable .
  • the content of the ⁇ 1 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), preferably 0.003 to 0.03% (w / V) is more preferable, and 0.01% (w / v) is particularly preferable.
  • the content of the ⁇ receptor blocker varies depending on the type of drug, but in the case of timolol, it is preferably 0.01 to 5% (w / v), and 0.1 to 0.5% (w / v) Is more preferred, 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 preferable, 0.25 to 1% (w / v) is more preferable, 0.25% (w / v) or 0.5 % (W / v) or 1% (w / v) are particularly preferred.
  • levobnolol 0.01 to 5% (w / v) is preferred, 0.25 to 0.5% (w / v) is more preferred, 0.25% (w / v) or 0.5 % (W / v) is particularly preferred.
  • methipranol 0.01 to 5% (w / v) is preferred, 0.3% (w / v) is particularly preferred.
  • the content of the parasympathetic agonist 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) 0.5% (w / v), 1% (w / v), 2% (w / v), 3% (w / v) or 4% (w / v) are particularly preferred.
  • the content of carbonic anhydrase inhibitor varies depending on the type of drug, but in the case of dorzolamide, it is preferably 0.01 to 5% (w / v), more preferably 0.5 to 2% (w / v) Preferably, 0.5% (w / v), 1% (w / v) or 2% (w / v) are particularly preferred.
  • 0.01 to 5% (w / v) is preferable, 0.1 to 2% (w / v) is more preferable, and 1% (w / v) is particularly preferable.
  • 0.0001 to 5% (w / v) is preferable, 0.001 to 1% (w / v) is more preferable, and 0.01 to 0.03% (w / v) is more preferable
  • 0.01% (w / v) or 0.03% (w / v) is particularly preferred.
  • 0.0001 to 5% (w / v) is preferable, 0.001 to 1% (w / v) is more preferable, and 0.004% (w / v) is particularly preferable.
  • the content of these other glaucoma or ocular hypertensive prophylactic or therapeutic agents is other glaucoma or ocular hypertension preventive or therapeutic agents in the form of salts, hydrates, or solvates. It may be calculated based on the free form, the salt, the hydrate and the solvate of the glaucoma or ocular hypertensive prophylactic or therapeutic agent.
  • the therapeutic agent etc. of the present invention is characterized in that glaucoma or ocular hypertension is prevented or treated by administering cepetaprost and an EP2 agonist in combination.
  • glaucoma in the therapeutic agents of the present invention include primary open angle glaucoma, secondary open angle glaucoma, normal tension glaucoma, aqueous humor hyperglaucoma, primary closed angle glaucoma, secondary closed angle glaucoma, plateau iris glaucoma, Examples thereof include mixed glaucoma, developmental glaucoma, steroid glaucoma, exfoliation glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma, plateau iris syndrome and the like.
  • cepetaprost and the EP2 agonist and the other glaucoma or ocular hypertension may be co-administered, or a combination containing any of these components may be co-administered with the remaining components, or may be a combination containing all the components.
  • the therapeutic agent and the like of the present invention can be administered orally or parenterally, and no special technique is required for their formulation, and they can be formulated using widely used techniques.
  • Dosage forms include eye drops, eye ointments, injections, tablets, capsules, granules, powders and the like, with eye drops or eye ointments being preferred.
  • the formulations can be prepared according to known methods. Preparations of EP2 agonist and other glaucoma or ocular hypertensive agents for prevention or treatment of ripasil, dipivefephrine, brimonidine, apraclonidine, apraclonidine, bunazocine, timolol, befnolol, carteolol, niprazirole, betaxolol, levobnolol, methi Planolol, pilocarpine, dorzolamide, brinzolamide, acetazolamide, isopropyl unoprostone, latanoprost, travoprost, bimatoprost, cosopto® combination ophthalmic solution, zaracam® combination ophthalmic solution, duotrava® combination
  • the pH of the eye drop may be within the range acceptable for the ophthalmic preparation, preferably in the range of 4 to 8, and more preferably in the range of 5 to 7.
  • the base When used as an eye ointment, it can be prepared using a widely used base, and examples of the base include white petrolatum, liquid paraffin and the like.
  • a filler, lubricant, binder, disintegrant, coating agent, coating agent and the like can be added as needed.
  • the bulking agent lactose, crystalline cellulose, starch, vegetable oil and the like can be mentioned, as lubricants, magnesium stearate, talc and the like can be mentioned, as binders, hydroxypropyl cellulose, polyvinyl pyrrolidone and the like can be mentioned, Disintegrants include carboxymethylcellulose calcium, low-substituted hydroxypropyl methylcellulose and the like, coating agents include hydroxypropyl methylcellulose, macrogol, silicone resin and the like, and coating agents include gelatin films and the like.
  • the administration method of the therapeutic agent etc. of the present invention can be suitably changed according to the dosage form, severity of the condition of the patient to be administered, age, body weight, administration route, physician's judgment etc., but contains cepetaprost and EP2 agonist
  • it can be administered 1 to 5 times a day, preferably once or twice a day, and most preferably once a day.
  • each formulation can be administered 1 to 3 times a day at different times or simultaneously, once a day Alternatively, it is preferable to administer twice, most preferably once a day.
  • the order of administration of the preparations is not limited, and within one hour, preferably within six hours, more preferably one hour after administration of one preparation.
  • the other preparation may be administered within the range of 30 minutes, more preferably within 30 minutes, particularly preferably within 5 minutes, and most preferably immediately.
  • One aspect of the present invention is a composition for preventing or treating glaucoma or ocular hypertension comprising cepetaprost, which is administered in combination with an EP2 agonist.
  • One aspect of the present invention is the use of a combination of cepetaprost and an EP2 agonist for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension.
  • 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 an EP2 agonist.
  • One aspect of the present invention is sepetaprost, for use in the prevention or treatment of glaucoma or ocular hypertension characterized in that it is used in combination with an EP2 agonist.
  • One aspect of the present invention is the combination of cepetaprost and an EP2 agonist for use in the prevention or treatment of glaucoma or ocular hypertension.
  • One aspect of the present invention is a composition for ocular pressure lowering containing cepetaprost, which is administered in combination with an EP2 agonist.
  • One aspect of the invention is a method of reducing intraocular pressure comprising administering to a subject in need thereof a therapeutically effective amount of Sepetaprost and a therapeutically effective amount of an EP2 agonist.
  • One aspect of the invention is the use of a combination of cepetaprost and an EP2 agonist for the manufacture of a medicament for intraocular pressure reduction.
  • One aspect of the present invention is the use of sepetaprost for the manufacture of a medicament for the reduction of intraocular pressure, characterized in that it is used in combination with an EP2 agonist.
  • One aspect of the invention is sepetaprost for use in intraocular pressure lowering, characterized in that it is used in combination with an EP2 agonist.
  • One aspect of the present invention is the combination of cepetaprost and an EP2 agonist for use in intraocular pressure reduction.
  • Omidenepag isopropyl Solution After dissolving Omidenepag isopropyl in purified water containing a solubilizing agent, an Omidenepag isopropyl solution of a desired concentration was prepared using a widely used method.
  • Sepetaprost solution 0.0003% (w / v) Sepetaprost solution (eye drops: 20 ⁇ L / eye)
  • Omidenepag isopropyl solution 0.0006% (w / v) Omidenepag isopropyl solution (eye drops: 20 ⁇ L / eye)
  • Experimental animals cynomolgus monkey (sex: male, 9 animals per group)
  • the change in intraocular pressure fall width (the amount of change in intraocular pressure value) represents the difference from the value before administration (0 hour) at each measurement time point of each individual in each group by the average value ⁇ SEM of 9 animals.
  • the combination administration group of cepetaprost and omidenepag isopropyl is an intraocular pressure lowering action superior to that of the drug alone administration group, that is, the cepetaprost administration group and the omidenepag isopropyl administration group, and a sustained effect of the action. showed that.
  • the present invention is useful as an agent for the prophylaxis or treatment of glaucoma or ocular hypertension.

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Abstract

The purpose of the present invention is to identify a combination of drugs for the prevention or treatment of glaucoma or ocular hypertension, said combination being useful as a prophylactic or therapeutic agent for glaucoma or ocular hypertension.　Combining sepetaprost and an EP2 agonist enhances the intraocular pressure–lowering effect in comparison to when either drug is used alone. The drugs may be administered concurrently or as a combination drug.

Description

セペタプロストとＥＰ２アゴニストとの組み合わせ医薬Combination medicine of sepetaprost and EP2 agonist

　本発明は、セペタプロストとＥＰ２アゴニストが組み合わされて投与されることを特徴とする緑内障若しくは高眼圧症の予防または治療剤に関する。また、本発明は、ＥＰ２アゴニストと併用されることを特徴とする、セペタプロストを含有する緑内障若しくは高眼圧症の予防または治療剤にも関する。 The present invention relates to an agent for the prophylaxis or treatment of glaucoma or ocular hypertension characterized in that cepetaprost and an EP2 agonist are administered in combination. The present invention also relates to an agent for the prophylaxis or treatment of glaucoma or ocular hypertension containing cepetaprost, which is characterized in that it is used in combination with an EP2 agonist.

　緑内障は、種々の病因により眼圧が上昇し、眼球の内部組織（網膜、視神経など）が障害を受けることで失明に至る危険性のある難治性の眼疾患である。緑内障の治療方法としては、眼圧下降療法が一般的であり、その代表的なものとして薬物療法、レーザー治療法、手術療法などがある。 Glaucoma is an intractable eye disease that may cause blindness due to increased intraocular pressure due to various etiologies and damage to internal tissues of the eye (retina, optic nerve, etc.). As a method for treating glaucoma, intraocular pressure reduction therapy is generally used, and drug therapy, laser therapy, surgical therapy and the like are representative thereof.

　薬物療法には、交感神経作動薬（ジピベフリンなどの非選択性刺激薬、ブリモニジンなどのα２受容体作動薬）、交感神経遮断薬（チモロール、ベフノロール、カルテオロール、ニプラジロール、ベタキソロール、レボブノロール、メチプラノロール（Ｍｅｔｉｐｒａｎｏｌｏｌ）などのβ受容体遮断薬、塩酸ブナゾシンなどのα１受容体遮断薬）、副交感神経作動薬（ピロカルピンなど）、炭酸脱水酵素阻害薬（アセタゾラミドなど）、プロスタグランジン類（イソプロピルウノプロストン、ラタノプロスト、トラボプロスト、ビマトプロストなど）、Ｒｈｏキナーゼ阻害剤（リパスジル）などの薬物が使用されている。 Drug therapy, sympathomimetics (nonselective stimulants such as dipivefrin, alpha 2 receptor agonists, such as brimonidine), sympatholytic (timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, Mechipurano Beta receptor blockers such as roll (Metipranolol), alpha 1 receptor blockers such as bunazosin hydrochloride), parasympathetic agonists (such as pilocarpine), carbonic anhydrase inhibitors (such as acetazolamide), prostaglandins (such as isopropyl uno Drugs such as prostone, latanoprost, travoprost, bimatoprost, etc., Rho kinase inhibitors (lipasdil) are used.

　また、より強力な眼圧下降の効果を得るために、眼圧下降作用を有する薬剤を組み合わせて使用することが複数報告されている。例えば、特許第２７２６６７２号公報（特許文献２）には、交感神経遮断薬とプロスタグランジン類の組み合わせの投与が報告されている。また、国際公開第２００２／３８１５８号（特許文献３）には、眼圧下降作用を有する薬剤をいくつか組み合わせて眼に投与することによる緑内障の治療方法が開示されている。さらに、国際公開第２００４／０１９９５１号（特許文献４）には、Ｒｈｏキナーゼ阻害剤とプロスタグランジン類の組み合わせの投与が、国際公開第２００４／０４５６４４号（特許文献５）にはＲｈｏキナーゼ阻害剤およびβ受容体遮断薬の組み合わせの投与が報告されている。また、ドルゾラミドとチモロールの配合剤、ラタノプロストとチモロールの配合剤、ブリモニジンとチモロールの配合剤などが市販されている（非特許文献１）。 In addition, in order to obtain a stronger effect of lowering the intraocular pressure, it has been reported several times that combined use of drugs having an intraocular pressure lowering action. For example, Japanese Patent No. 2726672 (patent document 2) reports administration of a combination of a sympatholytic agent and a prostaglandin. WO 2002/38158 (Patent Document 3) discloses a method for treating glaucoma by administering to the eye a combination of several drugs having an intraocular pressure lowering action. Furthermore, WO 2004/019951 (patent document 4) includes administration of a combination of a Rho kinase inhibitor and a prostaglandin, and WO 2004/045644 (patent document 5) a Rho kinase inhibitor. Administration of a combination of and and beta receptor blockers has been reported. In addition, combination agents of dorzolamide and timolol, combination agents of latanoprost and timolol, combination agents of brimonidine and timolol, and the like are commercially available (Non-Patent Document 1).

　ところで、セペタプロストは、式（１）

Figure JPOXMLDOC01-appb-C000001

で表される化合物であり、特許文献６に膨大な数の化合物の一つとして記載されている。これらの化合物は強力かつ持続的な眼圧下降作用を有することから、緑内障治療剤となりうることが記載されている。 By the way, Sepetaprost is an equation (1)
Figure JPOXMLDOC01-appb-C000001
And is described in Patent Document 6 as one of a vast number of compounds. It is described that these compounds can be a therapeutic agent for glaucoma because they have strong and sustained ocular hypotensive action.

国際公開第２０１０／１１３９５７号International Publication No. 2010/113957 特許第２７２６６７２号公報Patent No. 2726672 国際公開第２００２／３８１５８号WO 2002/38158 国際公開第２００４／０１９９５１号WO 2004/019591 国際公開第２００４／０４５６４４号WO 2004/045644 国際公開第２０１１／０１３６５１号International Publication No. 2011/013511

Ｃｌｉｎｉｃａｌ　Ｏｐｈｔｈａｌｍｏｌｏｇｙ，２０１０，４，１－９Clinical Ophthalmology, 2010, 4, 1-9

　緑内障若しくは高眼圧症の予防または治療剤として有用な、緑内障若しくは高眼圧症の予防または治療薬の組み合わせを見出すことは非常に興味のある課題である。 It is a very interesting task to find a combination of glaucoma or ocular hypertension preventive or therapeutic agents useful as a preventive or therapeutic agent for glaucoma or ocular hypertension.

　本発明者らは、緑内障若しくは高眼圧症の予防または治療剤との組み合わせによる効果を鋭意研究した結果、セペタプロストとＥＰ２アゴニストとを組み合わせることで各薬剤の単独使用時と比較して眼圧下降作用が増強することを見出し、本発明を完成させた。 As a result of intensive studies on the effects of the combination with a preventive or therapeutic agent for glaucoma or ocular hypertension, the present inventors combined cepetaprost with an EP2 agonist to lower the intraocular pressure compared with single use of each drug. The present invention has been completed.

　すなわち、本発明は以下に関する。 That is, the present invention relates to the following.

（１）セペタプロストとＥＰ２アゴニストが組み合わされて投与されることを特徴とする緑内障若しくは高眼圧症の予防または治療剤。
（２）セペタプロストとＥＰ２アゴニストを含有する配合剤である、（１）に記載の予防または治療剤。
（３）セペタプロストとＥＰ２アゴニストが、異なる時間に、または、同時に投与される、（１）に記載の予防または治療剤。
（４）ＥＰ２アゴニストと併用されることを特徴とする、セペタプロストを含有する緑内障若しくは高眼圧症の予防または治療剤。
（５）ＥＰ２アゴニストと異なる時間に、または同時に投与される、（４）に記載の予防または治療剤。
（６）ＥＰ２アゴニストが、オミデネパグ若しくはそのエステルまたはそれらの塩である（１）～（５）のいずれかに記載の予防または治療剤。 (1) An agent for the prophylaxis or treatment of glaucoma or ocular hypertension characterized in that cepetaprost and an EP2 agonist are administered in combination.
(2) The prophylactic or therapeutic agent according to (1), which is a combination containing cepetaprost and an EP2 agonist.
(3) The prophylactic or therapeutic agent according to (1), wherein cepetaprost and the EP2 agonist are administered at different times or simultaneously.
(4) An agent for the prophylaxis or treatment of glaucoma or ocular hypertension comprising cepetaprost, which is used in combination with an EP2 agonist.
(5) The prophylactic or therapeutic agent according to (4), which is administered at different times or simultaneously with the EP2 agonist.
(6) The prophylactic or therapeutic agent according to any one of (1) to (5), wherein the EP2 agonist is omidenepag or an ester thereof or a salt thereof.

　また、本発明は以下にも関する。 The present invention also relates to the following.

（７）セペタプロストとＥＰ２アゴニストとを組み合わせたことを特徴とする眼圧下降剤。
（８）ＥＰ２アゴニストと併用されることを特徴とする、セペタプロストを含有する眼圧下降剤。 (7) An intraocular pressure-lowering agent comprising a combination of sepetaprost and an EP2 agonist.
(8) An ocular pressure lowering agent containing sepetaprost, which is characterized by being used in combination with an EP2 agonist.

　さらに、本発明は以下にも関する。 Furthermore, the present invention also relates to the following.

（９）ＥＰ２アゴニストと組み合わされて投与されることを特徴とする、セペタプロストを含有する緑内障若しくは高眼圧症の予防または治療用組成物。
（１０）治療有効量のセペタプロスト及び治療有効量のＥＰ２アゴニストを、それを必要とする対象に投与することを含む、緑内障若しくは高眼圧症の予防または治療方法。
（１１）緑内障若しくは高眼圧症の予防または治療のための医薬の製造のための、セペタプロストとＥＰ２アゴニストの組み合わせの使用。
（１２）ＥＰ２アゴニストと併用されることを特徴とする、緑内障若しくは高眼圧症の予防または治療のための医薬の製造のための、セペタプロストの使用。
（１３）ＥＰ２アゴニストと併用されることを特徴とする、緑内障若しくは高眼圧症の予防または治療における使用のための、セペタプロスト。
（１４）緑内障若しくは高眼圧症の予防または治療における使用のための、セペタプロストとＥＰ２アゴニストの組み合わせ。 (9) A composition for preventing or treating glaucoma or ocular hypertension comprising cepetaprost, which is administered in combination with an EP2 agonist.
(10) A method for the prophylaxis or treatment of glaucoma or ocular hypertension comprising administering a therapeutically effective amount of cepetaprost and a therapeutically effective amount of an EP2 agonist to a subject in need thereof.
(11) Use of a combination of cepetaprost and an EP2 agonist for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension.
(12) Use of sepetaprost for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension characterized by being combined with an EP2 agonist.
(13) Sepetaprost, for use in the prevention or treatment of glaucoma or ocular hypertension, characterized in that it is used in combination with an EP2 agonist.
(14) Combination of cepetaprost and an EP2 agonist for use in the prevention or treatment of glaucoma or ocular hypertension.

　さらに、本発明は以下にも関する。 Furthermore, the present invention also relates to the following.

（１５）ＥＰ２アゴニストと組み合わされて投与されることを特徴とする、セペタプロストを含有する眼圧下降用組成物。
（１６）治療有効量のセペタプロスト及び治療有効量のＥＰ２アゴニストを、それを必要とする対象に投与することを含む、眼圧下降方法。
（１７）眼圧下降のための医薬の製造のための、セペタプロストとＥＰ２アゴニストの組み合わせの使用。
（１８）ＥＰ２アゴニストと併用されることを特徴とする、眼圧下降のための医薬の製造のための、セペタプロストの使用。
（１９）ＥＰ２アゴニストと併用されることを特徴とする、眼圧下降における使用のための、セペタプロスト。
（２０）眼圧下降における使用のための、セペタプロストとＥＰ２アゴニストの組み合わせ。 (15) A composition for ocular pressure lowering containing cepetaprost, which is administered in combination with an EP2 agonist.
(16) A method for reducing intraocular pressure, comprising administering a therapeutically effective amount of Sepetaprost and a therapeutically effective amount of an EP2 agonist to a subject in need thereof.
(17) Use of a combination of cepetaprost and an EP2 agonist for the manufacture of a medicament for lowering intraocular pressure.
(18) Use of sepetaprost for the preparation of a medicament for lowering intraocular pressure, characterized in that it is used in combination with an EP2 agonist.
(19) Sepetaprost, for use in lowering intraocular pressure, characterized in that it is used in combination with an EP2 agonist.
(20) Combination of cepetaprost and an EP2 agonist for use in intraocular pressure lowering.

　なお、前記（１）から（２０）の各構成は、任意に２以上を選択して組み合わせることができる。 In addition, each structure of said (1) to (20) can select 2 or more arbitrarily, and can combine them.

　セペタプロストとＥＰ２アゴニストとを組み合わせて眼に投与することで、眼圧下降作用が増強する。したがって、本発明は緑内障若しくは高眼圧症の予防または治療剤として有用である。さらに、本発明によれば、医薬品として十分な安全性が確保される。 The combination of sepetaprost and an EP2 agonist administered to the eye enhances the ocular hypotensive action. Therefore, the present invention is useful as an agent for the prophylaxis or treatment of glaucoma or ocular hypertension. Furthermore, according to the present invention, sufficient safety as a medicine is secured.

各投与群の経時的な眼圧下降幅の変化を示すグラフである。It is a graph which shows the change of the intraocular pressure fall width | variety over time of each administration group.

　以下、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.

　本発明は、セペタプロストとＥＰ２アゴニストが組み合わされて投与されることを特徴とする緑内障若しくは高眼圧症の予防または治療剤であり、以下、これらを単に「治療剤等」ともいう。 The present invention is an agent for the prophylaxis or treatment of glaucoma or ocular hypertension characterized in that cepetaprost and an EP2 agonist are administered in combination, and hereinafter, these are also simply referred to as "therapeutic agents etc."

　本発明の治療剤等において、セペタプロストは、下記式（１）

Figure JPOXMLDOC01-appb-C000002

で表される化合物（ＣＡＳ登録番号：１２６２８７３－０６－２）であり、２－プロパニル　４－｛（３Ｓ，５ａＲ，６Ｒ，７Ｒ，８ａＳ）－６－［（１Ｅ，３Ｒ）－４－（２，５－ジフルオロフェノキシ）－３－ヒドロキシ－１－ブテン－１－イル］－７－ヒドロキシオクタヒドロ－２Ｈ－シクロペンタ［ｂ］オキセピン－３－イル｝ブタノアートともいう。 In the therapeutic agent etc. of the present invention, sepetaprost has the following formula (1)
Figure JPOXMLDOC01-appb-C000002
And 2-propanyl 4-{(3S, 5aR, 6R, 7R, 8aS) -6-[(1E, 3R) -4- (2). It is also called 5, 5-difluorophenoxy) -3-hydroxy-1-buten-1-yl] -7-hydroxyoctahydro-2H-cyclopenta [b] oxepin-3-yl} butanolo.

　セペタプロストは、国際公開第２０１１／０１３６５１号（特許文献６）に記載の方法、当該技術分野における通常の方法等に従って製造することができる。 Sepetaprost can be produced according to the method described in International Publication WO2011 / 013 051 (Patent Document 6), the ordinary method in the art, and the like.

　セペタプロストに幾何異性体および／または光学異性体が存在する場合は、それらの異性体も本発明の範囲に含まれる。 When geometric and / or optical isomers exist in Sepetaprost, the isomers are also included in the scope of the present invention.

　セペタプロストにプロトン互変異性が存在する場合は、それらの互変異性体（ケト体、エノール体）も本発明に含まれる。 When proton tautomerism exists in Sepetaprost, their tautomers (keto form, enol form) are also included in the present invention.

　セペタプロストに結晶多形および／または結晶多形群（結晶多形システム）が存在する場合には、それらの結晶多形体および／または結晶多形群（結晶多形システム）も本発明に含まれる。ここで、結晶多形群（結晶多形システム）とは、それら結晶の製造、晶出、保存などの条件および／または状態（尚、本状態には製剤化した状態も含む）により、結晶形が種々変化する場合の各段階における結晶形および／またはその全体を意味する。 When crystalline polymorphisms and / or crystalline polymorphic groups (crystalline polymorphic system) exist in sepetaprost, those crystalline polymorphic forms and / or crystalline polymorphic groups (crystalline polymorphic system) are also included in the present invention. Here, the crystalline polymorphic group (crystalline polymorphic system) refers to a crystalline form depending on the conditions and / or conditions (also including the formulated condition in this condition) such as production, crystallization, storage, etc. of those crystals. Means the crystal form and / or the whole in each step when various changes occur.

　セペタプロストは、水和物または溶媒和物の形態をとってもよい。 Sepetaprost may be in the form of a hydrate or a solvate.

　本発明の治療剤等において、セペタプロストの含有量は、特に制限されず、また投与形態にもよるが、点眼剤の場合、セペタプロストの含有量は、０．０００００１～５％（ｗ／ｖ）が好ましく、０．００００１～０．０５％（ｗ／ｖ）がより好ましい。ここで、「％（ｗ／ｖ）」は、薬剤１００ｍＬ中に含まれる有効成分や添加剤の質量（ｇ）を意味する。例えば、セペタプロスト０．０１％（ｗ／ｖ）とは、薬剤１００ｍＬ中に含まれるセペタプロストの含有量が０．０１ｇであることを意味する。 In the therapeutic agent of the present invention, the content of cepetaprost is not particularly limited, and although it depends on the administration form, in the case of eye drops, the content of cepetaprost is 0.000001 to 5% (w / v) Preferably, 0.00001 to 0.05% (w / v) is more preferable. Here, "% (w / v)" means the mass (g) of the active ingredient and the additive contained in 100 mL of the drug. For example, Sepetaprost 0.01% (w / v) means that the content of Sepetaprost contained in 100 mL of the drug is 0.01 g.

　なお、セペタプロストの含有量は、セペタプロストが水和物や溶媒和物の形態である場合、セペタプロストのフリー体、水和物および溶媒和物のいずれを基準として計算されたものであってもよい。 In addition, when the cepetaprost is in the form of a hydrate or a solvate, the content of cepetaprost may be calculated based on any of the free form, the hydrate and the solvate of cepetaprost.

　本発明の治療剤等におけるＥＰ２アゴニストとは、ＥＰ２受容体に結合してアゴニスト活性を示す化合物を意味する。 The EP2 agonist in the therapeutic agent etc. of the present invention means a compound that binds to the EP2 receptor and exhibits agonist activity.

　ＥＰ２アゴニストの具体例としては、国際公開第２００９／１１３６００号に開示されている（６－｛［４－（ピラゾール－１－イル）ベンジル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸または（６－｛［４－（ピラゾール－１－イル）ベンジル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸イソプロピルなどのＥＰ２アゴニスト、国際公開第２００８／０１５５１７号に開示されている２－［３－［Ｎ－［４－（１Ｈ－ピラゾール－１－イル）ベンジル］－Ｎ－（ピリジン－３－イルスルホニル）アミノメチル］フェノキシ］酢酸　イソプロピルエステル（タプレネパグ　イソプロピルともいう）などのＥＰ２アゴニスト、国際公開第２００６／０９８９１８号に開示されているプロパン－２－イル　５－［［（２Ｒ）－１－［４－［（１Ｓ）－１－ヒドロキシヘキシル］フェニル］－５－オキソピロリジン－２－イル］メトキシメチル］チオフェン－２－カルボキシレート（シメネパグ　イソプロピルともいう）または５－［３－［１－［４－［１（Ｓ）－ヒドロキシヘキシル］フェニル］－５－オキソピロリジン－２（Ｓ）－イル］プロピル］チオフェン－２－カルボン酸　イソプロピルエステル（アガネパグ　イソプロピルともいう）などのＥＰ２アゴニストが例示される。中でも特に、（６－｛［４－（ピラゾール－１－イル）ベンジル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸または（６－｛［４－（ピラゾール－１－イル）ベンジル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸イソプロピルが好ましい。 As a specific example of the EP2 agonist, (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridine-2 disclosed in WO 2009/113600 is disclosed. EP2 agonists such as isopropyl (-ylamino) acetic acid or (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetate, WO 2008 / 2- [3- [N- [4- (1H-pyrazol-1-yl) benzyl] -N- (pyridin-3-ylsulfonyl) aminomethyl] phenoxy] acetic acid isopropyl ester disclosed in 015517 (Taprenepag EP2 agonists such as isopropyl), WO 2006/098 Propan-2-yl 5-[[(2R) -1- [4-[(1S) -1-hydroxyhexyl] phenyl] -5-oxopyrrolidin-2-yl] methoxymethyl disclosed in No. 18 Thiophene-2-carboxylate (also referred to as simenepag isopropyl) or 5- [3- [1- [4- [1 (S) -hydroxyhexyl] phenyl] -5-oxopyrrolidine-2 (S) -yl] propyl] Examples are EP2 agonists such as thiophene-2-carboxylic acid isopropyl ester (also referred to as aganepag isopropyl). In particular, (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetic acid or (6-{[4- (pyrazole-1-) Preferred) is isopropyl) benzyl) (pyridin-3-ylsulfonyl) aminomethyl} pyridin-2-ylamino) acetate.

　本発明の治療剤等において、ＥＰ２アゴニストの含有量は、特に制限されず、また投与形態にもよるが、点眼剤の場合、ＥＰ２アゴニストの含有量は、０．０００１～５％（ｗ／ｖ）が好ましく、０．００１～１％（ｗ／ｖ）がより好ましい。 In the therapeutic agent of the present invention, etc., the content of EP2 agonist is not particularly limited, and although it depends on the administration form, in the case of eye drops, the content of EP2 agonist is 0.0001 to 5% (w / v) Is preferred, and 0.001 to 1% (w / v) is more preferred.

　なお、これらＥＰ２アゴニストの含有量は、ＥＰ２アゴニストが塩や水和物や溶媒和物の形態である場合、ＥＰ２アゴニストのフリー体、塩、水和物および溶媒和物のいずれを基準として計算されたものであってもよい。 When the EP2 agonist is in the form of a salt, a hydrate or a solvate, the content of these EP2 agonists is calculated based on any of the free body, the salt, the hydrate and the solvate of the EP2 agonist. It may be

　本発明の治療剤等において、オミデネパグは、下記式（２）

Figure JPOXMLDOC01-appb-C000003

で表される化合物（ＣＡＳ登録番号：１１８７４５１－４１－７）であり、（６－｛［４－（ピラゾール－１－イル）ベンジル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸ともいう。ＥＰ２アゴニスト作用を有し、眼圧下降作用を示すことから、緑内障の治療剤として開発されている。 In the therapeutic agent etc. of the present invention, Omidenepag is represented by the following formula (2)
Figure JPOXMLDOC01-appb-C000003
(CAS registration number: 1187451-41-7), (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridine-2- Also known as ylamino) acetic acid. It is developed as a therapeutic agent for glaucoma because it has an EP2 agonistic action and exhibits an intraocular pressure lowering action.

　本発明の治療剤等において、オミデネパグのエステルは、オミデネパグのカルボキシル基が炭素数１～６の１価アルコールと脱水縮合することで形成されるエステルが好ましく、より好ましくは、オミデネパグのカルボキシル基が炭素数２～５、さらに好ましくは炭素数３～４の１価アルコールと脱水縮合することで形成されるエステルが好適である。具体的なエステルとしては、メチルエステル、エチルエステル、ｎ－プロピルエステル、イソプロピルエステル、ｎ－ブチルエステル、イソブチルエステル、ｓｅｃ－ブチルエステル、ｔｅｒｔ－ブチルエステル、ｎ－ペンチルエステルまたはｎ－ヘキシルエステルが挙げられ、好ましくは、エチルエステル、ｎ－プロピルエステル、イソプロピルエステルが挙げられ、より好ましくは、イソプロピルエステルが挙げられる。オミデネパグのイソプロピルエステルは、具体的には、下記式（３）

Figure JPOXMLDOC01-appb-C000004

で表される化合物（ＣＡＳ登録番号：１１８７４５１－１９－９）であり、オミデネパグ　イソプロピルまたは（６－｛［４－（ピラゾール－１－イル）ベンジル］（ピリジン－３－イルスルホニル）アミノメチル｝ピリジン－２－イルアミノ）酢酸イソプロピルともいう。ＥＰ２アゴニスト作用を有し、眼圧下降作用を示すことから、緑内障の治療剤として開発されている。 In the therapeutic agent of the present invention and the like, 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, and more preferably, the carboxyl group of omidenepag is carbon An ester formed by dehydration condensation with a monohydric alcohol having a number of 2 to 5, more preferably 3 to 4 carbon atoms is preferable. Specific esters include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, n-pentyl ester or n-hexyl ester Preferably, ethyl ester, n-propyl ester and isopropyl ester are mentioned, and more preferably isopropyl ester is mentioned. Specifically, the isopropyl ester of Omidenepag is represented by the following formula (3)
Figure JPOXMLDOC01-appb-C000004
Or a compound represented by the formula (CAS Registry Number: 1187451-19-9), and Omidenepag isopropyl or (6-{[4- (pyrazol-1-yl) benzyl] (pyridin-3-ylsulfonyl) aminomethyl} pyridine -2-ylamino) It is also called isopropyl acetate. It is developed as a therapeutic agent for glaucoma because it has an EP2 agonistic action and exhibits an intraocular pressure lowering action.

　本発明の治療剤等において、オミデネパグの塩またはオミデネパグのエステルの塩は、薬理上許容される塩であれば特に制限されない。具体的には、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、硫酸塩若しくはリン酸塩等の無機酸塩；酢酸塩、トリフルオロ酢酸塩、安息香酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、トリフルオロメタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、グルタミン酸塩若しくはアスパラギン酸塩等の有機酸塩；ナトリウム塩、カリウム塩、カルシウム塩若しくはマグネシウム塩等の金属塩；アンモニウム塩等の無機塩；またはトリエチルアミン塩若しくはグアニジン塩等の有機アミン塩等が挙げられ、好ましくは、塩酸塩またはトリフルオロ酢酸塩が挙げられる。 In the therapeutic agent of the present invention and the like, the salt of omidenepag or the salt of ester of omidenepag is not particularly limited as long as it is a pharmacologically acceptable salt. Specifically, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or phosphate; acetate, trifluoroacetate, benzoate, oxalate, Malonate, Succinate, Maleate, Fumarate, Tartrate, Citrate, Methanesulfonate, Ethanesulfonate, Trifluoromethanesulfonate, Benzenesulfonate, p-Toluenesulfonate Organic salts such as glutamate or asparaginate; 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 or trifluoroacetate salt is mentioned.

　本発明の治療剤等において、オミデネパグ若しくはそのエステルまたはそれらの塩は、米国特許出願公開第２０１２／０１９０８５２号明細書、米国特許出願公開第２０１１／００５４１７２号明細書、米国特許出願公開第２０１７／０１２１２８８号明細書、米国特許出願公開第２０１７／０１１４０４３号明細書に記載の方法、当該技術分野における通常の方法等に従って製造することができる。なお、本願で使用する「オミデネパグ若しくはそのエステルまたはそれらの塩」の語は、（１）オミデネパグ、（２）オミデネパグのエステル、（３）オミデネパグの塩、及び（４）オミデネパグのエステルの塩、を含む意味である。 In the therapeutic agent etc. of the present invention, Omidenepag or an ester thereof or a salt thereof is disclosed in US Patent Application Publication No. 2012/0190852, US Patent Application Publication No. 2011/0054172, US Patent Application Publication No. 2017/0121288. No. 201, U.S. Patent Application Publication No. 2017/0114043, and the usual methods in the art. In addition, the term "omidenepag or ester thereof or a salt thereof" used in the present application includes (1) Omidenepag, (2) ester of omidenepag, (3) salt of omidenepag, and (4) salt of ester of omidenepag It is an included meaning.

　オミデネパグ若しくはそのエステルまたはそれらの塩に幾何異性体および／または光学異性体が存在する場合は、それらの異性体も本発明の範囲に含まれる。 When geometric isomers and / or optical isomers exist in Omidenepag or an ester thereof or a salt thereof, the isomers are also included in the scope of the present invention.

　オミデネパグ若しくはそのエステルまたはそれらの塩にプロトン互変異性が存在する場合は、それらの互変異性体（ケト体、エノール体）も本発明に含まれる。 When proton tautomerism exists in Omidenepag or an ester thereof or a salt thereof, the tautomers (keto form, enol form) thereof are also included in the present invention.

　オミデネパグ若しくはそのエステルまたはそれらの塩に結晶多形および／または結晶多形群（結晶多形システム）が存在する場合には、それらの結晶多形体および／または結晶多形群（結晶多形システム）も本発明に含まれる。ここで、結晶多形群（結晶多形システム）とは、それら結晶の製造、晶出、保存などの条件および／または状態（尚、本状態には製剤化した状態も含む）により、結晶形が種々変化する場合の各段階における結晶形および／またはその全体を意味する。 When there is a crystalline polymorph and / or a crystalline polymorph group (crystalline polymorphic system) in Omidenepag or an ester thereof or a salt thereof, the crystalline polymorph and / or the crystalline polymorph group (crystalline polymorphic system) thereof Also included in the present invention. Here, the crystalline polymorphic group (crystalline polymorphic system) refers to a crystalline form depending on the conditions and / or conditions (also including the formulated condition in this condition) such as production, crystallization, storage, etc. of those crystals. Means the crystal form and / or the whole in each step when various changes occur.

　本発明の治療剤等において、オミデネパグ若しくはそのエステルまたはそれらの塩は、水和物または溶媒和物の形態をとってもよい。 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 a solvate.

　本発明の治療剤等において、オミデネパグ若しくはそのエステルまたはそれらの塩の含有量は、特に制限されず、また投与形態にもよるが、点眼剤の場合、本発明の薬剤に含有されるオミデネパグ若しくはそのエステルまたはそれらの塩の含有量の下限は０．０００３％（ｗ／ｖ）が好ましく、０．００１％（ｗ／ｖ）がより好ましく、０．００１３％（ｗ／ｖ）がさらに好ましく、０．００１５％（ｗ／ｖ）が特に好ましい。また、上記含有量の上限は、０．０３％（ｗ／ｖ）が好ましく、０．０１％（ｗ／ｖ）がより好ましく、０．００５％（ｗ／ｖ）がさらに好ましく、０．００３％（ｗ／ｖ）が特に好ましく、０．００２７％（ｗ／ｖ）が殊更に好ましい。より詳細に、上記含有量は、上記下限及び上限のいずれかを組み合わせた範囲であっても良いが、０．０００３～０．０３％（ｗ／ｖ）が好ましく、０．００１～０．０１％（ｗ／ｖ）がより好ましく、０．００１～０．００５％（ｗ／ｖ）がさらに好ましく、０．００１～０．００３％（ｗ／ｖ）が特に好ましく、０．００１３～０．００３％（ｗ／ｖ）が殊更に好ましく、０．００１５～０．００２７％（ｗ／ｖ）が格別好ましい。より具体的には、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）、０．００２２％（ｗ／ｖ）、０．００２３％（ｗ／ｖ）、０．００２４％（ｗ／ｖ）、０．００２５％（ｗ／ｖ）、０．００２６％（ｗ／ｖ）、０．００２７％（ｗ／ｖ）、０．００２８％（ｗ／ｖ）、０．００２９％（ｗ／ｖ）、０．００３０％（ｗ／ｖ）、０．００５％（ｗ／ｖ）、０．０１％（ｗ／ｖ）、０．０３％（ｗ／ｖ）及びこれらの量を上限または下限とする範囲が好ましい。 In the therapeutic agent and the like of the present invention, the content of omidenepag or its ester or a salt thereof is not particularly limited, and it depends on the administration form, but in the case of eye drops, the omidenepag contained in the agent of the present invention or its The lower limit of the content of the ester or a salt thereof is preferably 0.0003% (w / v), more preferably 0.001% (w / v), still more preferably 0.0013% (w / v), 0 .0015% (w / v) is particularly preferred. The upper limit of the content is preferably 0.03% (w / v), more preferably 0.01% (w / v), still more preferably 0.005% (w / v), and 0.003 % (W / v) is particularly preferred and 0.0027% (w / v) is particularly preferred. More specifically, although the content may be a range combining any of the above lower limit and the upper limit, 0.0003 to 0.03% (w / v) is preferable, and 0.001 to 0.01 is preferable. % (W / v) is more preferable, 0.001 to 0.005% (w / v) is more preferable, and 0.001 to 0.003% (w / v) is particularly preferable, and 0.0013 to 0. 003% (w / v) is particularly preferred and 0.0015 to 0.0027% (w / v) is particularly preferred. 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), 0.0022% (w / v), 0.0023% (w / v), 0.0024% (W / v), 0.0025% (w / v), 0.0026% (w / v), 0.0027% (w / v), 0.0028% (w / v), 0.0029% (W / v), 0.0030% (w / v), 0.005% (w / v), 0.01% (w / v), 0.03% (w / v) and their amounts Upper and lower limit It is preferred.

　なお、これらオミデネパグ若しくはそのエステルまたはそれらの塩の含有量は、オミデネパグ若しくはそのエステルまたはそれらの塩が、塩や水和物や溶媒和物の形態である場合、オミデネパグ若しくはそのエステルまたはそれらの塩のフリー体、塩、水和物および溶媒和物のいずれを基準として計算されたものであってもよい。 When the content of Omidenepag or an ester thereof or a salt thereof is in the form of a salt, a hydrate or a solvate, the Omidenepag or an ester thereof or a salt thereof, the Omidenepag or an ester thereof or a salt thereof It may be calculated based on any of the free form, salt, hydrate and solvate.

　本発明の治療剤等において、セペタプロストとＥＰ２アゴニストの他に、さらに、１または複数の他の緑内障若しくは高眼圧症の予防または治療薬とを組み合わせて使用してもよい。他の緑内障若しくは高眼圧症の予防または治療薬は、眼圧下降作用を有して緑内障治療に有用なものであればよく、非選択性交感神経作動薬、α２受容体作動薬、α１受容体遮断薬、β受容体遮断薬、副交感神経作動薬、炭酸脱水酵素阻害剤、プロスタグランジン類などが挙げられる。 In the therapeutic agent and the like of the present invention, in addition to cepetaprost and the EP2 agonist, one or more other glaucoma or ocular hypertension preventive or therapeutic agents may be used in combination. Other agents for preventing or treating glaucoma or ocular hypertension may be those which have an intraocular pressure lowering action and are useful for glaucoma treatment, and are nonselective sympathetic agonists, alpha 2 receptor agonists, alpha 1 Receptor blockers, beta receptor blockers, parasympathetic agonists, carbonic anhydrase inhibitors, prostaglandins and the like can be mentioned.

　非選択性交感神経作動薬の具体例としては、ジピベフリンが挙げられ、α２受容体作動薬の具体例としては、ブリモニジン、アプラクロニジンが挙げられ、α１受容体遮断薬の具体例としてはブナゾシンが挙げられ、β受容体遮断薬の具体例としては、チモロール、ベフノロール、カルテオロール、ニプラジロール、ベタキソロール、レボブノロール、メチプラノロールが挙げられ、副交感神経作動薬の具体例としてはピロカルピンが挙げられ、炭酸脱水酵素阻害剤の具体例としては、ドルゾラミド、ブリンゾラミド、アセタゾラミドが挙げられ、プロスタグランジン類の具体例としては、イソプロピルウノプロストン、ラタノプロスト、トラボプロスト、ビマトプロストが挙げられる。これらは、医薬として許容される塩の形態も含む。塩の具体例としては、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、硫酸塩若しくはリン酸塩等の無機酸塩；酢酸塩、トリフルオロ酢酸塩、安息香酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、トリフルオロメタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、グルタミン酸塩若しくはアスパラギン酸塩等の有機酸塩；ナトリウム塩、カリウム塩、カルシウム塩若しくはマグネシウム塩等の金属塩；アンモニウム塩等の無機塩；またはトリエチルアミン塩若しくはグアニジン塩等の有機アミン塩等が挙げられる。 Specific examples of nonselective sympathetic agonists include dipivefrine, specific examples of α 2 receptor agonists include brimonidine and apraclonidine, and specific examples of α 1 receptor blockers include bunazosin Specific examples of beta receptor blockers include timolol, befnolol, carteolol, niprazilol, betaxolol, levobnolol, and methipranol, and specific examples of parasympathomimetics include pilocarpine, carbonate Specific examples of the dehydrating enzyme inhibitor include dorzolamide, brinzolamide and acetazolamide, and specific examples of the prostaglandins include isopropyl unoprostone, latanoprost, travoprost and bimatoprost. These also include pharmaceutically acceptable salt forms. Specific examples of the salts include hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates or phosphates and other inorganic acid salts; acetates, trifluoroacetates, benzoates, oxalic acid Salt, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfone Acid salts, organic acid salts such as glutamate or aspartate; metal salts such as sodium salts, potassium salts, calcium salts or magnesium salts; inorganic salts such as ammonium salts; or organic amine salts such as triethylamine salts or guanidine salts Can be mentioned.

　さらに、他の緑内障若しくは高眼圧症の予防または治療薬は、水和物または溶媒和物の形態をとってもよい。 In addition, other glaucoma or ocular hypertensive prophylactic or therapeutic agents may be in the form of hydrates or solvates.

　本発明の治療剤等において、他の緑内障若しくは高眼圧症の予防または治療薬と組み合わせて使用する場合、その含有量は、特に制限されず、含有される予防または治療薬の種類や投与形態にもよるが、点眼剤の場合の好ましい含有量は以下の通りである。 When the therapeutic agent of the present invention is used in combination with other glaucoma or hypertensive prophylactic or therapeutic agents, the content thereof is not particularly limited, depending on the type and administration form of the preventive or therapeutic agents contained. Although depending on the matter, the preferable content in the case of eye drops is as follows.

　非選択性交感神経作動薬の含有量は、薬物の種類によって異なるが、ジピベフリンの場合には、０．００１～３％（ｗ／ｖ）が好ましく、０．０４～０．１％（ｗ／ｖ）がより好ましく、０．０４％（ｗ／ｖ）または０．１％（ｗ／ｖ）が特に好ましい。 The content of the nonselective sympathetic agonist varies depending on the type of drug, but in the case of dipivefrine, 0.001 to 3% (w / v) is preferable, and 0.04 to 0.1% (w / v). v) is more preferred, 0.04% (w / v) or 0.1% (w / v) is particularly preferred.

　α２受容体作動薬の含有量は、薬物の種類によって異なるが、ブリモニジンの場合には、０．０１～５％（ｗ／ｖ）が好ましく、０．１～０．５％（ｗ／ｖ）がより好ましく、０．１％（ｗ／ｖ）、０．１５％（ｗ／ｖ）、０．２％（ｗ／ｖ）または０．５％（ｗ／ｖ）が特に好ましい。また、アプラクロニジンの場合には、０．０１～５％（ｗ／ｖ）が好ましく、０．５～１％（ｗ／ｖ）がより好ましく、０．５％（ｗ／ｖ）が特に好ましい。 The content of the α 2 receptor agonist varies depending on the type of drug, but in the case of brimonidine, 0.01 to 5% (w / v) is preferable, and 0.1 to 0.5% (w / v) Is more preferred, 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 preferable, 0.5 to 1% (w / v) is more preferable, and 0.5% (w / v) is particularly preferable .

　α１受容体遮断薬の含有量は、薬物の種類によって異なるが、ブナゾシンの場合には、０．００１～０．３％（ｗ／ｖ）が好ましく、０．００３～０．０３％（ｗ／ｖ）がより好ましく、０．０１％（ｗ／ｖ）が特に好ましい。 The content of the α 1 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), preferably 0.003 to 0.03% (w / V) is more preferable, and 0.01% (w / v) is particularly preferable.

　β受容体遮断薬の含有量は、薬物の種類によって異なるが、チモロールの場合には、０．０１～５％（ｗ／ｖ）が好ましく、０．１～０．５％（ｗ／ｖ）がより好ましく、０．１％（ｗ／ｖ）、０．２５％（ｗ／ｖ）または０．５％（ｗ／ｖ）が特に好ましい。また、ベフノロールの場合には、０．０１～５％（ｗ／ｖ）が好ましく、０．２５～１％（ｗ／ｖ）がより好ましく、０．２５％（ｗ／ｖ）、０．５％（ｗ／ｖ）または１％（ｗ／ｖ）が特に好ましい。カルテオロールの場合には、０．０１～５％（ｗ／ｖ）が好ましく、１～２％（ｗ／ｖ）がより好ましく、１％（ｗ／ｖ）または２％（ｗ／ｖ）が特に好ましい。ニプラジロールの場合には、０．０１～５％（ｗ／ｖ）が好ましく、０．２５％（ｗ／ｖ）が特に好ましい。ベタキソロールの場合には、０．０１～５％（ｗ／ｖ）が好ましく、０．２５～０．５％（ｗ／ｖ）がより好ましく、０．２５％（ｗ／ｖ）または０．５％（ｗ／ｖ）が特に好ましい。レボブノロールの場合には、０．０１～５％（ｗ／ｖ）が好ましく、０．２５～０．５％（ｗ／ｖ）がより好ましく、０．２５％（ｗ／ｖ）または０．５％（ｗ／ｖ）が特に好ましい。メチプラノロールの場合には、０．０１～５％（ｗ／ｖ）が好ましく、０．３％（ｗ／ｖ）が特に好ましい。 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), and 0.1 to 0.5% (w / v) Is more preferred, 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 preferable, 0.25 to 1% (w / v) is more preferable, 0.25% (w / v) or 0.5 % (W / v) or 1% (w / v) are particularly preferred. In the case of carteolol, 0.01 to 5% (w / v) is preferred, 1 to 2% (w / v) is more preferred, 1% (w / v) or 2% (w / v) Particularly preferred. In the case of nipradilol, 0.01 to 5% (w / v) is preferred, 0.25% (w / v) is particularly preferred. In the case of betaxolol, 0.01 to 5% (w / v) is preferred, 0.25 to 0.5% (w / v) is more preferred, 0.25% (w / v) or 0.5 % (W / v) is particularly preferred. In the case of levobnolol, 0.01 to 5% (w / v) is preferred, 0.25 to 0.5% (w / v) is more preferred, 0.25% (w / v) or 0.5 % (W / v) is particularly preferred. In the case of methipranol, 0.01 to 5% (w / v) is preferred, 0.3% (w / v) is particularly preferred.

　副交感神経作動薬の含有量は、薬物の種類によって異なるが、ピロカルピンの場合には、０．０１～２０％（ｗ／ｖ）が好ましく、０．１～５％（ｗ／ｖ）がより好ましく、０．５％（ｗ／ｖ）、１％（ｗ／ｖ）、２％（ｗ／ｖ）、３％（ｗ／ｖ）または４％（ｗ／ｖ）が特に好ましい。 The content of the parasympathetic agonist 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) 0.5% (w / v), 1% (w / v), 2% (w / v), 3% (w / v) or 4% (w / v) are particularly preferred.

　炭酸脱水酵素阻害剤の含有量は、薬物の種類によって異なるが、ドルゾラミドの場合には、０．０１～５％（ｗ／ｖ）が好ましく、０．５～２％（ｗ／ｖ）がより好ましく、０．５％（ｗ／ｖ）、１％（ｗ／ｖ）または２％（ｗ／ｖ）が特に好ましい。また、ブリンゾラミドの場合には、０．０１～５％（ｗ／ｖ）が好ましく、０．１～２％（ｗ／ｖ）がより好ましく、１％（ｗ／ｖ）が特に好ましい。また、アセタゾラミドの場合には、０．０１～５％（ｗ／ｖ）が好ましく、１～５％（ｗ／ｖ）がより好ましい。なお、アセタゾラミドを経口投与する場合には、１日量として２５０～１０００ｍｇを使用することができる。 The content of carbonic anhydrase inhibitor varies depending on the type of drug, but in the case of dorzolamide, it is preferably 0.01 to 5% (w / v), more preferably 0.5 to 2% (w / v) Preferably, 0.5% (w / v), 1% (w / v) or 2% (w / v) are particularly preferred. In the case of brinzolamide, 0.01 to 5% (w / v) is preferable, 0.1 to 2% (w / v) is more preferable, and 1% (w / v) is particularly preferable. In the case of acetazolamide, 0.01 to 5% (w / v) is preferable, and 1 to 5% (w / v) is more preferable. When acetazolamide is orally administered, 250 to 1000 mg can be used as a daily dose.

　プロスタグランジン類の含有量は、薬物の種類によって異なるが、ラタノプロストの場合には、０．０００１～５％（ｗ／ｖ）が好ましく、０．０００５～１％（ｗ／ｖ）がより好ましく、０．００１～０．１％（ｗ／ｖ）がさらに好ましく、０．００５％（ｗ／ｖ）が特に好ましい。イソプロピルウノプロストンの場合には、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～１％（ｗ／ｖ）がより好ましく、０．１２～０．１５％（ｗ／ｖ）がさらに好ましく、０．１２％（ｗ／ｖ）または０．１５％（ｗ／ｖ）が特に好ましい。ビマトプロストの場合には、０．０００１～５％（ｗ／ｖ）が好ましく、０．００１～１％（ｗ／ｖ）がより好ましく、０．０１～０．０３％（ｗ／ｖ）がさらに好ましく、０．０１％（ｗ／ｖ）または０．０３％（ｗ／ｖ）が特に好ましい。トラボプロストの場合には、０．０００１～５％（ｗ／ｖ）が好ましく、０．００１～１％（ｗ／ｖ）がより好ましく、０．００４％（ｗ／ｖ）が特に好ましい。 The content of prostaglandins varies depending on the type of drug, but in the case of latanoprost, 0.0001 to 5% (w / v) is preferable, 0.0005 to 1% (w / v) is more preferable 0.001 to 0.1% (w / v) is more preferable, and 0.005% (w / v) is particularly preferable. In the case of isopropyl unoprostone, 0.001 to 5% (w / v) is preferable, 0.01 to 1% (w / v) is more preferable, 0.12 to 0.15% (w / v) Is more preferred, 0.12% (w / v) or 0.15% (w / v) is particularly preferred. In the case of bimatoprost, 0.0001 to 5% (w / v) is preferable, 0.001 to 1% (w / v) is more preferable, and 0.01 to 0.03% (w / v) is more preferable Preferably, 0.01% (w / v) or 0.03% (w / v) is particularly preferred. In the case of travoprost, 0.0001 to 5% (w / v) is preferable, 0.001 to 1% (w / v) is more preferable, and 0.004% (w / v) is particularly preferable.

　なお、これら他の緑内障若しくは高眼圧症の予防または治療薬の含有量は、他の緑内障若しくは高眼圧症の予防または治療薬が塩や水和物や溶媒和物の形態である場合、他の緑内障若しくは高眼圧症の予防または治療薬のフリー体、塩、水和物および溶媒和物のいずれを基準として計算されたものであってもよい。 The content of these other glaucoma or ocular hypertensive prophylactic or therapeutic agents is other glaucoma or ocular hypertension preventive or therapeutic agents in the form of salts, hydrates, or solvates. It may be calculated based on the free form, the salt, the hydrate and the solvate of the glaucoma or ocular hypertensive prophylactic or therapeutic agent.

　本発明の治療剤等は、セペタプロストとＥＰ２アゴニストが組み合わされて投与されることで緑内障若しくは高眼圧症を予防または治療するところに特徴がある。本発明の治療剤等における緑内障としては、原発開放隅角緑内障、続発開放隅角緑内障、正常眼圧緑内障、房水産生過多緑内障、原発閉塞隅角緑内障、続発閉塞隅角緑内障、プラトー虹彩緑内障、混合型緑内障、発達緑内障、ステロイド緑内障、落屑緑内障、アミロイド緑内障、血管新生緑内障、悪性緑内障、水晶体の嚢性緑内障、ｐｌａｔｅａｕ　ｉｒｉｓ　ｓｙｎｄｒｏｍｅなどが例示される。 The therapeutic agent etc. of the present invention is characterized in that glaucoma or ocular hypertension is prevented or treated by administering cepetaprost and an EP2 agonist in combination. Examples of glaucoma in the therapeutic agents of the present invention include primary open angle glaucoma, secondary open angle glaucoma, normal tension glaucoma, aqueous humor hyperglaucoma, primary closed angle glaucoma, secondary closed angle glaucoma, plateau iris glaucoma, Examples thereof include mixed glaucoma, developmental glaucoma, steroid glaucoma, exfoliation glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma, plateau iris syndrome and the like.

　本発明の治療剤等において、投与形態としては、セペタプロストを含有する製剤とＥＰ２アゴニストを含有する別の製剤を投与（併用投与）してもよく、また、セペタプロストとＥＰ２アゴニストを含有する１つの製剤（配合剤）で投与してもよい。また、セペタプロストとＥＰ２アゴニストの他に、さらに、１または複数の他の緑内障若しくは高眼圧症の予防または治療薬を組み合わせて使用する場合は、セペタプロストとＥＰ２アゴニストと、他の緑内障若しくは高眼圧症の予防または治療薬を併用投与してもよく、これらのうち任意の成分を配合した配合剤と残りの成分とを併用投与してもよく、すべての成分を配合した配合剤としてもよい。 In the therapeutic agent of the present invention, as a dosage form, a preparation containing cepetaprost and another preparation containing an EP2 agonist may be administered (coadministered), and one preparation containing cepetaprost and an EP2 agonist You may administer by (compounded drug). In addition, when used in combination with one or more other glaucoma or ocular hypertension preventive or therapeutic agents in addition to cepetaprost and the EP2 agonist, the cepetaprost and the EP2 agonist and the other glaucoma or ocular hypertension A preventive or therapeutic agent may be co-administered, or a combination containing any of these components may be co-administered with the remaining components, or may be a combination containing all the components.

　本発明の治療剤等は経口でも非経口でも投与することができ、これらの製剤化には特別な技術は必要なく、汎用される技術を用いて製剤化をすることができる。投与剤型としては、点眼剤、眼軟膏、注射剤、錠剤、カプセル剤、顆粒剤、散剤などが挙げられ、点眼剤または眼軟膏が好ましい。 The therapeutic agent and the like of the present invention can be administered orally or parenterally, and no special technique is required for their formulation, and they can be formulated using widely used techniques. Dosage forms include eye drops, eye ointments, injections, tablets, capsules, granules, powders and the like, with eye drops or eye ointments being preferred.

　セペタプロストとＥＰ２アゴニストと、他の緑内障若しくは高眼圧症の予防または治療薬とを別々に製剤化する場合は、それぞれ公知の方法に準じて製剤を調製することができる。ＥＰ２アゴニストや他の緑内障若しくは高眼圧症の予防または治療薬の製剤としては、既に市販されているリパスジル、ジピベフリン、ブリモニジン、アプラクロニジン、ブナゾシン、チモロール、ベフノロール、カルテオロール、ニプラジロール、ベタキソロール、レボブノロール、メチプラノロール、ピロカルピン、ドルゾラミド、ブリンゾラミド、アセタゾラミド、イソプロピルウノプロストン、ラタノプロスト、トラボプロスト、ビマトプロスト、コソプト（登録商標）配合点眼液、ザラカム（登録商標）配合点眼液、デュオトラバ（登録商標）配合点眼液などの製剤またはそれに準じたものを使用することもできる。 When sepetaprost, an EP2 agonist, and other glaucoma or ocular hypertensive prophylactic or therapeutic agents are separately formulated, the formulations can be prepared according to known methods. Preparations of EP2 agonist and other glaucoma or ocular hypertensive agents for prevention or treatment of ripasil, dipivefephrine, brimonidine, apraclonidine, apraclonidine, bunazocine, timolol, befnolol, carteolol, niprazirole, betaxolol, levobnolol, methi Planolol, pilocarpine, dorzolamide, brinzolamide, acetazolamide, isopropyl unoprostone, latanoprost, travoprost, bimatoprost, cosopto® combination ophthalmic solution, zaracam® combination ophthalmic solution, duotrava® combination ophthalmic solution It is also possible to use preparations such as or the like.

　また、おのおのの成分を配合した１つの製剤を調製する場合も、公知の方法に準じて調製することができる。 Moreover, also when preparing one formulation which mix | blended each component, it can prepare according to a well-known method.

　点眼剤とする場合は、精製水、緩衝液などにセペタプロストやＥＰ２アゴニストを添加、攪拌した後、ｐＨ調整剤によりｐＨを調整することで所望の点眼剤を調製できる。また、必要に応じて点眼剤に汎用されている添加剤を用いることができ、添加剤としては、等張化剤、緩衝化剤、界面活性剤、安定化剤、防腐剤、可溶化剤などが挙げられる。 When it is used as an eye drop, a desired eye drop can be prepared by adjusting the pH with a pH adjuster after adding and stirring cepetaprost and an EP2 agonist to purified water, buffer solution and the like. In addition, additives widely used in eye drops can be used as needed, and as additives, tonicity agents, buffering agents, surfactants, stabilizers, preservatives, solubilizers, etc. Can be mentioned.

　点眼剤のｐＨは眼科製剤に許容される範囲内にあればよく、ｐＨ４～８の範囲が好ましく、ｐＨ５～７の範囲がより好ましい。 The pH of the eye drop may be within the range acceptable for the ophthalmic preparation, preferably in the range of 4 to 8, and more preferably in the range of 5 to 7.

　眼軟膏とする場合は、汎用される基剤を用いて調製することができ、基剤としては、白色ワセリン、流動パラフィンなどが挙げられる。 When used as an eye ointment, it can be prepared using a widely used base, and examples of the base include white petrolatum, liquid paraffin and the like.

　錠剤、カプセル剤、顆粒剤、散剤などの経口剤とする場合は、増量剤、滑沢剤、結合剤、崩壊剤、コーティング剤、皮膜剤などを必要に応じて加え調製することができる。増量剤としては、乳糖、結晶セルロース、デンプン、植物油などが挙げられ、滑沢剤としては、ステアリン酸マグネシウム、タルクなどが挙げられ、結合剤としては、ヒドロキシプロピルセルロース、ポリビニルピロリドンなどが挙げられ、崩壊剤としては、カルボキシメチルセルロースカルシウム、低置換ヒドロキシプロピルメチルセルロースなどが挙げられ、コーティング剤としては、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコン樹脂などが挙げられ、皮膜剤としては、ゼラチン皮膜などが挙げられる。 In the case of oral preparation such as tablet, capsule, granule, powder and the like, a filler, lubricant, binder, disintegrant, coating agent, coating agent and the like can be added as needed. As the bulking agent, lactose, crystalline cellulose, starch, vegetable oil and the like can be mentioned, as lubricants, magnesium stearate, talc and the like can be mentioned, as binders, hydroxypropyl cellulose, polyvinyl pyrrolidone and the like can be mentioned, Disintegrants include carboxymethylcellulose calcium, low-substituted hydroxypropyl methylcellulose and the like, coating agents include hydroxypropyl methylcellulose, macrogol, silicone resin and the like, and coating agents include gelatin films and the like.

　本発明の治療剤等の投与方法は、剤型、投与すべき患者の症状の軽重、年齢、体重、投与経路、医師の判断などに応じて適宜変えることができるが、セペタプロストとＥＰ２アゴニストを含有する配合剤の場合は、１日に１～５回投与することができ、１日に１回または２回投与することが好ましく、１日に１回投与することが最も好ましい。セペタプロストを含有する製剤とＥＰ２アゴニストを含有する製剤を併用投与する場合は、それぞれの製剤を、異なる時間に、または、同時に、１日に１～３回投与することができ、１日に１回または２回投与することが好ましく、１日に１回投与することが最も好ましい。なお、併用投与において、異なる時間に製剤を投与する場合は、製剤を投与する順番に制限はなく、一の製剤が投与された後、１２時間以内、好ましくは６時間以内、より好ましくは１時間以内、さらに好ましくは３０分以内、特に好ましくは５分以内、最も好ましくは速やかに他の製剤が投与されればよい。上記投与方法において、点眼投与の場合は、１回につき、１～３滴投与することが好ましく、１または２滴投与することがより好ましく、１滴投与することが最も好ましい。 The administration method of the therapeutic agent etc. of the present invention can be suitably changed according to the dosage form, severity of the condition of the patient to be administered, age, body weight, administration route, physician's judgment etc., but contains cepetaprost and EP2 agonist In the case of a combination drug, it can be administered 1 to 5 times a day, preferably once or twice a day, and most preferably once a day. When coadministering a formulation containing cepetaprost and a formulation containing an EP2 agonist, each formulation can be administered 1 to 3 times a day at different times or simultaneously, once a day Alternatively, it is preferable to administer twice, most preferably once a day. When the preparations are administered at different times in combination administration, the order of administration of the preparations is not limited, and within one hour, preferably within six hours, more preferably one hour after administration of one preparation. The other preparation may be administered within the range of 30 minutes, more preferably within 30 minutes, particularly preferably within 5 minutes, and most preferably immediately. In the above administration method, in the case of eye drop administration, it is preferable to administer 1 to 3 drops per dose, more preferably 1 or 2 drops, and most preferably 1 drop.

　上記本発明の治療剤等の詳細な説明は、本発明のＥＰ２アゴニストと併用されることを特徴とする、セペタプロストを含有する緑内障若しくは高眼圧症の予防または治療剤にも適用される。上記本発明の治療剤等の詳細な説明は、本発明のセペタプロストとＥＰ２アゴニストとを組み合わせたことを特徴とする眼圧下降剤にも適用される。上記本発明の治療剤等の詳細な説明は、本発明のＥＰ２アゴニストと併用されることを特徴とする、セペタプロストを含有する眼圧下降剤にも適用される。 The above detailed description of the therapeutic agent etc. of the present invention also applies to a glaucoma- or ocular hypertension preventive or therapeutic agent containing cepetaprost, which is characterized by being used in combination with the EP2 agonist of the present invention. The above detailed description of the therapeutic agent and the like of the present invention also apply to an intraocular pressure-lowering agent characterized by combining the cepetaprost of the present invention and an EP2 agonist. The above detailed description of the therapeutic agent and the like of the present invention also applies to an intraocular pressure lowering agent containing cepetaprost, which is characterized by being used in combination with the EP2 agonist of the present invention.

　また、上記本発明の治療剤等の詳細な説明は、本発明の以下に示す態様にも適用される。 The detailed description of the therapeutic agent and the like of the present invention also applies to the following aspects of the present invention.

　本発明の一態様は、ＥＰ２アゴニストと組み合わされて投与されることを特徴とする、セペタプロストを含有する緑内障若しくは高眼圧症の予防または治療用組成物である。 One aspect of the present invention is a composition for preventing or treating glaucoma or ocular hypertension comprising cepetaprost, which is administered in combination with an EP2 agonist.

　本発明の一態様は、治療有効量のセペタプロスト及び治療有効量のＥＰ２アゴニストを、それを必要とする対象に投与することを含む、緑内障若しくは高眼圧症の予防または治療方法である。 One aspect of the present invention is a method for the prophylaxis or treatment of glaucoma or ocular hypertension comprising administering a therapeutically effective amount of Sepetaprost and a therapeutically effective amount of an EP2 agonist to a subject in need thereof.

　本発明の一態様は、緑内障若しくは高眼圧症の予防または治療のための医薬の製造のための、セペタプロストとＥＰ２アゴニストの組み合わせの使用である。 One aspect of the present invention is the use of a combination of cepetaprost and an EP2 agonist for the manufacture of a medicament for the prevention or treatment of glaucoma or ocular hypertension.

　本発明の一態様は、ＥＰ２アゴニストと併用されることを特徴とする、緑内障若しくは高眼圧症の予防または治療のための医薬の製造のための、セペタプロストの使用である。 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 an EP2 agonist.

　本発明の一態様は、ＥＰ２アゴニストと併用されることを特徴とする、緑内障若しくは高眼圧症の予防または治療における使用のための、セペタプロストである。 One aspect of the present invention is sepetaprost, for use in the prevention or treatment of glaucoma or ocular hypertension characterized in that it is used in combination with an EP2 agonist.

　本発明の一態様は、緑内障若しくは高眼圧症の予防または治療における使用のための、セペタプロストとＥＰ２アゴニストの組み合わせである。 One aspect of the present invention is the combination of cepetaprost and an EP2 agonist for use in the prevention or treatment of glaucoma or ocular hypertension.

　本発明の一態様は、ＥＰ２アゴニストと組み合わされて投与されることを特徴とする、セペタプロストを含有する眼圧下降用組成物である。 One aspect of the present invention is a composition for ocular pressure lowering containing cepetaprost, which is administered in combination with an EP2 agonist.

　本発明の一態様は、治療有効量のセペタプロスト及び治療有効量のＥＰ２アゴニストを、それを必要とする対象に投与することを含む、眼圧下降方法である。 One aspect of the invention is a method of reducing intraocular pressure comprising administering to a subject in need thereof a therapeutically effective amount of Sepetaprost and a therapeutically effective amount of an EP2 agonist.

　本発明の一態様は、眼圧下降のための医薬の製造のための、セペタプロストとＥＰ２アゴニストの組み合わせの使用である。 One aspect of the invention is the use of a combination of cepetaprost and an EP2 agonist for the manufacture of a medicament for intraocular pressure reduction.

　本発明の一態様は、ＥＰ２アゴニストと併用されることを特徴とする、眼圧下降のための医薬の製造のための、セペタプロストの使用である。 One aspect of the present invention is the use of sepetaprost for the manufacture of a medicament for the reduction of intraocular pressure, characterized in that it is used in combination with an EP2 agonist.

　本発明の一態様は、ＥＰ２アゴニストと併用されることを特徴とする、眼圧下降における使用のための、セペタプロストである。 One aspect of the invention is sepetaprost for use in intraocular pressure lowering, characterized in that it is used in combination with an EP2 agonist.

　本発明の一態様は、眼圧下降における使用のための、セペタプロストとＥＰ２アゴニストの組み合わせである。 One aspect of the present invention is the combination of cepetaprost and an EP2 agonist for use in intraocular pressure reduction.

　以下に薬理試験の結果を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。 Although the results of pharmacological tests are shown below, these are for the purpose of better understanding the present invention, and do not limit the scope of the present invention.

［薬理試験］
［実施例１］
　セペタプロストとＥＰ２アゴニストとの組み合わせの有用性を調べるため、実験動物（正常眼圧サル）にセペタプロストとＥＰ２アゴニストであるオミデネパグ　イソプロピルを併用投与したときの眼圧下降効果を検討した。 [Pharmacology test]
Example 1
In order to investigate the usefulness of the combination of cepetaprost with an EP2 agonist, the intraocular pressure-lowering effect of coadministration of cepetaprost with the EP2 agonist omidenepag isopropyl was examined in an experimental animal (normal intraocular pressure monkey).

（被験化合物溶液の調製）
（１）セペタプロスト溶液の調製
　セペタプロストを、可溶化剤を含む精製水に溶解した後、汎用される方法を用いて、所望の濃度のセペタプロスト溶液を調製した。 (Preparation of test compound solution)
(1) Preparation of Sepetaprost Solution After septaprost was dissolved in purified water containing a solubilizing agent, a widely used method was used to prepare a sepetaprost solution of a desired concentration.

（２）オミデネパグ　イソプロピル溶液の調製
　オミデネパグ　イソプロピルを、可溶化剤を含む精製水に溶解した後、汎用される方法を用いて、所望の濃度のオミデネパグ　イソプロピル溶液を調製した。 (2) Preparation of Omidenepag Isopropyl Solution After dissolving Omidenepag isopropyl in purified water containing a solubilizing agent, an Omidenepag isopropyl solution of a desired concentration was prepared using a widely used method.

（試験方法）
　セペタプロストとオミデネパグ　イソプロピルとを併用投与したときの眼圧下降効果を検討した。比較対象として、セペタプロストを単独投与またはオミデネパグ　イソプロピルを単独投与したときの眼圧下降効果についても検討した。コントロールには、セペタプロスト溶液の基剤およびオミデネパグ　イソプロピル溶液の基剤を投与した。 (Test method)
The intraocular pressure lowering effect of coadministration of Sepetaprost and Omidenepag isopropyl was examined. As a comparative object, the ocular pressure lowering effect when cepetaprost was administered alone or omidenepag isopropyl alone was also examined. As controls, a cepetaprost solution base and an omidenepag isopropyl solution base were administered.

（試験に使用した薬剤および動物）
　セペタプロスト溶液：０．０００３％（ｗ／ｖ）セペタプロスト溶液（点眼量：２０μＬ／ｅｙｅ）
　オミデネパグ　イソプロピル溶液：０．０００６％（ｗ／ｖ）オミデネパグ　イソプロピル溶液（点眼量：２０μＬ／ｅｙｅ）
　実験動物：カニクイザル（性別：雄性、一群９匹） (Medications and animals used in the study)
Sepetaprost solution: 0.0003% (w / v) Sepetaprost solution (eye drops: 20 μL / eye)
Omidenepag isopropyl solution: 0.0006% (w / v) Omidenepag isopropyl solution (eye drops: 20 μL / eye)
Experimental animals: cynomolgus monkey (sex: male, 9 animals per group)

（投与方法および測定方法）
〔１〕セペタプロストとオミデネパグ　イソプロピルとの併用投与
（１）０．４％塩酸オキシブプロカイン点眼液（商品名：ベノキシール（登録商標）点眼液０．４％）を実験動物の片眼に一滴点眼し局所麻酔をした。 (Method of administration and method of measurement)
[1] combined administration of Sepetapurosuto and Omidenepagu isopropyl (1) 0.4% oxybuprocaine hydrochloride ophthalmic solution: drop was instilled into one eye (trade name Benokishiru ® ophthalmic solution 0.4%) and experimental animals I was locally anesthetized.

（２）被験化合物溶液投与直前に眼圧を測定し、投与前の眼圧値（０時間）とした。 (2) The intraocular pressure was measured immediately before administration of the test compound solution, and the intraocular pressure value (0 hour) before administration was taken.

（３）セペタプロスト溶液を実験動物の片眼に点眼した（対側眼は無処置）。少し時間をおいて（約５分後）オミデネパグ　イソプロピル溶液を同一眼に点眼した。 (3) The cepetaprost solution was instilled into one eye of the experimental animal (the opposite eye was not treated). After a short time (about 5 minutes), the Omidenepag isopropyl solution was instilled in the same eye.

（４）セペタプロスト溶液点眼２、４、６および８時間後に０．４％塩酸オキシブプロカイン点眼液を一滴ずつ眼圧測定眼に点眼し局所麻酔後、眼圧を測定した。また、眼圧は各３回測定し、その平均値を算出した。眼圧変化値（ｍｍＨｇ）は各測定時点について投与前の眼圧値からの差を算出した。 (4) Sepetaprost Solution Instillation After 2, 4, 6 and 8 hours, 0.4% oxybuprocaine hydrochloride was instilled drop by drop into a tonometric eye, and after topical anesthesia, the intraocular pressure was measured. The intraocular pressure was measured three times each and the average value was calculated. The intraocular pressure change value (mmHg) was calculated as the difference from the intraocular pressure value before administration for each measurement time point.

〔２〕セペタプロストの単独投与
　オミデネパグ　イソプロピル溶液をオミデネパグ　イソプロピル溶液の基剤に代え、他は上記併用投与試験と同じ方法で試験をした。 [2] Single administration of cepetaprost The Omidenepag isopropyl solution was replaced with the base of the Omidenepag isopropyl solution, and the others were tested in the same manner as the above-mentioned combined administration test.

〔３〕オミデネパグ　イソプロピルの単独投与
　セペタプロスト溶液をセペタプロスト溶液の基剤に代え、他は上記併用投与試験と同じ方法で試験をした。 [3] Omidenepag Isopropyl alone administration The cepetaprost solution was replaced with the base of the cepetaprost solution, and the others were tested in the same manner as the above-mentioned combined administration test.

〔４〕コントロール
　セペタプロスト溶液をセペタプロスト溶液の基剤に、オミデネパグ　イソプロピル溶液をオミデネパグ　イソプロピル溶液の基剤に代え、他は上記併用投与試験と同じ方法で試験をした。 [4] Control The sepetaprost solution was used as the base of the sepetaprost solution, the omidenepag isopropyl solution was replaced with the base of the omidenepag isopropyl solution, and the others were tested in the same manner as in the above-mentioned combined administration test.

（結果）
　各投与群の経時的な眼圧下降幅の変化を図１及び表１に示す。眼圧下降幅の変化（眼圧値の変化量）は、各個体の各測定時点について投与前の値（０時間）からの差を各群ともに９匹の平均値±ＳＥＭで示す。コントロール群とセペタプロスト群、オミデネパグ　イソプロピル群、あるいはセペタプロスト／オミデネパグ　イソプロピル併用群との比較、及びセペタプロスト／オミデネパグ　イソプロピル併用群とセペタプロスト群あるいはオミデネパグ　イソプロピル群との比較は、Ｂａｒｔｌｅｔｔ検定を実施後、分散が均一である場合はＤｕｎｎｅｔｔ検定、不均一である場合はＳｔｅｅｌ検定を用いた。コントロール群に対する有意水準は、Ｄｕｎｎｅｔｔ検定において、＃＃：ｐ＜０．０１で示し、Ｓｔｅｅｌ検定において、＊：ｐ＜０．０５、＊＊：ｐ＜０．０１で示した。 (result)
Changes in intraocular pressure fall width over time in each administration group are shown in FIG. 1 and Table 1. The change in intraocular pressure fall width (the amount of change in intraocular pressure value) represents the difference from the value before administration (0 hour) at each measurement time point of each individual in each group by the average value ± SEM of 9 animals. Comparison between the control group and the cepetaprost group, the omidenepag isopropyl group, or the cepetaprost / omidenepag isopropyl combination group, and the cepetaprost / omidenepag isopropyl combination group with the sepetaprost group or the omidenepag isopropyl group, after the Bartlett test was performed, and the dispersion was uniform In some cases, Dunnett's test was used, and in the case of heterogeneity, Steel's test was used. The significance level with respect to the control group is indicated by ##: p <0.01 in Dunnett's test, and *: p <0.05, **: p <0.01 in Steel's test.

Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005

　図１及び表１から明らかなように、セペタプロストとオミデネパグ　イソプロピルの併用投与群は、薬剤単独投与群、すなわち、セペタプロスト投与群およびオミデネパグ　イソプロピル投与群よりも優れた眼圧下降作用およびその作用の持続効果を示した。 As is clear from FIG. 1 and Table 1, the combination administration group of cepetaprost and omidenepag isopropyl is an intraocular pressure lowering action superior to that of the drug alone administration group, that is, the cepetaprost administration group and the omidenepag isopropyl administration group, and a sustained effect of the action. showed that.

　以上より、セペタプロストとＥＰ２アゴニストを組み合わせることにより、より強い眼圧下降作用およびその作用の持続効果が得られることがわかった。 From the above, it was found that by combining Sepetaprost with the EP2 agonist, a stronger intraocular pressure lowering action and a sustained effect of the action can be obtained.

　セペタプロストとＥＰ２アゴニストとを組み合わせて眼に投与することで、眼圧下降作用が増強する。したがって、本発明は緑内障若しくは高眼圧症の予防または治療剤として有用である。 The combination of sepetaprost and an EP2 agonist administered to the eye enhances the ocular hypotensive action. Therefore, the present invention is useful as an agent for the prophylaxis or treatment of glaucoma or ocular hypertension.

Claims (6)

　セペタプロストとＥＰ２アゴニストが組み合わされて投与されることを特徴とする緑内障若しくは高眼圧症の予防または治療剤。 An agent for the prophylaxis or treatment of glaucoma or ocular hypertension characterized in that cepetaprost and an EP2 agonist are administered in combination. 　セペタプロストとＥＰ２アゴニストを含有する配合剤である、請求項１に記載の予防または治療剤。 The prophylactic or therapeutic agent according to claim 1, which is a combination containing cepetaprost and an EP2 agonist. 　セペタプロストとＥＰ２アゴニストが、異なる時間に、または、同時に投与される、請求項１に記載の予防または治療剤。 The prophylactic or therapeutic agent according to claim 1, wherein cepetaprost and the EP2 agonist are administered at different times or simultaneously. 　ＥＰ２アゴニストと併用されることを特徴とする、セペタプロストを含有する緑内障若しくは高眼圧症の予防または治療剤。 An agent for preventing or treating glaucoma or ocular hypertension comprising cepetaprost, which is used in combination with an EP2 agonist. 　ＥＰ２アゴニストと異なる時間に、または同時に投与される、請求項４に記載の予防または治療剤。 The prophylactic or therapeutic agent according to claim 4, which is administered at different times or simultaneously with the EP2 agonist. 　ＥＰ２アゴニストが、オミデネパグ若しくはそのエステルまたはそれらの塩である請求項１～５のいずれか１項に記載の予防または治療剤。 The prophylactic or therapeutic agent according to any one of claims 1 to 5, wherein the EP2 agonist is omidenepag or an ester thereof or a salt thereof.
PCT/JP2018/046971 2017-12-21 2018-12-20 Medicament comprising combination of sepetaprost and ep2 agonist Ceased WO2019124489A1 (en)

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