Eye drop containing sepetaprost

Abstract

The purpose of the present invention is to provide a sepetaprost-containing eye drop having exceptional formulation stability.　The present invention relates to an eye drop containing sepetaprost, the eye drop being accommodated in an ethylene-oxide-gas-sterilized eye drop container.

Description

Cepetaprost-containing eye drops

[0001] The present invention relates to an eye drop solution containing sepetaprost.

[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] Here, sepetaprost is a compound represented by the formula (1): and is described as one of a vast number of compounds in Patent Documents 1 and 2. It is also described that this compound has a potent and sustained intraocular pressure-reducing effect and therefore may be a potential therapeutic agent for glaucoma (Non-Patent Document 1).

[0005] In addition, in order to obtain a more potent intraocular pressure-reducing effect, several reports have been made on the use of sepetaprost in combination with other drugs having intraocular pressure-reducing effects.For example, Patent Document 3 reports the combined administration of sepetaprost and a β-receptor blocker, Patent Document 4 reports the combined administration of sepetaprost and a Rho kinase inhibitor, and Patent Document 5 reports the combined administration of sepetaprost and an EP2 agonist.Furthermore, a pharmaceutical preparation for treating or preventing glaucoma or ocular hypertension, which contains sepetaprost as an active ingredient, has been reported, and is administered to patients for whom other glaucoma or ocular hypertension treatment drugs are insufficient (Patent Document 6).In addition, a pharmaceutical composition containing sepetaprost for treating, preventing, and / or inhibiting the progression of myopia has also been reported (Patent Document 7).

[0006] On the other hand, excellent formulation stability is required in the formulation design of ophthalmic solutions. For example, a decrease in the content of the active ingredient over time during storage can lead to a deterioration in the quality of the formulation, which can be a problem.

[0007] International Publication No. WO 2011 / 013651 International Publication No. WO 2012 / 102357 International Publication No. WO 2019 / 124523 International Publication No. WO 2019 / 124488 International Publication No. WO 2019 / 124489 International Publication No. WO 2022 / 034909 International Publication No. WO 2021 / 145356

[0008] Invest Ophthalmol Vis Sci. 2015 Apr;56(4):2547-52

[0009] An object of the present invention is to provide a sepetaprost-containing ophthalmic solution having excellent formulation stability.

[0010] The present inventors have been conducting extensive research into the formulation stability of ophthalmic solutions containing sepetaprost, and have found that when ophthalmic solutions containing sepetaprost are filled into containers that have been sterilized by electron beam, the content of sepetaprost in the ophthalmic solution decreases. To solve this problem, the present inventors have conducted further extensive research and have unexpectedly found that when ophthalmic solutions containing sepetaprost are filled into containers that have been sterilized by ethylene oxide gas, the decrease in the content of sepetaprost in the ophthalmic solution can be effectively suppressed, thereby completing the present invention. Specifically, the present invention provides the following:

[0011] (1) An eye drop solution containing cepetaprost, the eye drop solution being contained in an eye drop container sterilized with ethylene oxide gas. (2) The eye drop solution according to (1), wherein the concentration of cepetaprost is 0.001 to 0.01% (w / v). (3) The eye drop solution according to (2), wherein the concentration of cepetaprost is 0.001 to 0.003% (w / v). (4) The eye drop solution according to any one of (1) to (3), wherein the eye drop container is made of resin. (5) The eye drop solution according to any one of (1) to (4), wherein the eye drop container is made of polyethylene or polypropylene. (6) The eye drop solution according to any one of (1) to (5), further comprising at least one selected from the group consisting of an isotonicity agent, a preservative, a buffer, a surfactant, a stabilizer, an antioxidant, and a pH adjuster. (7) The eye drop solution according to any one of (1) to (6), wherein the eye drop solution is an aqueous eye drop solution. (8) An ophthalmic pharmaceutical product, in which an eye drop solution containing sepetaprost is contained in an eye drop container sterilized with ethylene oxide gas. (9) A method for stabilizing sepetaprost in an eye drop solution, comprising containing an eye drop solution containing sepetaprost in an eye drop container sterilized with ethylene oxide gas. (10) A method for producing an ophthalmic pharmaceutical product, comprising containing an eye drop solution containing sepetaprost in an eye drop container sterilized with ethylene oxide gas. (11) A method for stabilizing sepetaprost in an eye drop solution, comprising containing an eye drop solution containing sepetaprost in an eye drop container and then sterilizing with ethylene oxide gas.

[0012] It should be noted that any two or more of the above configurations (1) to (11) can be selected and combined.

[0013] According to the present invention, it is possible to suppress a decrease in the content of sepetaprost in an eye drop containing sepetaprost, thereby providing an eye drop containing sepetaprost with excellent formulation stability.

[0014] The present invention will be described in detail below, but the present invention is not particularly limited thereto.

[0015] The eye drops of the present invention contain cepetaprost and are contained in an eye drop container sterilized with ethylene oxide gas. "Ethylene oxide gas" may also be abbreviated as EOG.

[0016] 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.

[0017] 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.

[0018] When cepetaprost has geometric isomers and / or optical isomers, these isomers are also included within the scope of the present invention.

[0019] When cepetaprost has proton tautomerism, the tautomers (keto form, enol form) are also included in the present invention.

[0020] 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.

[0021] Sepetaprost may be in the form of a hydrate or solvate.

[0022] In the ophthalmic solution of the present invention, the content of sepetaprost is not particularly limited as long as it is a pharmaceutically acceptable amount, but the lower limit of the content of sepetaprost is preferably 0.0001% (w / v) or more, more preferably 0.0003% (w / v) or more, and even more preferably 0.001% (w / v) or more. The upper limit of the content of sepetaprost is preferably 0.1% (w / v) or less, more preferably 0.03% (w / v) or less, even more preferably 0.01% (w / v) or less, even more preferably 0.005% (w / v) or less, and particularly preferably 0.003% (w / v) or less. More specifically, the content can be any range combining any of the above lower and upper limits, such as 0.0001 to 0.1% (w / v), 0.0003 to 0.03% (w / v), 0.001 to 0.01% (w / v), 0.001 to 0.005% (w / v), and 0.001 to 0.003% (w / v). More specifically, preferred contents include, for example, 0.001% (w / v), 0.002% (w / v), and 0.003% (w / v). Here, "% (w / v)" refers to the mass (g) of the active ingredient (sepetaprost) and additives contained in 100 mL of the ophthalmic solution. For example, 0.001% (w / v) of sepetaprost means that the content of sepetaprost in 100 mL of the ophthalmic solution is 0.001 g. In this specification, numerical values ​​(e.g., content, concentration, pH, etc.) may be accompanied by the term "about," and in such cases, it 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. Therefore, for example, "about 10 to 20" includes "9 to 22."

[0023] 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.

[0024] The ophthalmic solution of the present invention may contain additives 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.

[0025] 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, and among these, non-ionic tonicity adjusting agents are preferred.

[0026] Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., and among these, sodium chloride is preferred.

[0027] 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.

[0028] 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.

[0029] 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).

[0030] 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).

[0031] 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).

[0032] 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.

[0033] 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.

[0034] Examples of parabens include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate.

[0035] The alcohols include, for example, chlorobutanol.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] Examples of boric acid or salts thereof include boric acid, sodium borate, and potassium borate.

[0042] Examples of citric acid or salts thereof include citric acid, sodium citrate, disodium citrate, etc. Among these, sodium citrate is preferably used.

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

[0044] Examples of carbonic acid or its salts include sodium carbonate and sodium hydrogen carbonate.

[0045] Examples of tartaric acid or salts thereof include tartaric acid, sodium tartrate, potassium tartrate, and the like.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] Examples of anionic surfactants include phospholipids such as lecithin.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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).

[0058] 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.

[0059] 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.

[0060] 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).

[0061] 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 an appropriate amount of hydrochloric acid and / or sodium hydroxide, for example.

[0062] 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.

[0063] 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.

[0064] The eye drops of the present invention preferably contain water as a base, and are preferably aqueous eye drops.

[0065] 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.

[0066] 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.

[0067] The ophthalmic solution of the present invention contains cepetaprost as an active ingredient and is useful for preventing or treating glaucoma or ocular hypertension, or for reducing intraocular pressure. Therefore, the ophthalmic solution of the present invention can be said to be a preventive or therapeutic agent for glaucoma or ocular hypertension, or an intraocular pressure-reducing agent. 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, and preferably includes primary open-angle glaucoma, normal-tension glaucoma, and primary angle-closure glaucoma. The eye drops of the present invention may contain an active ingredient other than cepetaprost, or may contain cepetaprost as the only active ingredient.

[0068] The dosage and administration of the ophthalmic solution of the present invention are not particularly limited as long as they are sufficient to achieve the desired efficacy, and can be appropriately selected depending on the symptoms of the disease, the age and weight of the patient, etc.

[0069] Specifically, the ophthalmic solution of the present invention can be administered by instillation at a dose of 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and particularly preferably 1 drop, 1 to 4 times a day, preferably 1 to 3 times a day, more preferably 1 to 2 times a day, and particularly preferably once a day, every day to once a week. It is preferable to administer 1 drop once a day, every day. Here, 1 drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, and more preferably about 0.02 to about 0.05 mL.

[0070] <Eye drop container> In the present invention, the eye drop solution is contained in an eye drop container that has been sterilized with ethylene oxide gas (ethylene oxide gas sterilized eye drop container). After the eye drop solution is filled into the container body, the eye drop container can be sealed in a conventional manner. An inner stopper, cap, etc. is attached to the opening of the neck at the top of the eye drop container body.

[0071] In the present invention, any eye drop container can be used without particular limitation as long as it is sterilized using ethylene oxide gas. For example, a multi-dose eye drop container can be used.

[0072] A "multidose eye drop container" refers to an eye drop container comprising a container body and a cap that can be attached to the container body, and the cap can be freely opened and closed. Examples of multidose eye drop containers in the present invention include PFMD (Preservative-Free Multi-Dose) eye drop containers that exhibit preservative effects without containing preservatives due to their physical structure, such as containers that exhibit preservative effects by having a check valve in the outlet hole or containers that exhibit preservative effects by using a delaminated bottle with a filter. Such multidose eye drop containers typically contain multiple doses of eye drop solution for use over a certain period of time, and the eye drop solution contained therein can be repeatedly instilled multiple times.

[0073] Multidose eye drop containers are generally formed from multiple components, and although there is no particular limit to the number of components, they are preferably two-piece eye drop containers consisting of two components (container body and cap) or three-piece eye drop containers consisting of three components (container body, inner stopper, and cap). Among PFMD eye drop containers, there are some in which the inner stopper (nozzle) and cap are integrated into one component until the first time the container is opened, and after opening, the inner stopper (nozzle) and cap separate to form two components. In the present invention, such PFMD eye drop containers are referred to as two-piece eye drop containers consisting of two components: the container body and the cap with a nozzle (two-piece PFMD eye drop container).

[0074] In the present invention, when an eye drop container is formed from multiple components, if the container body has been sterilized with ethylene oxide gas, the container is said to be sterilized with ethylene oxide gas. In the present invention, the effects of the present invention can be obtained as long as at least the container body has been sterilized with ethylene oxide gas. There are no particular restrictions on the sterilization method for components other than the container body, such as the inner stopper and cap, and conventional sterilization methods (gamma ray sterilization, electron beam sterilization, EOG sterilization, hydrogen peroxide sterilization, high-pressure steam sterilization, etc.) can be applied.

[0075] In the present invention, the material of the eye drop container is not particularly limited, and resins can be used, such as polyethylene (PE), polypropylene (PP), polypropylene-polyethylene copolymer, polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyvinyl chloride, acrylic resin, and polystyrene. Polyethylene may also be classified by its density, such as low-density polyethylene (LDPE), medium-density polyethylene (MDPE), and high-density polyethylene (HDPE). Preferred examples of materials for the eye drop container of the present invention include polyethylene, polypropylene, propylene-ethylene copolymer, and polyethylene terephthalate. More preferred examples include polyethylene, polypropylene, and propylene-ethylene copolymer. Particularly preferred examples include polyethylene and polypropylene. Here, propylene-ethylene copolymer is not particularly limited as long as it is a propylene polymer containing an ethylene component, but is preferably a propylene polymer containing 10 mol% or less of an ethylene component. When the eye drop container is formed from multiple components, the components may be formed from the same material or from different materials. Furthermore, the material may constitute a part or the whole of a component, or may be a coating. The eye drop container may be commercially available or manufactured by a known method. The eye drop container may be manufactured by a general manufacturing method such as blow molding, injection molding, or injection blow molding, and the manufacturing method is not particularly limited.

[0076] In the present invention, when referring to the material of an eye drop container, such as a "resin" eye drop container or a "polyethylene" eye drop container, it means that at least a part or the whole of the eye drop container body is made of that material (resin, polyethylene, etc.).

[0077] In the present invention, the eye drop container used is an eye drop container sterilized with ethylene oxide gas. The ethylene oxide gas sterilization can be performed using a conventional method for sterilizing eye drop containers using ethylene oxide gas, and is not particularly limited. For example, the eye drop container can be sterilized by exposing it to ethylene oxide gas at a predetermined temperature and relative humidity for a predetermined time, and then aeration can be performed, if necessary, to remove the ethylene oxide gas. Alternatively, commercially available eye drop containers that have been sterilized with ethylene oxide gas can be used.

[0078] In the present invention, the gas used in ethylene oxide gas sterilization may be ethylene oxide gas alone or a mixed gas with carbon dioxide, etc. When a mixed gas is used, the volume ratio of ethylene oxide gas to other gases is, for example, 5:95 to 50:50, preferably 10:90 to 40:60, more preferably 15:85 to 30:70, and particularly preferably 20:80.

[0079] The temperature for ethylene oxide gas sterilization is, for example, 20 to 80°C, preferably 30 to 60°C.

[0080] The relative humidity for ethylene oxide gas sterilization is, for example, 20 to 90%, preferably 30 to 80%.

[0081] The time for ethylene oxide gas sterilization can be, for example, 1 to 10 hours, preferably 2 to 5 hours.

[0082] In the present invention, aeration is not necessarily required after ethylene oxide gas sterilization. However, if aeration is performed, air, nitrogen, argon, or carbon dioxide can be used, and the aeration time is preferably 8 hours or longer, more preferably 12 hours or longer, and most preferably 24 hours or longer.

[0083] In the present invention, the residual ethylene oxide concentration in the eye drop container is, for example, 0 to 10 ppm, preferably 0 to 5 ppm, more preferably 0 to 1 ppm, even more preferably 0 to 0.5 ppm or less, and particularly preferably undetectable. The residual ethylene oxide concentration can be measured in accordance with the "Method for Determining Residual Ethylene Oxide in Medical Devices" of the Japan Medical Plastics Association.

[0084] In the present invention, the volume of the eye drop container is not particularly limited as long as it is within the range normally used for eye drop containers, but is preferably 0.2 to 32 mL, more preferably 1 to 17 mL, and even more preferably 3 to 12 mL.

[0085] In the present invention, the total amount of the eye drop solution contained in the eye drop container is not particularly limited as long as it is within the range that can usually be contained in an eye drop container, but is preferably 0.2 to 30 mL, more preferably 1 to 15 mL, and even more preferably 3 to 10 mL.

[0086] [Ophthalmic Pharmaceutical Product] The ophthalmic pharmaceutical product of the present invention is an ophthalmic pharmaceutical product in which an eye drop solution containing cepetaprost is contained in an eye drop container sterilized by ethylene oxide gas. The ophthalmic pharmaceutical product of the present invention comprises an eye drop solution containing cepetaprost and an eye drop container sterilized by ethylene oxide gas. In such an ophthalmic pharmaceutical product, the eye drop solution containing cepetaprost has excellent formulation stability. The above-mentioned description of the eye drop solution is also applicable to this embodiment.

[0087] [Method for stabilizing sepetaprost in ophthalmic solution] The method for stabilizing sepetaprost in ophthalmic solution of the present invention comprises placing the sepetaprost-containing ophthalmic solution in an ethylene oxide gas sterilized eye drop container. The method for stabilizing sepetaprost in ophthalmic solution of the present invention is characterized by placing the sepetaprost-containing ophthalmic solution in an ethylene oxide gas sterilized eye drop container, and other steps are not particularly limited. This method can stabilize sepetaprost in the ophthalmic solution. Here, stabilizing sepetaprost in the ophthalmic solution refers to suppressing a decrease in the sepetaprost content in the ophthalmic solution during storage. Alternatively, the method for stabilizing sepetaprost in ophthalmic solution of the present invention may comprise placing the sepetaprost-containing ophthalmic solution in an ophthalmic solution container and then sterilizing it with ethylene oxide gas. The above description of the ophthalmic solution is also applicable to this embodiment.

[0088] [Method for producing an ophthalmic pharmaceutical product] The method for producing an ophthalmic pharmaceutical product of the present invention is a method for producing an ophthalmic pharmaceutical product, comprising filling an eye drop solution containing cepetaprost into an eye drop container sterilized with ethylene oxide gas. The production method of the present invention is characterized by filling an eye drop solution containing cepetaprost into an eye drop container sterilized with ethylene oxide gas, and other steps are not particularly limited. In the ophthalmic pharmaceutical product produced by such a production method, the eye drop solution containing cepetaprost has excellent formulation stability. The above-mentioned description of the eye drop solution is also applicable to this embodiment.

[0089] The present invention will be described in detail below with reference to test examples (stability tests) and formulation examples, but these are intended to provide a better understanding of the present invention and are not intended to limit the scope of the present invention in any way.

[0090] <Stability Test> The influence of different container sterilization methods on the stability of the cepetaprost-containing ophthalmic solution was evaluated.

[0091] 1. Preparation of Drug Solutions Drug Solutions A to C were prepared according to the formulations shown in Table 1 according to conventional methods in the art. Specifically, purified water was added to cepetaprost (0.001 g), sodium citrate hydrate (0.3 g), polysorbate 80 (0.1 g), D-mannitol (4 g), benzalkonium chloride (0.005 g), and sodium edetate hydrate (0.12 g), followed by stirring. An appropriate amount of pH adjuster (sodium hydroxide / dilute hydrochloric acid) was added to adjust the pH, and an appropriate amount of purified water was added to bring the total volume to 100 mL to prepare Drug Solution A containing 0.001% (w / v) of sepetaprost. Similarly, Drug Solution B containing 0.003% (w / v) of sepetaprost and Drug Solution C containing 0.01% (w / v) of sepetaprost were prepared. In Table 1 below, the "%" for the amount of each component means "% (w / v)".

[0092]

[0093] 2. Preparation of Cepetaprost-Containing Ophthalmic Solution in an Eye Drop Container (Example 1) The eye drop container was a three-piece multi-dose eye drop container consisting of an eye drop container body (made of PP), an inner stopper (made of PP), and a cap (made of PE), which was sterilized with ethylene oxide gas (EOG). Drug Solution A (3 mL) was filled into the eye drop container body, and the inner stopper and cap were attached and sealed to prepare the cepetaprost-containing eye drop solution in the eye drop container of Example 1.

[0094] Example 2 The eye drop container was a three-piece multi-dose eye drop container consisting of an eye drop container body (made of PP), an inner stopper (made of PP), and a cap (made of PE), which was sterilized with ethylene oxide gas (EOG). Drug solution B (3 mL) was filled into the eye drop container body, and the inner stopper and cap were attached to seal the container, thereby preparing the cepetaprost-containing eye drop solution in the eye drop container of Example 2.

[0095] (Example 3) The eye drop container was a three-piece multi-dose eye drop container consisting of an eye drop container body (made of PE), an inner stopper (made of PE), and a cap (made of PP), which was sterilized with ethylene oxide gas (EOG). Drug solution B (3 mL) was filled into the eye drop container body, and the inner stopper and cap were attached and sealed to prepare the cepetaprost-containing eye drop solution in the eye drop container of Example 3.

[0096] Example 4 The eye drop container was a three-piece multi-dose eye drop container consisting of an eye drop container body (made of PP), an inner stopper (made of PP), and a cap (made of PE), which was sterilized with ethylene oxide gas (EOG). The eye drop container body was filled with drug solution C (3 mL), and the inner stopper and cap were attached and sealed to prepare the cepetaprost-containing eye drop solution in the eye drop container of Example 4.

[0097] (Comparative Example 1) The eye drop container was a three-piece multi-dose eye drop container consisting of an eye drop container body (made of PE), an inner stopper (made of PE), and a cap (made of PP), which was sterilized by electron beam (EB) before use. Drug solution A (3 mL) was filled into the eye drop container body, and the inner stopper and cap were attached and sealed to prepare the cepetaprost-containing eye drop solution in the eye drop container of Comparative Example 1.

[0098] (Comparative Example 2) The eye drop container was a three-piece multi-dose eye drop container consisting of an eye drop container body (made of PE), an inner stopper (made of PE), and a cap (made of PP), which was sterilized by electron beam (EB) before use. Drug solution B (3 mL) was filled into the eye drop container body, and the inner stopper and cap were attached and sealed to prepare the cepetaprost-containing eye drop solution in the eye drop container of Comparative Example 2.

[0099] (Comparative Example 3) The eye drop container was a three-piece multi-dose eye drop container consisting of an eye drop container body (made of PE), an inner stopper (made of PE), and a cap (made of PP), which was sterilized by electron beam (EB) before use. Drug solution C (3 mL) was filled into the eye drop container body, and the inner stopper and cap were attached and sealed to prepare the cepetaprost-containing eye drop solution in the eye drop container of Comparative Example 3.

[0100] 3. Test Method The cepetaprost-containing eye drops in eye drop containers of Examples 1 to 4 and Comparative Examples 1 to 3 were stored at 40° C. for 6 months, and the cepetaprost content of each solution was measured.

[0101] Then, based on the measured sepetaprost content, the residual rate of sepetaprost content was calculated using the following formula: Residual rate of sepetaprost = (measured value after storage / measured value immediately after filling) x 100%

[0102] 4. Test Results The test results are shown in Tables 2 to 4. Table 2 shows the residual rates (%) of sepetaprost when the preparations of Example 1 and Comparative Example 1, each containing 0.001% (w / v) sepetaprost, were stored at 40°C for 6 months. Table 3 shows the residual rates (%) of sepetaprost when the preparations of Examples 2 and 3 and Comparative Example 2, each containing 0.003% (w / v) sepetaprost, were stored at 40°C for 6 months. Table 4 shows the residual rates (%) of sepetaprost when the preparations of Example 4 and Comparative Example 3, each containing 0.01% (w / v) sepetaprost, were stored at 40°C for 6 months.

[0103]

[0104]

[0105]

[0106] As can be seen from Tables 2 to 4, the preparations of Examples 1 to 4 contained in containers sterilized by ethylene oxide gas showed a higher residual rate of sepetaprost than the preparations of Comparative Examples 1 to 3 contained in containers sterilized by electron beam irradiation. The above results demonstrate that by containing an ophthalmic solution containing sepetaprost in an ethylene oxide gas sterilized container, the thermal stability of sepetaprost in the ophthalmic solution is maintained and the decrease in its content is controlled.

[0107] <Formulation Examples> [Formulation Examples] Representative formulation examples of the present invention are shown below. The following formulation examples are contained in EOG sterilized eye drop containers. It should be noted that the present invention is not limited to these formulation examples. In the following formulation examples, the blending amount (% (w / v)) of each component is the content (g) in 100 mL of the ophthalmic solution.

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[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] According to the present invention, a decrease in the content of sepetaprost in a sepetaprost-containing ophthalmic solution can be suppressed, and therefore, a sepetaprost-containing ophthalmic solution having excellent formulation stability can be provided, which is useful.

Claims

1. An eye drop solution containing cepetaprost, which is contained in an ethylene oxide gas sterilized eye drop container.

2. The eye drop solution according to claim 1, wherein the concentration of cepetaprost is 0.001 to 0.01% (w / v).

3. The eye drop solution according to claim 2, wherein the concentration of cepetaprost is 0.001 to 0.003% (w / v).

4. The eye drop solution according to any one of claims 1 to 3, wherein the eye drop container is made of resin.

5. The eye drop solution according to any one of claims 1 to 4, wherein the eye drop container is made of polyethylene or polypropylene.

6. The ophthalmic solution according to any one of claims 1 to 5, further comprising at least one selected from the group consisting of an isotonicity agent, a preservative, a buffer, a surfactant, a stabilizer, an antioxidant and a pH adjuster.

7. The eye drop according to any one of claims 1 to 6, which is an aqueous eye drop.

8. An ophthalmic pharmaceutical product, comprising an eye drop solution containing cepetaprost contained in an ethylene oxide gas sterilized eye drop container.

9. A method for stabilizing cepetaprost in an eye drop solution, comprising placing the eye drop solution containing cepetaprost in an eye drop container sterilized with ethylene oxide gas.

10. A method for producing an ophthalmic pharmaceutical product, comprising packaging an eye drop solution containing cepetaprost in an ethylene oxide gas sterilized eye drop container.

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