Sepetaprost-containing eye drop for lowering intraocular pressure during night sleep in patients suffering from glaucoma or ocular hypertension

Abstract

The purpose of the present invention is to discover an eye drop capable of effectively lowering intraocular pressure even at night, especially during night sleep, in patients with glaucoma or ocular hypertension.　The present invention is an eye drop for lowering intraocular pressure during night sleep in patients suffering from glaucoma or ocular hypertension, the eye drop containing sepetaprost at a concentration of 0.002% (w / v) as an active ingredient.

Description

Cepetaprost-containing eye drops for reducing intraocular pressure during nighttime sleep in patients with glaucoma or ocular hypertension

[0001] The present invention relates to an eye drop solution containing cepetaprost for reducing intraocular pressure during nighttime sleep in patients suffering from glaucoma or ocular hypertension.

[0002] Glaucoma is an intractable eye disease caused by elevated intraocular pressure due to various causes, which can lead to blindness due to damage to internal tissues of the eye (retina, optic nerve, etc.). Treatment for glaucoma is generally carried out by intraocular pressure reduction therapy, and representative treatments include drug therapy, laser therapy, and surgery.

[0003] Pharmacotherapy includes sympathomimetics (nonselective stimulants such as dipivefrine, alpha-agonists such as brimonidine, ２ receptor agonists), sympatholytics (beta-receptor blockers such as timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, metipranolol, etc., alpha-receptor blockers such as bunazosin hydrochloride, etc. １ Receptor blockers), parasympathomimetics (pilocarpine, etc.), carbonic anhydrase inhibitors (acetazolamide, etc.), prostaglandins (isopropyl unoprostone, latanoprost, travoprost, bimatoprost, etc.), Rho kinase inhibitors (ripasudil), etc. are used.

[0004] Among these drugs, eye drops containing latanoprost have been widely used around the world since their international launch in 1996 due to their potent intraocular pressure-reducing effect and good tolerability.

[0005] On the other hand, cepetaprost has the formula (1) It is a compound represented by the formula (I), and is described in Patent Document 1 as one of a vast number of compounds. It is described that these compounds have a strong and sustained intraocular pressure-reducing effect and therefore can be used as a therapeutic agent for glaucoma. Furthermore, Patent Document 2 describes that cepetaprost exhibits an excellent intraocular pressure-reducing effect in patients for whom other therapeutic agents for glaucoma or ocular hypertension are insufficient. However, to date, there have been no literature or research reports describing whether cepetaprost exhibits an intraocular pressure-reducing effect at night, particularly during nighttime sleep, in patients with glaucoma or ocular hypertension.

[0006] International Publication No. 2011 / 013651 International Publication No. 2022 / 034909

[0007] The present inventors have conducted extensive research into the intraocular pressure-reducing effect of glaucoma therapeutic agents and have found that latanoprost ophthalmic solution, an existing glaucoma therapeutic agent, cannot effectively reduce intraocular pressure at night in patients with glaucoma or ocular hypertension. Therefore, it is an extremely interesting task to find an ophthalmic solution that can effectively reduce intraocular pressure at night, particularly during sleep, in patients with glaucoma or ocular hypertension.

[0008] As a result of extensive research, the present inventors have found that cepetaprost can effectively reduce intraocular pressure in patients with glaucoma or ocular hypertension at night, particularly during sleep, and have thus completed the present invention. Specifically, the present invention provides the following.

[0009] That is, the present invention provides the following: [1] An eye drop solution for reducing intraocular pressure during nighttime sleep in patients suffering from glaucoma or ocular hypertension, containing 0.002% (w / v) cepetaprost as an active ingredient. [2] The eye drop solution according to [1], wherein nighttime is between 8:00 PM and 8:00 AM. [3] The eye drop solution according to [1] or [2], wherein nighttime is between midnight and 4:00 AM. [4] The eye drop solution according to any of [1] to [3], which is administered by instillation once daily at a dose of one or two drops. [5] The eye drop solution according to any of [1] to [4], which reduces intraocular pressure during nighttime sleep in the patient by 20% or more when evaluated by the rate of change in intraocular pressure. [6] The eye drop solution according to any of [1] to [4], which reduces intraocular pressure during nighttime sleep in the patient by 23% or more when evaluated by the rate of change in intraocular pressure. [7] The ophthalmic solution according to any one of [1] to [4], characterized in that the intraocular pressure during nighttime sleep in the patient is reduced by 20 to 35% when evaluated by the rate of change in intraocular pressure. [8] The ophthalmic solution according to any one of [1] to [7], characterized in that the intraocular pressure during nighttime sleep in the patient is reduced by 20% or more for at least 4 hours after administration when evaluated by the rate of change in intraocular pressure. [9] The ophthalmic solution according to any one of [1] to [8], characterized in that the intraocular pressure during nighttime sleep in the patient is reduced by 20% or more for at least 4 hours after administration when evaluated by the rate of change in intraocular pressure.

[10] The ophthalmic solution according to any one of [1] to [9], wherein the intraocular pressure during nighttime sleep before the start of administration of the ophthalmic solution is 21 mmHg or more and 26 mmHg or less.

[11] The ophthalmic solution according to any one of [1] to

[10] , is to be administered within 3 hours before going to bed.

[12] The ophthalmic solution according to any one of [1] to

[11] , which is administered between 17:00 and 23:00.

[13] The ophthalmic solution according to any one of [1] to

[12] , wherein the patient suffering from glaucoma or ocular hypertension is a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep.

[14] A method for reducing intraocular pressure during nighttime sleep in a patient suffering from glaucoma or ocular hypertension, comprising administering by instillation to the patient an ophthalmic solution containing 0.002% (w / v) cepetaprost as an active ingredient.

[15] Use of a pharmaceutical composition containing 0.002% (w / v) of sepetaprost as an active ingredient in the manufacture of eye drops for reducing intraocular pressure during nighttime sleep in patients suffering from glaucoma or ocular hypertension.

[16] A therapeutic agent for glaucoma or ocular hypertension containing 0.002% (w / v) of sepetaprost as an active ingredient, the therapeutic agent being characterized in that it is used to administer to patients suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep.

[17] An eye drop solution containing cepetaprost at a concentration of 0.002% (w / v) as an active ingredient, characterized in that the eye drop solution is used in a method for selecting a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep and suppressing the onset or progression of visual field impairment in the patient, the method comprising: i) measuring the daytime intraocular pressure and the intraocular pressure during nighttime sleep in a patient suffering from glaucoma or ocular hypertension who has not been administered the eye drop solution; ii) selecting a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep based on the intraocular pressure measured in step i); and iii) administering the eye drop solution once a day to the patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep selected in step ii).

[18] A method for suppressing the onset or progression of visual field impairment in a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep, comprising the steps of: i) measuring the daytime intraocular pressure and the intraocular pressure during nighttime sleep in a patient suffering from glaucoma or ocular hypertension who has not been administered eye drops containing 0.002% (w / v) cepetaprost as an active ingredient; ii) selecting a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep based on the intraocular pressure measured in the step i); and iii) administering the eye drops once daily to the patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep and selected in the step ii).

[0010] It should be noted that any two or more of the above configurations [1] to

[18] can be selected and combined.

[0011] As will be described in detail in the Examples below, it has been suggested that cepetaprost can effectively reduce intraocular pressure at night, particularly during sleep, in patients with glaucoma or ocular hypertension. Therefore, according to the present invention, an eye drop for reducing intraocular pressure at night, particularly during sleep, in patients with glaucoma or ocular hypertension can be provided.

[0012] Figure 1 is a graph plotting the mean change in intraocular pressure (IOP) (mmHg) from baseline at 24:00, 4:00, 8:00, 12:00, 16:00, and 20:00 after administration of the eye drops at 8:00 PM (20:00) the night before, 6 weeks and 3 months after the start of administration. Error bars indicate standard deviation. Figure 2 is a graph plotting the mean percent change in intraocular pressure (IOP) from baseline at 24:00, 4:00, 8:00, 12:00, 16:00, and 20:00 after administration of the eye drops at 8:00 PM (20:00) the night before, 6 weeks and 3 months after the start of administration. Error bars indicate standard deviation.

[0013] Hereinafter, embodiments of the present invention will be described in detail.

[0014] [Ophthalmic Solution] The cepetaprost contained in the ophthalmic solution of the present invention is represented by the following formula (1): The compound is represented by the formula (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 or ONO-9054. In this specification, the term "ophthalmic solution" is synonymous with terms such as "eye drops," "eye drops," and "ophthalmic composition." The ophthalmic solution of the present invention contains cepetaprost as an active ingredient, and may contain, for example, cepetaprost alone as the sole active ingredient, or may contain cepetaprost in combination with another active ingredient.

[0015] Sepetaprost can be manufactured according to the methods described in International Publication No. 2011 / 013651 (Patent Document 1) and International Publication No. 2018 / 003945, or conventional methods in the technical field.

[0016] When cepetaprost has geometric isomers and / or optical isomers, these isomers are also included within the scope of the present invention.

[0017] When cepetaprost has proton tautomerism, the tautomers (keto form, enol form) are also included in the present invention.

[0018] When cepetaprost has crystalline polymorphs and / or crystalline polymorphic groups (crystalline polymorphic systems), these crystalline polymorphs and / or crystalline polymorphic groups (crystalline polymorphic systems) are also included in the present invention. Here, the crystalline polymorphic groups (crystalline polymorphic systems) refer to the crystalline forms and / or the entire crystalline forms at each stage when the crystalline form changes depending on the conditions and / or states (including the formulated state) of the production, crystallization, storage, etc. of the crystals.

[0019] Sepetaprost may be in the form of a hydrate or solvate.

[0020] The ophthalmic solution of the present invention contains 0.002% (w / v) cepetaprost as the active ingredient. Here, "% (w / v)" refers to the mass (g) of the active ingredient (cepetaprost) and additives contained in 100 mL of ophthalmic solution. For example, 0.001% (w / v) cepetaprost means that the content of cepetaprost in 100 mL of ophthalmic solution is 0.001 g. Note that, in this specification, numerical values ​​(e.g., content, concentration, pH, etc.) may be accompanied by the term "about," and in such cases, this is intended to include a range of ±10% of the value. For example, "about 10" includes "9 to 11." When referring to a numerical range indicated using "to," "about" applies to both endpoints of the range. Thus, for example, "about 10 to 20" includes "9 to 22."

[0021] When sepetaprost is in the form of a hydrate or a solvate, the content of sepetaprost may be calculated based on any of the free form, hydrate, and solvate of sepetaprost. The same applies to the contents of other components.

[0022] [Additives] Additives may be used in the ophthalmic solution of the present invention as needed. Examples of additives that can be added include isotonicity agents, preservatives, buffers, surfactants, stabilizers, antioxidants, pH adjusters, and bases. These may be used alone or in appropriate combinations of two or more, and may be blended in appropriate amounts.

[0023] Examples of the tonicity adjusting agent that can be incorporated into the ophthalmic solution of the present invention include ionic tonicity adjusting agents and non-ionic tonicity adjusting agents.

[0024] Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., and among these, sodium chloride is preferred.

[0025] Examples of non-ionic tonicity agents include mannitol, glycerin, propylene glycol, polyethylene glycol, sorbitol, trehalose, maltose, and sucrose, with mannitol (preferably D-mannitol) being preferred.

[0026] When an isotonic agent is incorporated into the ophthalmic solution of the present invention, the isotonic agent may be used alone or in combination of two or more components.

[0027] When an isotonic agent is incorporated into the ophthalmic solution of the present invention, the content of the isotonic agent can be appropriately adjusted depending on the type of the isotonic agent, etc., but is preferably 0.001 to 20% (w / v), more preferably 0.01 to 15% (w / v), and even more preferably 0.1 to 10% (w / v).

[0028] More specifically, when the tonicity agent to be added is an ionic tonicity agent, the content of the ionic tonicity agent is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), and even more preferably 0.5 to 1% (w / v). Specific preferred contents include, for example, 0.5% (w / v), 0.55% (w / v), 0.6% (w / v), 0.65% (w / v), 0.7% (w / v), 0.75% (w / v), 0.8% (w / v), 0.85% (w / v), 0.9% (w / v), 0.95% (w / v), and 1% (w / v).

[0029] More specifically, when the tonicity agent to be added is a nonionic tonicity agent, the content of the nonionic tonicity agent is preferably 0.01 to 20% (w / v), more preferably 0.5 to 10% (w / v), and even more preferably 1 to 6% (w / v).More specifically preferred contents include, for example, 1% (w / v), 2% (w / v), 3% (w / v), 4% (w / v), 5% (w / v), and 6% (w / v).

[0030] Examples of preservatives that can be incorporated into the ophthalmic solution of the present invention include invert soaps, parabens, alcohols, and organic acids or salts thereof, with invert soaps being preferred.

[0031] Examples of cationic soaps include benzalkonium chloride (also called benzalkonium chloride), benzalkonium bromide (also called benzalkonium bromide), benzethonium chloride (also called benzethonium chloride), benzethonium bromide (also called benzethonium bromide), chlorhexidine or a salt thereof, and among these, benzalkonium chloride is preferred.

[0032] Examples of parabens include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate.

[0033] The alcohols include, for example, chlorobutanol.

[0034] Examples of organic acids and salts thereof include sorbic acid and salts thereof, and examples of sorbic acid and salts thereof include sodium sorbate and potassium sorbate.

[0035] When a preservative is incorporated into the ophthalmic solution of the present invention, the preservative may be used alone or in combination of two or more components.

[0036] When a preservative is incorporated into the ophthalmic solution of the present invention, the content of the preservative can be appropriately adjusted depending on the type of preservative, but is preferably 0.00001 to 1% (w / v), more preferably 0.0001 to 0.1% (w / v), more preferably 0.0005 to 0.01% (w / v), and most preferably 0.001 to 0.0075% (w / v). More specifically, for example, 0.001% (w / v), 0.002% (w / v), 0.003% (w / v), 0.004% (w / v), 0.005% (w / v), 0.006% (w / v), 0.007% (w / v), or 0.0075% (w / v) is preferred.

[0037] Examples of buffering agents that can be incorporated into the ophthalmic solution of the present invention include phosphoric acid or a salt thereof, boric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol, etc., of which phosphoric acid or a salt thereof and citric acid or a salt thereof are preferred, and citric acid or a salt thereof is more preferred. These also include hydrates.

[0038] Examples of phosphoric acid or salts thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.

[0039] Examples of boric acid or salts thereof include boric acid, sodium borate, and potassium borate.

[0040] Examples of citric acid or salts thereof include citric acid, sodium citrate, disodium citrate, etc. Among these, sodium citrate is preferably used.

[0041] Examples of acetic acid or salts thereof include acetic acid, sodium acetate, potassium acetate, and the like.

[0042] Examples of carbonic acid or its salts include sodium carbonate and sodium hydrogen carbonate.

[0043] Examples of tartaric acid or salts thereof include tartaric acid, sodium tartrate, potassium tartrate, and the like.

[0044] When a buffering agent is incorporated into the ophthalmic solution of the present invention, the buffering agent may be used alone or in combination of two or more components.

[0045] When a buffering agent is incorporated into the ophthalmic solution of the present invention, the content of the buffering agent can be appropriately adjusted depending on the type of buffering agent, etc., but is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), and even more preferably 0.1 to 0.5% (w / v).More specifically, for example, 0.1% (w / v), 0.2% (w / v), 0.3% (w / v), 0.4% (w / v), or 0.5% (w / v) is preferred.

[0046] Examples of surfactants that can be incorporated into the ophthalmic solution of the present invention include cationic surfactants, anionic surfactants, and nonionic surfactants, and among these, nonionic surfactants are preferred.

[0047] Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxylethyl-2-alkylimidazolines.

[0048] Examples of anionic surfactants include phospholipids such as lecithin.

[0049] Examples of nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, and polyoxyethylene hydrogenated castor oil. Examples of suitable glycerin-based glycerin include polyoxyl castor oils such as polyoxyl 35 castor oil and polyoxyl 40 castor oil; polyoxyethylene polyoxypropylene glycols such as polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid esters such as sucrose stearate; and tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS). Among these, polyoxyethylene sorbitan fatty acid esters are preferred, with polysorbate 80 being more preferred.

[0050] When a surfactant is incorporated into the ophthalmic solution of the present invention, the surfactant may be used alone or in combination of two or more components.

[0051] When a surfactant is incorporated into the ophthalmic solution of the present invention, the content of the surfactant can be appropriately adjusted depending on the type of surfactant, etc., but is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.02 to 1% (w / v), and particularly preferably 0.05 to 0.3% (w / v). More specifically, for example, 0.05% (w / v), 0.1% (w / v), 0.2% (w / v), or 0.3% (w / v) is preferred.

[0052] Examples of stabilizers that can be incorporated into the ophthalmic solution of the present invention include edetic acid or its salts, sulfites, monoethanolamine, cyclodextrin, dextran, taurine, etc., and among these, edetic acid or its salts are preferred.

[0053] Examples of edetic acid or salts thereof include edetic acid (ethylenediaminetetraacetic acid), monosodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate, etc., and hydrates thereof may also be used. Among these, disodium edetate (hereinafter also referred to as sodium edetate) is most preferably used in the present invention.

[0054] When a stabilizer is incorporated into the ophthalmic solution of the present invention, the stabilizer may be used alone or in combination of two or more components.

[0055] When a stabilizer is incorporated into the ophthalmic solution of the present invention, the content of the stabilizer can be adjusted as appropriate depending on the type of stabilizer, etc., and is preferably 0.001 to 5% (w / v), more preferably 0.005 to 1% (w / v), even more preferably 0.01 to 0.5% (w / v), and particularly preferably 0.05 to 0.5% (w / v), 0.05 to 0.2% (w / v), 0.1 to 0.3% (w / v), or 0.1 to 0.2% (w / v). More specifically, preferred contents include, for example, 0.11% (w / v), 0.12% (w / v), 0.13% (w / v), 0.14% (w / v), 0.15% (w / v), 0.16% (w / v), 0.17% (w / v), 0.18% (w / v), 0.19% (w / v), and 0.2% (w / v).

[0056] Examples of antioxidants that can be incorporated into the ophthalmic solution of the present invention include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, and 2-mercaptobenzimidazole.

[0057] When an antioxidant is incorporated into the ophthalmic solution of the present invention, the antioxidant may be used alone or in combination of two or more components.

[0058] When an antioxidant is incorporated into the ophthalmic solution of the present invention, the content of the antioxidant can be appropriately adjusted depending on the type of antioxidant, etc., but is preferably 0.001 to 5% (w / v), more preferably 0.01 to 3% (w / v), and even more preferably 0.1 to 2% (w / v).

[0059] The pH adjuster that can be incorporated into the ophthalmic solution of the present invention includes an acid or a base. Examples of acids include hydrochloric acid, phosphoric acid, citric acid, and acetic acid, and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. The pH of the ophthalmic solution of the present invention can be adjusted by adding these pH adjusters as appropriate. Specifically, the pH of the ophthalmic solution can be adjusted by adding appropriate amounts of hydrochloric acid and sodium hydroxide, for example.

[0060] When a pH adjuster is incorporated into the ophthalmic solution of the present invention, the pH adjuster may be used alone or in combination of two or more components.

[0061] The ophthalmic solution of the present invention may have a pH in the range of, for example, 5 to 8. A more preferred pH range is 5.5 to 7.5, and an even more preferred pH range is 6 to 7. More specifically, preferred pH values ​​include, for example, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0, with pH 6.5 being particularly preferred.

[0062] The eye drops of the present invention preferably contain water as a base, and are preferably aqueous eye drops.

[0063] The osmotic pressure ratio of the ophthalmic solution of the present invention may be within the range acceptable for ophthalmic preparations, for example, 0.5 to 2.0, preferably 0.6 to 1.5, more preferably 0.7 to 1.2, and even more preferably 0.9 to 1.1.

[0064] The osmotic pressure ratio is defined as the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9% (w / v) sodium chloride aqueous solution) based on the 17th Edition of the Japanese Pharmacopoeia, and the osmotic pressure can be measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. Furthermore, the standard solution for measuring the osmotic pressure ratio (0.9% (w / v) sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650°C for 40 to 50 minutes, allowing it to cool in a desiccator (silica gel), accurately weighing 0.900 g of the dried solution, and dissolving it in purified water to make exactly 100 mL; alternatively, a commercially available standard solution for measuring the osmotic pressure ratio (0.9% (w / v) sodium chloride aqueous solution) can be used.

[0065] [Dosage and Administration] The ophthalmic solution of the present invention is administered by instillation, for example, at a dose of 1 or 2 drops once a day. However, other dosage and administration methods are not particularly limited as long as they are sufficient to achieve the desired medicinal effect, and can be appropriately selected depending on the symptoms of the disease, the age and weight of the patient, etc.

[0066] Specifically, the ophthalmic solution of the present invention is administered by instillation at a dose of, for example, 1 or 2 drops, preferably 1 drop, once a day, daily to once a week, preferably daily, where 1 drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, more preferably about 0.02 to about 0.05 mL.

[0067] Furthermore, although there are no particular limitations on the time of day for administration, the eye drops of the present invention are used to reduce intraocular pressure at night, particularly during nighttime sleep, and therefore can be administered, for example, before going to bed, preferably within 6 hours, more preferably within 5 hours, and even more preferably within 4 hours before going to bed. Administration within 3 hours before going to bed is particularly preferred. More specifically, the eye drops of the present invention can be administered preferably between 17:00 and 23:00, more preferably between 18:00 and 22:00, and particularly preferably between 19:00 and 21:00. For example, if the patient goes to bed at 23:00, administration is expected to begin at 20:00.

[0068] Furthermore, the ophthalmic solution of the present invention can be administered to a patient, for example, by measuring the patient's intraocular pressure at night and / or during nighttime sleep before starting administration of the ophthalmic solution, determining whether the patient is suitable for administration of the ophthalmic solution of the present invention, and administering the ophthalmic solution to the patient if the patient is suitable. Suitable patients include, for example, patients described below.

[0069] [Uses] The eye drops of the present invention are administered to patients suffering from glaucoma or ocular hypertension and are used to reduce intraocular pressure in these patients "at night," particularly "during nighttime sleep." Examples of glaucoma in the present invention include primary open-angle glaucoma, secondary open-angle glaucoma, normal-tension glaucoma, excessive aqueous humor production glaucoma, primary angle-closure glaucoma, secondary angle-closure glaucoma, plateau iris glaucoma, mixed glaucoma, developmental glaucoma, steroid-induced glaucoma, exfoliation glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, lenticular capsular glaucoma, and plateau iris syndrome, among which primary open-angle glaucoma, normal-tension glaucoma, and primary angle-closure glaucoma are preferred, and primary open-angle glaucoma is particularly preferred. As such, the eye drops of the present invention can be used to treat glaucoma or ocular hypertension, and can therefore be referred to as, for example, a therapeutic agent for glaucoma or ocular hypertension. Furthermore, in the present invention, the glaucoma and ocular hypertension to be treated may be glaucoma and ocular hypertension, respectively, whose intraocular pressure peaks during nighttime sleep. Therefore, the eye drops of the present invention for reducing intraocular pressure during nighttime sleep in patients suffering from glaucoma or ocular hypertension may be, for example, eye drops for treating glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep.

[0070] Here, the ophthalmic solution of the present invention has an intraocular pressure-reducing effect even at night, particularly during nocturnal sleep. Therefore, the total load on the eyeball due to intraocular pressure (e.g., the total load when considering the area under the intraocular pressure value-time curve (AUC)) can be reduced more than that of glaucoma therapeutic agents (e.g., latanoprost ophthalmic solution) that have a weak intraocular pressure-reducing effect at night, particularly during nocturnal sleep, and therefore is expected to have an effect of further suppressing the progression of glaucoma (visual field impairment, etc.). Therefore, the ophthalmic solution of the present invention can be expected to have an advantageous therapeutic effect compared to other glaucoma therapeutic agents, such as latanoprost ophthalmic solution, that have a weak intraocular pressure-reducing effect at night, particularly during nocturnal sleep.

[0071] In the present invention, "nighttime" refers to, for example, the time between 20:00 and 8:00, preferably the time between 22:00 and 6:00, and more preferably the time between 24:00 and 4:00. Furthermore, "nighttime sleep" refers to the time when one is sleeping "at night."

[0072] In the present invention, the phrase "reducing intraocular pressure in a patient during nighttime sleep" can mean, for example, that the ophthalmic solution of the present invention has a sufficient intraocular pressure-reducing effect even during nighttime sleep, whereas latanoprost ophthalmic solution has a weak intraocular pressure-reducing effect during nighttime sleep. For example, it can also mean that the ophthalmic solution of the present invention has an intraocular pressure-reducing effect of a certain value or more even during nighttime sleep, as evaluated by the intraocular pressure change rate as described below. It can also mean that the intraocular pressure in a patient during nighttime sleep is reduced by such an intraocular pressure change rate. Furthermore, for example, it can also mean that the ophthalmic solution of the present invention has a sufficient intraocular pressure-reducing effect during nighttime sleep that is comparable to that during the daytime (daytime), compared to latanoprost ophthalmic solution. For example, it can also mean that the ophthalmic solution of the present invention has an intraocular pressure-reducing effect during nighttime sleep that is comparable to that during the daytime, as evaluated by the intraocular pressure change rate as described below.

[0073] The eye drops of the present invention for reducing intraocular pressure during nighttime sleep can also be referred to as, for example, an intraocular pressure-reducing agent during nighttime sleep. Furthermore, as will be seen from the examples described below, they can also be referred to as eye drops that bring about a greater reduction in intraocular pressure during nighttime sleep compared to other glaucoma drugs (e.g., latanoprost eye drops). In another embodiment, the eye drops of the present invention can also be referred to as eye drops for suppressing an increase in intraocular pressure during nighttime sleep. In yet another embodiment, the eye drops of the present invention can also be referred to as eye drops for reducing high intraocular pressure levels (e.g., 21 mmHg or higher) during nighttime sleep.

[0074] In the present invention, the target patient is not particularly limited as long as the patient is suffering from glaucoma or ocular hypertension. For example, the target patient may be a patient whose intraocular pressure during nighttime sleep before the start of administration of the eye drops is 21 mmHg or higher, for example, 21 mmHg to 26 mmHg. Patients with such high intraocular pressure during nighttime sleep have a relatively high impact on the total intraocular pressure load on the eyeball, and administration of the eye drops of the present invention is expected to produce a more advantageous therapeutic effect. Therefore, such patients are suitable for administration of the eye drops of the present invention. Note that the "nighttime sleep before the start of administration of the eye drops" refers to the "nighttime sleep" from 24 hours before the initial administration of the eye drops of the present invention until the initial administration. The intraocular pressure value here may be the average intraocular pressure value during nighttime sleep, or the intraocular pressure value at any time during nighttime sleep. Note that the target patient in the present invention is a mammal, including livestock such as cows and pigs, rabbits, monkeys, dogs, cats, and humans, and preferably humans.

[0075] Furthermore, among patients suffering from glaucoma or ocular hypertension, there are a certain number of patients whose intraocular pressure is highest during nighttime sleep, i.e., whose intraocular pressure peaks during nighttime sleep. Since the eye drops of the present invention can effectively reduce intraocular pressure during nighttime sleep, more advantageous therapeutic effects are expected if the patient to whom the eye drops are administered is a glaucoma patient or an ocular hypertension patient whose intraocular pressure peaks during nighttime sleep. Therefore, in the present invention, the target patient may also be a glaucoma patient or an ocular hypertension patient whose intraocular pressure peaks during nighttime sleep. Here, a glaucoma patient or an ocular hypertension patient whose intraocular pressure peaks during nighttime sleep refers to a glaucoma patient or an ocular hypertension patient whose intraocular pressure is highest during nighttime sleep, for example, a patient whose intraocular pressure is highest during nighttime sleep and whose intraocular pressure difference between daytime and nighttime sleep is 1 to 10 mmHg.

[0076] The ophthalmic solution of the present invention can also be used in a method for selecting a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep, and suppressing the onset or progression of visual field impairment in the patient. The method includes, for example, the following steps: i) measuring the daytime intraocular pressure and the intraocular pressure during nighttime sleep in a patient suffering from glaucoma or ocular hypertension who has not been administered the ophthalmic solution of the present invention; ii) selecting a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep based on the intraocular pressure measured in step i); and iii) administering the ophthalmic solution of the present invention once daily to the patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep, selected in step ii).

[0077] Therefore, the eye drops of the present invention are characterized by containing, for example, 0.002% (w / v) cepetaprost as an active ingredient, and are used in a method for selecting a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep, and suppressing the onset or progression of visual field impairment in the patient. The method can also be described as comprising the steps of: i) measuring the daytime intraocular pressure and the intraocular pressure during nighttime sleep in a patient suffering from glaucoma or ocular hypertension who has not been administered the eye drops; ii) selecting a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep based on the intraocular pressure measured in step i); and iii) administering the eye drops once a day to the patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep selected in step ii).

[0078] In the present invention, the reduction in intraocular pressure due to eye drops can be evaluated, for example, by the intraocular pressure change rate. Here, the intraocular pressure change rate is determined by comparing the intraocular pressure value of a patient at a certain time T (e.g., 8:00) before the start of administration of the eye drops (before the start of treatment; baseline) with that after the start of administration of the eye drops (after the start of treatment). Specifically, it is calculated using the following formula. Note that a negative value for the intraocular pressure change rate means that the intraocular pressure has decreased; for example, an intraocular pressure change rate of -20% means that the intraocular pressure has decreased by 20%. Intraocular pressure change rate (%) = {[intraocular pressure (mmHg) at time T after the start of administration of eye drops - intraocular pressure (mmHg) at time T before the start of administration of eye drops] / [intraocular pressure (mmHg) at time T before the start of administration of eye drops]} × 100%

[0079] The intraocular pressure change rate can be calculated not only at a specific time but also over a specific period of time by calculating the average value of the intraocular pressure change rates at multiple times within the specific period of time.

[0080] In the present invention, the rate of change in intraocular pressure can be evaluated, for example, 6 weeks or 3 months after the start of administration of the eye drop (start of treatment with the eye drop).

[0081] The ophthalmic solution of the present invention reduces intraocular pressure in a patient at night, particularly during nighttime sleep, by, for example, 20% or more, preferably 23% or more, when evaluated by the rate of change in intraocular pressure.Furthermore, the ophthalmic solution of the present invention reduces intraocular pressure in a patient at night, particularly during nighttime sleep, by, for example, 20 to 35%, preferably 23 to 35%, when evaluated by the rate of change in intraocular pressure.

[0082] The eye drops of the present invention are used so as to be administered once a day, and can maintain a state in which the intraocular pressure is reduced by, for example, 20% or more (preferably 23%) in the above-mentioned evaluation of the rate of change in intraocular pressure, for at least 4 hours (e.g., at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, or more) from the time of actual administration by instillation.

[0083] Furthermore, the ophthalmic solution of the present invention can be administered by eye drop administration to a patient so that the intraocular pressure of the patient at night, particularly during nighttime sleep, can be maintained at a level lowered by, for example, 20% or more (preferably 23%) in the evaluation of the rate of change in intraocular pressure, for example, at least between 24:00 and 4:00 (preferably at least between 20:00 and 8:00).

[0084] Furthermore, as will be apparent from the examples described below, the ophthalmic solution of the present invention is expected to reduce intraocular pressure in patients at night, particularly during nighttime sleep, to a greater extent than other therapeutic agents for glaucoma or ocular hypertension (e.g., latanoprost ophthalmic solution).

[0085] When the ophthalmic solution of the present invention is evaluated based on the rate of change in intraocular pressure, the difference between the rate of change in intraocular pressure during the daytime and the rate of change in intraocular pressure during sleep at night is, for example, within 15%, preferably within 13%, and more preferably within 10%. Here, "daytime" refers to, for example, the period between 8:00 and 20:00.

[0086] Furthermore, as will be apparent from the examples described later, the ophthalmic solution of the present invention is expected to be able to reduce the difference between the rate of change in intraocular pressure during the daytime and the rate of change in intraocular pressure during sleep at night, compared to other therapeutic agents for glaucoma or ocular hypertension (e.g., latanoprost ophthalmic solution).

[0087] The above detailed description of the eye drops and the like of the present invention also applies to the following aspects of the present invention.

[0088] One aspect of the present invention is a method for reducing intraocular pressure during nighttime sleep in a patient suffering from glaucoma or ocular hypertension, comprising administering to the patient an eye drop solution containing 0.002% (w / v) cepetaprost as an active ingredient. This method of the present invention is a method for reducing intraocular pressure during nighttime sleep in a patient suffering from glaucoma or ocular hypertension, comprising administering to the patient an eye drop solution containing 0.002% (w / v) cepetaprost as an active ingredient. The detailed description of the eye drop solution of the present invention above also applies to this method of the present invention.

[0089] One aspect of the present invention is the use of a pharmaceutical composition containing 0.002% (w / v) cepetaprost as an active ingredient in the manufacture of an eye drop solution for reducing intraocular pressure during nighttime sleep in patients suffering from glaucoma or ocular hypertension. The use of the present invention is characterized by the use of a pharmaceutical composition containing 0.002% (w / v) cepetaprost as an active ingredient in the manufacture of an eye drop solution for reducing intraocular pressure during nighttime sleep in patients suffering from glaucoma or ocular hypertension. The detailed description of the eye drop solution of the present invention above also applies to the use of the present invention.

[0090] One aspect of the present invention is a therapeutic agent for glaucoma or ocular hypertension, containing 0.002% (w / v) cepetaprost as an active ingredient, characterized in that it is administered to patients suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep. The therapeutic agent of the present invention is a therapeutic agent for glaucoma or ocular hypertension, containing 0.002% (w / v) cepetaprost as an active ingredient, characterized in that it is administered to patients suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep. The detailed description of the eye drops of the present invention above also applies to this therapeutic agent of the present invention.

[0091] One aspect of the present invention is a method for suppressing the onset or progression of visual field impairment in a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep, the method comprising the steps of: i) measuring the daytime intraocular pressure and the intraocular pressure during nighttime sleep in a patient suffering from glaucoma or ocular hypertension who has not been administered eye drops containing 0.002% (w / v) cepetaprost as an active ingredient; ii) selecting a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep based on the intraocular pressure measured in the step i); and iii) administering the eye drops once daily to the patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep and selected in the step ii). The method of the present invention is a method for selecting a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep and suppressing the onset or progression of visual field impairment in the patient, comprising the steps of: i) measuring the daytime intraocular pressure and the intraocular pressure during nighttime sleep in a patient suffering from glaucoma or ocular hypertension who has not been administered an eye drop solution containing 0.002% (w / v) cepetaprost as an active ingredient; ii) selecting a patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep based on the intraocular pressure measured in step i); and iii) administering the eye drops once daily to the patient suffering from glaucoma or ocular hypertension whose intraocular pressure peaks during nighttime sleep selected in step ii). The detailed description of the eye drops of the present invention above also applies to the method of the present invention.

[0092] The following clinical trial results are presented to aid in a better understanding of the present invention and are not intended to limit the scope of the present invention in any way.

[0093] <Clinical Trial> 1. Preparation of Ophthalmic Solution Ophthalmic Solution 1 containing 0.002% (w / v) cepetaprost was prepared according to a conventional method in the art. Specifically, 0.002 g of cepetaprost, polysorbate 80, sodium citrate, disodium edetate, and sodium chloride were added with water for injection and stirred. An appropriate amount of sodium hydroxide or hydrochloric acid was added as a pH adjuster to adjust the pH, and an appropriate amount of water for injection was added to make up a total volume of 100 mL to prepare Ophthalmic Solution 1. In this clinical trial, the 0.002% cepetaprost ophthalmic solution in Ophthalmic Solution 1 is also referred to as 0.002% DE-126 ophthalmic solution.

[0094] 2. Study Method This study was a randomized, investigator-blinded, active-controlled, parallel-group, multicenter study evaluating the 24-hour intraocular pressure-lowering properties of DE-126 ophthalmic solution 0.002% compared with latanoprost ophthalmic solution 0.005% (Pfizer, Xalatan®) in subjects with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). The study consisted of a screening period of up to 35 days, including a washout period of up to 28 days (plus a 7-day window), and a 3-month treatment period.

[0095] Eligible subjects were randomized in a 1:1 ratio to receive either one drop of DE-126 ophthalmic solution 0.002% instilled into both eyes once daily at 8:00 PM (DE-126 group; N=17) or one drop of latanoprost ophthalmic solution 0.005% instilled into both eyes once daily at 8:00 PM (latanoprost group; N=16). Subjects were treated for 3 months with scheduled visits at baseline (Visit 3, Day -1) and follow-up visits at the investigational site (Visits 4-6, Week 2-Month 3+1). The study included three overnight visits: baseline, Week 6+1, and Month 3+1.

[0096] Six weeks and three months after the start of eye drop administration, intraocular pressure (IOP) was measured 4 hours (24:00), 8 hours (04:00), 12 hours (08:00), 16 hours (12:00), 20 hours (16:00), and 24 hours (20:00) after eye drop administration at 8:00 PM (20:00) the previous night. Measurements were performed by applanation tonometry. Intraocular pressure was also measured before the start of eye drop administration (baseline) at 24:00, 04:00, 08:00, 12:00, 16:00, and 20:00.

[0097] 3. Test Results The test results are shown in Figures 1 and 2. Figure 1 is a graph plotting the mean change from baseline in IOP (mmHg) for the mean intraocular pressure of the test eye measured 4 hours (24:00), 8 hours (04:00), 12 hours (08:00), 16 hours (12:00), 20 hours (16:00), and 24 hours (20:00) after administration of the eye drops at 8:00 PM (20:00) the previous night, 6 weeks and 3 months after the start of administration of the eye drops. Figure 2 is a graph plotting the mean percent change in IOP (%) from baseline for the mean IOP of the test eye measured at 4 hours (24:00), 8 hours (04:00), 12 hours (08:00), 16 hours (12:00), 20 hours (16:00), and 24 hours (20:00) after administration of the eye drops at 8:00 PM (20:00) the night before, 6 weeks and 3 months after the start of administration of the eye drops. The IOP change values ​​and IOP change percentages were calculated using the following formulas. The mean IOP values ​​at 24:00, 4:00, 8:00, 12:00, 16:00, and 20:00 before the start of administration (baseline) were all in the range of 21 mmHg to 26 mmHg. Change in intraocular pressure (mmHg) = intraocular pressure at time T after the start of eye drop administration (mmHg) - intraocular pressure at time T before the start of eye drop administration (mmHg) Intraocular pressure change rate (%) = {[intraocular pressure at time T after the start of eye drop administration (mmHg) - intraocular pressure at time T before the start of eye drop administration (mmHg)] / [intraocular pressure at time T before the start of eye drop administration (mmHg)]} × 100%

[0098] 4. Discussion The results of this study revealed that DE-126 ophthalmic solution 0.002% exhibited a numerically greater intraocular pressure-lowering effect than latanoprost ophthalmic solution 0.005% 4 hours (24:00) and 8 hours (04:00) after administration at 8:00 PM (20:00), i.e., at night. Since 4 hours (24:00) and 8 hours (04:00) after administration at 8:00 PM (20:00) correspond to nighttime sleep, this suggests that cepetaprost can effectively lower intraocular pressure in patients with glaucoma or ocular hypertension, even during nighttime sleep.

[0099] As described in the above examples, it has been suggested that cepetaprost can effectively reduce intraocular pressure at night, particularly during sleep, in patients with glaucoma or ocular hypertension. Therefore, according to the present invention, an eye drop for reducing intraocular pressure at night, particularly during sleep, in patients with glaucoma or ocular hypertension can be provided.

Claims

1. An eye drop for reducing intraocular pressure during night-time sleep in patients suffering from glaucoma or ocular hypertension, containing 0.002% (w / v) of sepetaprost as an active ingredient.

2. The eye drop according to claim 1, wherein night-time is between 20:00 and 8:

00.

3. The eye drop according to claim 1 or 2, wherein night-time is between 24:00 and 4:

00.

4. The eye drop according to any one of claims 1 to 3, which is used for once-daily instillation administration of 1 or 2 drops per administration.

5. The eye drop according to any one of claims 1 to 4, characterized in that when evaluated by the intraocular pressure change rate, the intraocular pressure during night-time sleep in the patient is reduced by 20% or more.

6. The eye drop according to any one of claims 1 to 4, characterized in that when evaluated by the intraocular pressure change rate, the intraocular pressure during night-time sleep in the patient is reduced by 23% or more.

7. The eye drop according to any one of claims 1 to 4, characterized in that when evaluated by the intraocular pressure change rate, the intraocular pressure during night-time sleep in the patient is reduced by 20 to 35%.

8. The eye drop according to any one of claims 1 to 7, characterized in that when evaluated by the intraocular pressure change rate, the intraocular pressure during night-time sleep in the patient is continuously reduced by 20% or more for at least 4 hours after administration.

9. The eye drop according to any one of claims 1 to 8, characterized in that when evaluated by the intraocular pressure change rate, the intraocular pressure during night-time sleep in the patient is continuously reduced by 20% or more between at least 24:00 and 4:

00.

10. The eye drop according to any one of claims 1 to 9, wherein the intraocular pressure value during night-time sleep before the start of eye drop administration is 21 mmHg or more and 26 mmHg or less.

11. The eye drop according to any one of claims 1 to 10, which is used for instillation within 3 hours before bedtime.

12. The eye drop according to any one of claims 1 to 11, which is used for instillation between 17:00 and 23:

00.

13. The eye drop according to any one of claims 1 to 12, wherein the patient suffering from glaucoma or ocular hypertension is a patient suffering from glaucoma or ocular hypertension who exhibits peak intraocular pressure during night-time sleep.

14. A therapeutic agent for glaucoma or ocular hypertension, containing sepetaprost at a concentration of 0.002% (w / v) as an active ingredient, which is used to be administered to a patient suffering from glaucoma or ocular hypertension that exhibits peak intraocular pressure during nighttime sleep.

15. An eye drop containing sepetaprost at a concentration of 0.002% (w / v) as an active ingredient, which is used in a method for suppressing the onset or progression of visual field impairment in a patient suffering from glaucoma or ocular hypertension that exhibits peak intraocular pressure during nighttime sleep, and the method includes: i) a step of measuring the daytime intraocular pressure and the intraocular pressure during nighttime sleep in a patient suffering from glaucoma or ocular hypertension who has not been administered the eye drop; ii) a step of selecting a patient suffering from glaucoma or ocular hypertension that exhibits peak intraocular pressure during nighttime sleep based on the intraocular pressure measured in the step i); and iii) a step of administering the eye drop once a day to the patient suffering from glaucoma or ocular hypertension that exhibits peak intraocular pressure during nighttime sleep and has been selected in the step ii.

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