Composition for ophthalmic use containing sepetaprost

Abstract

The purpose of the present invention is to discover a method for stabilizing a composition for ophthalmic use containing sepetaprost, more specifically, a method that facilitates retention of sepetaprost stability at high temperatures, and further, a method that facilitates the retention of shelf life of this composition for ophthalmic use.　The present invention is a composition for ophthalmic use, which contains sepetaprost at a concentration of 0.0001 to 0.003% (w / v) and has a pH within a range from 5 to 8.

Description

Ophthalmic compositions containing sepetaprost

[0001] The present invention relates to an ophthalmic composition containing sepetaprost (hereinafter also referred to as the ophthalmic composition of the present invention).

[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] However, there have been no research reports to date on the stability and preservative effectiveness of ophthalmic compositions containing cepetaprost.

[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] The present inventors have conducted various studies on ophthalmic compositions containing sepetaprost, and have unexpectedly found that when an ophthalmic composition containing sepetaprost is stored at high temperatures, sepetaprost becomes unstable. Furthermore, the present inventors have unexpectedly found that the type of tonicity agent contained in the ophthalmic composition affects the preservative effectiveness.

[0010] Therefore, the problem to be solved by the present invention is to find a method for stabilizing an ophthalmic composition containing sepetaprost, more specifically, to find a method capable of maintaining sepetaprost stable even at high temperatures (e.g., 70°C), and further to find a method capable of maintaining the preservative effectiveness of the ophthalmic composition.

[0011] In order to solve the above problems, the present inventors have conducted extensive research and found that, in an ophthalmic composition containing sepetaprost, the stability of sepetaprost can be increased by adjusting the pH to 5 to 8, and that the stability of sepetaprost can be further increased by adding edetic acid or a salt thereof, thereby completing the present invention.

[0012] Furthermore, the present inventors have unexpectedly found that adding an ionic tonicity agent to an ophthalmic composition can enhance preservative effectiveness.On the other hand, they have found that adding an ionic tonicity agent reduces preservative effectiveness in the presence of benzalkonium chloride, and adding a nonionic tonicity agent can maintain preservative effectiveness.Furthermore, the present inventors have found that by selecting a sterilization method for an ophthalmic composition containing sepetaprost, high storage stability of sepetaprost in the ophthalmic composition can be maintained.

[0013] That is, the present invention provides the following: [1] An ophthalmic composition containing cepetaprost at a concentration of 0.0001 to 0.003% (w / v) and having a pH in the range of 5 to 8. [2] The ophthalmic composition according to [1], further containing edetic acid or a salt thereof at a concentration of more than 0.01% (w / v). [3] The ophthalmic composition according to [2], wherein the concentration of edetic acid or a salt thereof is 0.05% (w / v) or more. [4] The ophthalmic composition according to [2], wherein the concentration of edetic acid or a salt thereof is 0.05 to 0.5% (w / v). [5] The ophthalmic composition according to [2], wherein the concentration of edetic acid or a salt thereof is 0.05 to 0.2% (w / v). [6] The ophthalmic composition according to any of [1] to [5], wherein the pH is in the range of 6 to 7. [7] The ophthalmic composition according to any of [1] to [5], wherein the pH is 6.5. [8] The ophthalmic composition according to any one of [1] to [7], further comprising an isotonicity adjusting agent. [9] The ophthalmic composition according to [8], wherein the isotonicity adjusting agent is an ionic isotonicity adjusting agent.

[10] The ophthalmic composition according to [9], wherein the ophthalmic composition does not contain benzalkonium chloride.

[11] The ophthalmic composition according to [9], wherein the ophthalmic composition does not contain a preservative.

[12] The ophthalmic composition according to any one of [9] to

[11] , wherein the ophthalmic composition does not contain a non-ionic isotonicity adjusting agent.

[13] The ophthalmic composition according to [8], wherein the isotonicity adjusting agent is a non-ionic isotonicity adjusting agent.

[14] The ophthalmic composition according to

[13] , further comprising benzalkonium chloride.

[15] The ophthalmic composition according to

[13] or

[14] , wherein the ophthalmic composition does not contain an ionic isotonicity adjusting agent.

[16] An ophthalmic composition comprising cepetaprost at a concentration of 0.0001 to 0.003% (w / v), a non-ionic tonicity agent, and benzalkonium chloride, and having a pH in the range of 5 to 8.

[17] The ophthalmic composition according to

[16] , which does not contain an ionic tonicity agent.

[18] An ophthalmic composition comprising cepetaprost at a concentration of 0.0001 to 0.003% (w / v) and an ionic tonicity agent, does not contain benzalkonium chloride, and has a pH in the range of 5 to 8.

[19] The ophthalmic composition according to

[18] , which does not contain a preservative.

[20] An ophthalmic composition comprising cepetaprost at a concentration of 0.0001 to 0.003% (w / v), edetic acid or a salt thereof at a concentration of more than 0.01% (w / v), and an ionic tonicity agent, which is free of non-ionic tonicity agents and benzalkonium chloride, and has a pH in the range of 5 to 8.

[21] An ophthalmic composition comprising cepetaprost at a concentration of 0.0001 to 0.003% (w / v), edetic acid or a salt thereof at a concentration of more than 0.01% (w / v), and a non-ionic tonicity agent and benzalkonium chloride, which is free of ionic tonicity agents, and has a pH in the range of 5 to 8.

[22] The ophthalmic composition according to any one of

[12] to

[17] ,

[20] , and

[21] , wherein the nonionic tonicity agent is at least one selected from the group consisting of mannitol, glycerin, propylene glycol, polyethylene glycol, sorbitol, trehalose, maltose, and sucrose.

[23] The ophthalmic composition according to

[22] , wherein the nonionic tonicity agent is mannitol.

[24] The ophthalmic composition according to any one of [9] to

[12] ,

[15] , and

[17] to

[23] , wherein the ionic tonicity agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

[25] The ophthalmic composition according to

[24] , wherein the ionic tonicity agent is sodium chloride.

[26] The ophthalmic composition according to any one of [1] to

[25] , further comprising a buffer.

[27] The ophthalmic composition according to any one of [1] to

[26] , further comprising a surfactant.

[28] The ophthalmic composition according to any one of [1] to

[27] , which is a sterilized ophthalmic composition.

[29] The ophthalmic composition according to

[28] , wherein the sterilization is filter sterilization.

[30] An ophthalmic composition comprising cepetaprost at a concentration of 0.0001 to 0.003% (w / v), polysorbate 80 at a concentration of 0.05 to 0.3% (w / v), sodium citrate hydrate at a concentration of 0.1 to 0.5% (w / v), sodium edetate at a concentration of 0.05 to 0.5% (w / v), and sodium chloride at a concentration of 0.5 to 1% (w / v), the ophthalmic composition being free of benzalkonium chloride and having a pH of 6 to 7.

[31] An ophthalmic composition comprising cepetaprost at a concentration of 0.0001 to 0.003% (w / v), polysorbate 80 at a concentration of 0.05 to 0.3% (w / v), sodium citrate hydrate at a concentration of 0.1 to 0.5% (w / v), sodium edetate at a concentration of 0.05 to 0.5% (w / v), mannitol at a concentration of 1 to 6% (w / v), and benzalkonium chloride at a concentration of 0.001 to 0.0075% (w / v), and having a pH of 6 to 7.

[32] An ophthalmic composition comprising cepetaprost at a concentration of 0.0001 to 0.003% (w / v), polysorbate 80 at a concentration of 0.05 to 0.3% (w / v), sodium citrate hydrate at a concentration of 0.1 to 0.5% (w / v), sodium edetate at a concentration of 0.05 to 0.5% (w / v), and sodium chloride at a concentration of 0.5 to 1% (w / v), the composition being benzalkonium chloride-free and having a pH of 6.5.

[33] An ophthalmic composition containing cepetaprost at a concentration of 0.0001 to 0.003% (w / v), polysorbate 80 at a concentration of 0.05 to 0.3% (w / v), sodium citrate hydrate at a concentration of 0.1 to 0.5% (w / v), sodium edetate at a concentration of 0.05 to 0.5% (w / v), mannitol at a concentration of 1 to 6% (w / v), and benzalkonium chloride at a concentration of 0.001 to 0.0075% (w / v), and having a pH of 6.5.

[34] The ophthalmic composition according to any one of [1] to

[33] , wherein the concentration of cepetaprost is 0.001 to 0.003% (w / v).

[35] The ophthalmic composition according to any one of [1] to

[33] , wherein the concentration of sepetaprost is 0.002 to 0.003% (w / v).

[36] The ophthalmic composition according to any one of [1] to

[33] , wherein the concentration of sepetaprost is 0.002% (w / v).

[37] The ophthalmic composition comprising sepetaprost at a concentration of 0.002 to 0.003% (w / v) and having a pH in the range of 6 to 7.

[38] The ophthalmic composition comprising sepetaprost at a concentration of 0.002% (w / v) and having a pH in the range of 6 to 7.

[39] The ophthalmic composition according to any one of [1] to

[38] , wherein the ophthalmic composition is an eye drop.

[40] The ophthalmic composition according to any one of [1] to

[39] , wherein the ophthalmic composition is contained in a unit-dose eye drop container.

[41] The ophthalmic composition according to any one of [1] to

[39] , which is contained in a multidose eye dropper container.

[42] The ophthalmic composition according to any one of [1] to

[41] , which is contained in a plastic eye dropper container.

[43] The ophthalmic composition according to any one of [1] to

[42] , for preventing or treating glaucoma or ocular hypertension.

[0014] The present invention also relates to the following:

[44] A method for stabilizing sepetaprost in an ophthalmic composition containing sepetaprost at a concentration of 0.0001 to 0.003% (w / v), comprising adjusting the pH to a range of 5 to 8.

[45] The method according to

[44] , wherein the pH of an ophthalmic composition containing sepetaprost at a concentration of 0.002 to 0.003% (w / v) is adjusted to a range of 6 to 7.

[46] The method according to

[44] or

[45] , wherein the pH of an ophthalmic composition containing sepetaprost at a concentration of 0.002% (w / v) is adjusted to a range of 6 to 7.

[47] A method for stabilizing a sepetaprost-containing ophthalmic composition, comprising adding edetic acid or a salt thereof at a concentration of more than 0.01% (w / v) and adjusting the pH to a range of 5 to 8.

[48] ​​A method for imparting preservative effect to an ophthalmic composition containing sepetaprost, characterized by blending an ionic tonicity agent.

[49] A method for imparting preservative effect to an ophthalmic composition containing sepetaprost, characterized by blending a non-ionic tonicity agent and benzalkonium chloride.

[50] A method for stabilizing sepetaprost in an ophthalmic composition containing sepetaprost, comprising a step of sterilizing the ophthalmic composition containing sepetaprost.

[51] The method according to

[50] , wherein the sterilization is filter sterilization.

[52] A method for suppressing a decrease in the content of sepetaprost in an ophthalmic composition, comprising a step of filter sterilizing the ophthalmic composition containing sepetaprost.

[53] A method for stabilizing sepetaprost in an ophthalmic composition, comprising a step of placing the ophthalmic composition according to any one of [1] to

[43] in a plastic eye dropper container.

[54] An ophthalmic pharmaceutical product, characterized in that the ophthalmic composition according to any one of [1] to

[43] is contained in a unit-dose eye dropper container or a multi-dose eye dropper container.

[55] An ophthalmic pharmaceutical product, characterized in that the ophthalmic composition according to any one of [1] to

[43] is contained in a plastic eye dropper container.

[56] A method for producing an ophthalmic pharmaceutical product, comprising a step of sterilizing the ophthalmic composition according to any one of [1] to

[43] .

[57] The production method according to

[56] , wherein the sterilization is filter filtration sterilization.

[58] The manufacturing method according to

[56] or

[57] , further comprising a step of placing the sterilized ophthalmic composition in an eye drop container.

[59] The manufacturing method according to

[56] to

[58] , wherein the eye drop container is a plastic eye drop container.

[60] The manufacturing method according to

[56] to

[59] , wherein the eye drop container is a unit-dose or multi-dose eye drop container.

[0015] It should be noted that any two or more of the above structures [1] to

[60] can be selected and combined.

[0016] According to the present invention, it is possible to provide an ophthalmic composition that can increase the stability of sepetaprost in the ophthalmic composition and maintain its stability even when exposed to high temperatures during distribution or storage. Furthermore, in addition to maintaining the stability of sepetaprost, the present invention also provides an ophthalmic composition that can maintain its preservative effectiveness by using an appropriate type of isotonic agent. Furthermore, in the present invention, it is possible to provide an ophthalmic composition that can maintain high storage stability of sepetaprost in the ophthalmic composition by selecting a sterilization method for the ophthalmic composition containing sepetaprost.

[0017] Fig. 1 is a graph showing the test results in Test Example 1. Fig. 2 is a graph showing the test results in Test Example 2. Fig. 3 is a photograph showing the test results in Test Example 4.

[0018] The present invention will be described in detail below.

[0019] In the present invention, cepetaprost 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.

[0020] 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.

[0021] When cepetaprost has geometric isomers and / or optical isomers, these isomers are also included within the scope of the present invention.

[0022] When cepetaprost has proton tautomerism, the tautomers (keto form, enol form) are also included in the present invention.

[0023] 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.

[0024] Sepetaprost may be in the form of a hydrate or solvate.

[0025] In the ophthalmic composition of the present invention, the content of sepetaprost is 0.0001 to 0.003% (w / v). The lower limit of the content of sepetaprost is preferably 0.0001% (w / v) or more, more preferably 0.0003% (w / v) or more, even more preferably 0.001% (w / v) or more, and even more preferably 0.0015% (w / v) or more, and the upper limit is preferably 0.003% (w / v) or less, more preferably 0.0025% (w / v) or less, and even more preferably 0.002% (w / v) or less. More specifically, the content can be within a range that arbitrarily combines any of the above lower limits and upper limits, and examples thereof include 0.0001 to 0.003% (w / v), 0.0003 to 0.003% (w / v), 0.0015 to 0.003% (w / v), 0.001 to 0.003% (w / v), 0.002 to 0.003% (w / v), 0.0001 to 0.025% (w / v), 0.0003 to 0.025% (w / v), 0.0015 to 0.025% (w / v), 0.001 to 0.025% (w / v), 0.0001 to 0.002% (w / v), 0.0003 to 0.002% (w / v), and 0.001 to 0.002% (w / v). More specifically, preferred contents include, for example, 0.001% (w / v), 0.002% (w / v), and 0.003% (w / v), with 0.002% (w / v) being preferred. This content can also be used as a preferred content when the ophthalmic composition is an eye drop. Here, "% (w / v)" refers to the mass (g) of the active ingredient (sepetaprost) and additives contained in 100 mL of the ophthalmic composition. For example, 0.001% (w / v) of cepetaprost means that the content of cepetaprost in 100 mL of the ophthalmic composition is 0.001 g. In this specification, numerical values ​​(e.g., content, concentration, pH, etc.) may be accompanied by the term "about," which means a range of ±10% of the value. For example, "about 10" includes "9 to 11." The term "about" in reference to numerical ranges expressed using "to" applies to both endpoints of the range. Thus, for example, "about 10 to 20" includes "9 to 22."

[0026] 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.

[0027] The ophthalmic composition of the present invention can contain, for example, edetic acid or a salt thereof.

[0028] Examples of edetic acid or salts thereof in the present invention 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.

[0029] In the ophthalmic composition of the present invention, the content of edetic acid or a salt thereof is more than 0.01% (w / v). The lower limit of edetic acid or a salt thereof is, for example, preferably 0.05% (w / v) or more and more preferably 0.05% (w / v), and more preferably 0.1% (w / v) or more and more preferably 0.1% (w / v). The upper limit is, for example, preferably 0.5% (w / v) or less and more preferably 0.3% (w / v) or less and more preferably 0.2% (w / v) or less. More specifically, the content can be within a range that combines any of the above lower limits and upper limits, and examples include ranges of 0.05 to 0.5% (w / v), more than 0.05% (w / v) and not more than 0.5% (w / v), 0.05 to 0.2% (w / v), more than 0.05% (w / v) and not more than 0.2% (w / v), 0.1 to 0.3% (w / v), more than 0.1% (w / v) and not more than 0.3% (w / v), 0.1 to 0.2% (w / v), and more than 0.1% (w / v) and not more than 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).

[0030] The ophthalmic composition of the present invention has a pH in the range of 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 preferred. The pH of the ophthalmic composition can be adjusted, for example, by adding an appropriate amount of a pH adjuster, as described below.

[0031] Furthermore, additives can be used in the ophthalmic composition 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 can be used alone or in appropriate combinations of two or more, and can be blended in appropriate amounts.

[0032] Examples of the tonicity adjusting agent that can be incorporated into the ophthalmic composition of the present invention include ionic tonicity adjusting agents and non-ionic tonicity adjusting agents.

[0033] Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., and among these, sodium chloride is preferred.

[0034] 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.

[0035] When an isotonicity agent is incorporated into the ophthalmic composition of the present invention, the isotonicity agent may be used alone or in combination of two or more components. For example, when the ophthalmic composition of the present invention contains an ionic isotonicity agent, it may not contain a nonionic isotonicity agent, and may contain only an ionic isotonicity agent as the isotonicity agent. When the ophthalmic composition of the present invention contains a nonionic isotonicity agent, it may not contain an ionic isotonicity agent, and may contain only a nonionic isotonicity agent as the isotonicity agent.

[0036] In the present invention, when an ionic tonicity agent is incorporated into an ophthalmic composition, it can impart preservative properties to the ophthalmic composition, as shown in the examples described below. Therefore, an ionic tonicity agent is preferably incorporated into the ophthalmic composition of the present invention. Furthermore, the ophthalmic composition of the present invention may optionally contain a preservative such as benzalkonium chloride. However, when the ophthalmic composition contains an ionic tonicity agent, it is preferable not to incorporate a preservative such as benzalkonium chloride.

[0037] In the present invention, the nonionic tonicity agent is preferably incorporated when the ophthalmic composition of the present invention contains benzalkonium chloride as a preservative, as described below.

[0038] When an isotonic agent is blended into the ophthalmic composition 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).

[0039] 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).

[0040] 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).

[0041] Examples of preservatives that can be incorporated into the ophthalmic composition of the present invention include cationic soaps, parabens, alcohols, and organic acids or salts thereof.

[0042] Examples of cationic soaps include benzalkonium chloride (also referred to as benzalkonium chloride), benzalkonium bromide (also referred to as benzalkonium bromide), benzethonium chloride (also referred to as benzethonium chloride), benzethonium bromide (also referred to as benzethonium bromide), chlorhexidine or a salt thereof, etc. When the ophthalmic composition of the present invention contains benzalkonium chloride as a preservative, the incorporation of an ionic tonicity agent reduces the preservative effectiveness, as shown in the examples below. Therefore, when the ophthalmic composition of the present invention contains benzalkonium chloride, it is preferable that it does not contain an ionic tonicity agent. Furthermore, when the ophthalmic composition of the present invention contains benzalkonium chloride, it is preferable that a non-ionic tonicity agent be incorporated as the tonicity agent.

[0043] Examples of parabens include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate.

[0044] The alcohols include, for example, chlorobutanol.

[0045] 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.

[0046] When a preservative is incorporated into the ophthalmic composition of the present invention, the preservative may be used alone or in combination of two or more components. The ophthalmic composition of the present invention may not contain a preservative, and in this case, it is preferable that the ophthalmic composition contains an ionic tonicity adjusting agent as the tonicity adjusting agent and does not contain a nonionic tonicity adjusting agent.

[0047] When a preservative is incorporated into the ophthalmic composition of the present invention, the content of the preservative can be appropriately adjusted depending on the type of preservative, etc., 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.

[0048] Examples of buffering agents that can be incorporated into the ophthalmic composition 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.

[0049] 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.

[0050] Examples of boric acid or salts thereof include boric acid, sodium borate, and potassium borate.

[0051] Examples of citric acid or salts thereof include citric acid, sodium citrate, disodium citrate, etc. Among these, sodium citrate is preferably used.

[0052] Examples of acetic acid or salts thereof include acetic acid, sodium acetate, potassium acetate, and the like.

[0053] Examples of carbonic acid or its salts include sodium carbonate and sodium hydrogen carbonate.

[0054] Examples of tartaric acid or salts thereof include tartaric acid, sodium tartrate, potassium tartrate, and the like.

[0055] When a buffering agent is incorporated into the ophthalmic composition of the present invention, the buffering agent may be used alone or in combination of two or more components.

[0056] When a buffer is incorporated into the ophthalmic composition of the present invention, the content of the buffer can be appropriately adjusted depending on the type of buffer, 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.

[0057] Examples of surfactants that can be incorporated into the ophthalmic composition of the present invention include cationic surfactants, anionic surfactants, and nonionic surfactants, and among these, nonionic surfactants are preferred.

[0058] 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.

[0059] Examples of anionic surfactants include phospholipids such as lecithin.

[0060] 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.

[0061] When a surfactant is incorporated into the ophthalmic composition of the present invention, the surfactant may be used alone or in combination of two or more components.

[0062] When a surfactant is incorporated into the ophthalmic composition 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.

[0063] Examples of stabilizers that can be incorporated into the ophthalmic composition of the present invention include, in addition to the above-mentioned edetic acid or a salt thereof, sulfites, monoethanolamine, cyclodextrin, dextran, taurine, etc.

[0064] When a stabilizer is blended in the ophthalmic composition of the present invention, the stabilizer may be used alone or in combination of two or more components.

[0065] When a stabilizer is blended in the ophthalmic composition of the present invention in addition to the above-mentioned edetic acid or a salt thereof, the content of the stabilizer can be appropriately adjusted depending on the type of stabilizer, etc., but is preferably 0.001 to 5% (w / v), more preferably 0.005 to 1% (w / v), and even more preferably 0.01 to 0.5% (w / v).

[0066] Examples of antioxidants that can be incorporated into the ophthalmic composition of the present invention include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, and 2-mercaptobenzimidazole.

[0067] When an antioxidant is incorporated into the ophthalmic composition of the present invention, the antioxidant may be used alone or in combination of two or more components.

[0068] When an antioxidant is incorporated into the ophthalmic composition 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).

[0069] The pH adjuster that can be incorporated into the ophthalmic composition 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 composition of the present invention can be adjusted by adding these pH adjusters as appropriate. Specifically, the pH of the ophthalmic composition can be adjusted by adding appropriate amounts of hydrochloric acid and sodium hydroxide, for example.

[0070] When a pH adjuster is incorporated into the ophthalmic composition of the present invention, the pH adjuster may be used alone or in combination of two or more components.

[0071] When the ophthalmic composition of the present invention is an eye drop, the base is preferably water.

[0072] The osmotic pressure ratio of the ophthalmic composition 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.

[0073] 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.

[0074] The ophthalmic composition 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. 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 primary open-angle glaucoma, normal-tension glaucoma, and primary angle-closure glaucoma. The ophthalmic composition of the present invention may contain an active ingredient other than cepetaprost, or may contain cepetaprost as the only active ingredient.

[0075] The ophthalmic composition of the present invention can be administered orally or parenterally, for example, by eye drops, intravitreal administration, intraconjunctival administration, intracameral administration, subconjunctival administration, sub-Tenon's administration, or punctal plug administration. The dosage form of the ophthalmic composition of the present invention includes eye drops, eye ointments, injections, punctal plugs, tablets, capsules, granules, powders, etc., with eye drops being particularly preferred.

[0076] The dosage and administration method of the ophthalmic composition of the present invention 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, the dosage form of the ophthalmic composition, etc.

[0077] Specifically, in the case of eye drops, the solution can be administered in a single 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 one drop once a day every day. Here, one 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.

[0078] The ophthalmic composition of the present invention is preferably a sterilized ophthalmic composition. Examples of sterilization methods for ophthalmic compositions include electron beam (EB) sterilization, ethylene oxide gas (EOG) sterilization, hydrogen peroxide sterilization, gamma ray sterilization, filter sterilization, and autoclave (AC) sterilization. For the ophthalmic composition of the present invention, filter sterilization is preferred as a sterilization method for the ophthalmic composition.

[0079] In the present invention, "electron beam sterilization" or "EB sterilization" refers to a sterilization method that can kill bacteria and the like by utilizing electron beams, and is not particularly limited as long as it is a method of sterilization using electron beams. For example, the irradiation dose can be selected appropriately from 1 to 100 kGy, and the irradiation time can be selected appropriately from several seconds to several minutes.

[0080] In the present invention, "ethylene oxide gas sterilization" or "EOG sterilization" refers to a sterilization method that can kill bacteria and the like using ethylene oxide gas, and is not particularly limited as long as it is a method of sterilization using ethylene oxide gas. For example, the sterilization temperature is 30 to 60°C, the sterilization time is 1 to 10 hours, and the gas used may be ethylene oxide gas alone or a mixed gas of ethylene oxide gas and carbon dioxide or the like, and can be selected appropriately.

[0081] In the present invention, "hydrogen peroxide sterilization" refers to a sterilization method that can kill bacteria and the like using hydrogen peroxide, and is not particularly limited as long as it is a method of sterilization using hydrogen peroxide.

[0082] In the present invention, "gamma ray sterilization" refers to a sterilization method that can kill bacteria and the like by utilizing gamma rays, and is not particularly limited as long as it is a method that uses gamma rays for sterilization treatment.

[0083] In the present invention, "filter sterilization" refers to a sterilization method in which bacteria and the like are removed by filtration using a membrane filter (e.g., 0.22 μm pore size). The membrane filter may be made of a material such as PVDF (polyvinylidene fluoride), PES (polyethersulfone), PTFE (polytetrafluoroethylene), or MCE (mixed cellulose ester), and may have a different pore size.

[0084] In the present invention, "high-pressure steam (AC) sterilization" refers to a sterilization method that can kill bacteria and the like using an autoclave, and is not particularly limited as long as it is a method of sterilization using an autoclave. For example, AC sterilization is preferably carried out under conditions such as 115 to 118°C for 30 minutes, 121 to 124°C for 15 to 20 minutes, or 126 to 129°C for 10 minutes, and is continued until the object reaches a sterile state.

[0085] The ophthalmic composition of the present invention can be stored in an airtight container, for example, an eye drop container. From the viewpoint of material, examples of the eye drop container include resin (plastic) eye drop containers. Furthermore, from the viewpoint of functionality, examples of the eye drop container include "multi-dose eye drop containers" and "unit-dose eye drop containers."

[0086] In the present invention, the term "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 resealed. Such a multidose eye drop container typically contains multiple doses of eye drops (ophthalmic composition) for use over a certain period of time. Furthermore, when the ophthalmic composition of the present invention does not contain a preservative such as benzalkonium chloride, the ophthalmic composition may be contained in a PFMD (Preservative Free Multi Dose) container. The volume of the ophthalmic composition filled in a multidose eye drop container or a PFMD container is, for example, preferably 1 to 20 mL, more preferably 1 to 15 mL, even more preferably 1 to 10 mL, even more preferably 2.5 to 10 mL, and particularly preferably 5 mL.

[0087] On the other hand, a "unit-dose eye drop container" refers to an eye drop container in which a cap is fused and sealed to the mouth of the bottle, and which is intended to be used by breaking and opening the fused portion between the cap and the bottle-shaped body. The unit-dose eye drop container contains an amount of eye drop solution (ophthalmic composition) for one or several uses. The eye drop solution contained in a unit-dose eye drop container generally does not contain a preservative such as benzalkonium chloride. The amount of the composition filled in the unit-dose eye drop container is, for example, preferably 0.1 to 1 mL, more preferably 0.1 to 0.5 mL, even more preferably 0.3 to 0.5 mL, and particularly preferably 0.3 mL or 0.4 mL.

[0088] In the present invention, the multi-dose eye dropper container and unit-dose eye dropper container can be made from a variety of resins (plastics) without any particular limitations. Examples of resins that can be used include polyethylene (PE), polypropylene (PP), polypropylene-polyethylene copolymer, polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyvinyl chloride, acrylic resin, and polystyrene. Polyethylene is further classified by density, and examples include low-density polyethylene (LDPE), medium-density polyethylene (MDPE), and high-density polyethylene (HDPE). Among these, polyethylene, polypropylene, propylene-ethylene copolymer, and polyethylene terephthalate are preferably used in the present invention. Here, the 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.

[0089] The eye drop container may be formed from one or more components, and may be a one-piece, two-piece, or three-piece eye drop container. For example, a three-piece eye drop container is formed from three components: a container body that holds the ophthalmic composition of the present invention, an inner stopper, and a cap. Also included in the category of eye drop containers is an integrally molded container that is simultaneously blow-molded and filled with a drug solution, depending on the number of components. When a container is formed from multiple components, the components may be formed from the same material or from different materials. Furthermore, a material may constitute or coat part or all of the components. The container may be commercially available or manufactured by a known method.

[0090] One aspect of the present invention is a method for stabilizing sepetaprost in an ophthalmic composition, which comprises adjusting the pH of the ophthalmic composition containing sepetaprost at a concentration of 0.0001 to 0.003% (w / v) to a range of 5 to 8. The stabilization method of the present invention comprises adjusting the pH of the ophthalmic composition containing sepetaprost at a concentration of 0.0001 to 0.003% (w / v) to a range of 5 to 8. The above detailed description of the ophthalmic composition of the present invention also applies to this stabilization method.

[0091] One aspect of the present invention is a method for stabilizing an ophthalmic composition containing cepetaprost, characterized by incorporating edetic acid or a salt thereof at a concentration of more than 0.01% (w / v) and adjusting the pH to a range of 5 to 8. The stabilization method of the present invention is characterized by incorporating edetic acid or a salt thereof at a concentration of more than 0.01% (w / v) into an ophthalmic composition containing cepetaprost and adjusting the pH to a range of 5 to 8. The above detailed description of the ophthalmic composition of the present invention also applies to this stabilization method.

[0092] One aspect of the present invention is a method for imparting preservative effect to an ophthalmic composition containing cepetaprost, characterized by incorporating an ionic tonicity agent. The method for imparting preservative effect of the present invention is characterized by incorporating an ionic tonicity agent into the ophthalmic composition containing cepetaprost. Note that the detailed description of the ophthalmic composition of the present invention above also applies to this method for imparting preservative effect.

[0093] One aspect of the present invention is a method for imparting preservative effect to an ophthalmic composition containing cepetaprost, characterized by blending a nonionic tonicity agent and benzalkonium chloride. The method for imparting preservative effect of the present invention is characterized by blending a nonionic tonicity agent and benzalkonium chloride to an ophthalmic composition containing cepetaprost. Note that the detailed description of the ophthalmic composition of the present invention above also applies to this method for imparting preservative effect.

[0094] One aspect of the present invention is a method for stabilizing sepetaprost in an ophthalmic composition, comprising a step of sterilizing the ophthalmic composition containing sepetaprost. The stabilization method of the present invention is characterized by comprising a step of sterilizing the ophthalmic composition containing sepetaprost. The detailed description of the ophthalmic composition of the present invention above also applies to this stabilization method.

[0095] One aspect of the present invention is a method for suppressing a decrease in the content of cepetaprost in an ophthalmic composition, comprising a step of subjecting an ophthalmic composition containing cepetaprost to filter filtration sterilization. The method for suppressing a decrease in the content of cepetaprost of the present invention is characterized by comprising a step of subjecting the ophthalmic composition to filter filtration sterilization. The detailed description of the ophthalmic composition of the present invention above also applies to the method for suppressing a decrease in the content of cepetaprost.

[0096] One aspect of the present invention is a method for stabilizing cepetaprost in the ophthalmic composition of the present invention, comprising the step of placing the ophthalmic composition of the present invention in a plastic eye drop container. The stabilization method of the present invention is characterized by including the step of placing the ophthalmic composition of the present invention in a plastic eye drop container. Note that the detailed description of the ophthalmic composition of the present invention also applies to this stabilization method.

[0097] One aspect of the present invention is an ophthalmic pharmaceutical product, characterized in that the ophthalmic composition of the present invention is contained in a unit-dose or multi-dose eye drop container. The ophthalmic pharmaceutical product of the present invention is characterized in that the ophthalmic composition of the present invention is contained in a unit-dose or multi-dose eye drop container. Note that the detailed description of the ophthalmic composition of the present invention also applies to this ophthalmic pharmaceutical product.

[0098] One aspect of the present invention is an ophthalmic pharmaceutical product, characterized in that the ophthalmic composition of the present invention is contained in a plastic eye dropper container. The ophthalmic pharmaceutical product of the present invention is characterized in that the ophthalmic composition of the present invention is contained in a plastic eye dropper container. Note that the detailed description of the ophthalmic composition of the present invention also applies to this ophthalmic pharmaceutical product.

[0099] One aspect of the present invention is a method for producing an ophthalmic pharmaceutical product, comprising a step of sterilizing the ophthalmic composition of the present invention. The production method of the present invention is characterized by comprising a step of sterilizing the ophthalmic composition of the present invention. Note that the detailed description of the ophthalmic composition of the present invention also applies to this production method.

[0100] The present invention will be described in detail below by way of test examples and formulation examples, but these examples are provided for a better understanding of the present invention and are not intended to limit the scope of the present invention in any way.

[0101] [Test Example 1] The effect of pH on the stability of sepetaprost in an ophthalmic composition containing sepetaprost was examined. The effect of sodium edetate on the stability of sepetaprost was also examined.

[0102] (1) Preparation of Test Formulations 1 to 4 Test Formulations 1 to 4 were prepared according to conventional methods in the art, as shown in Table 1. Specifically, water for injection was added to 0.003 g of cepetaprost, 0.3 g of sodium dihydrogen phosphate dihydrate, and 0.1 g of polysorbate 80, and the mixture was stirred. An appropriate amount of sodium hydroxide or dilute 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 the total volume of 100 mL, thereby preparing Test Formulation 1. Test Formulations 2 to 4 were also prepared in the same manner as Test Formulation 1.

[0103]

[0104] (2) Test Method Test Formulations 1 to 4 were filled into glass containers and stored at 70°C for up to 4 weeks. The concentrations of sepetaprost in the test formulations were measured by high-performance liquid chromatography immediately before the start of storage and 1, 2, and 4 weeks after the start of storage. The residual rate (%) of sepetaprost was calculated by setting the concentration of sepetaprost immediately before the start of storage as 100%.

[0105] (3) Test Results and Discussion The test results are shown in Figure 1. As shown in Figure 1, Test Formulations 1 and 3, whose pH was adjusted to 4.5 or 8.5, showed a significant decrease in the residual rate of sepetaprost after storage at high temperatures. Furthermore, Test Formulation 2 (containing no sodium edetate), whose pH was adjusted to 6.5, showed a decrease in the residual rate of sepetaprost after two weeks. On the other hand, Test Formulation 2 showed a higher residual rate than Test Formulations 1 and 3. Next, Test Formulation 4, whose pH was adjusted to 6.5 and contained sodium edetate, maintained a high residual rate of sepetaprost even after four weeks of storage at 70°C. These results demonstrated that adjusting the pH to 5-8, particularly pH 6.5, in ophthalmic compositions containing sepetaprost enhances the stability of sepetaprost. Furthermore, the inclusion of edetic acid or a salt thereof further enhanced the stability of sepetaprost.

[0106] Test Example 2 The effect of the concentration of sodium edetate on the stability of sepetaprost in an ophthalmic composition containing sepetaprost was examined.

[0107] (1) Preparation of Test Formulations 5 to 9 Test Formulations 5 to 9 were prepared according to the same method as Test Formulation 1, as shown in Table 2. Test Formulations 5 to 9 were spiked with 0.000001% (w / v) iron (III) nitrate.

[0108]

[0109] (2) Test Method Test Formulations 5 to 9 were filled into polyethylene containers and stored at 70°C for 4 weeks. After 4 weeks of storage, the concentrations of cepetaprost and the concentrations of total cepetaprost analogs and hydrolysates in the test formulations were measured by high-performance liquid chromatography. The total amount of analogs (%) and the amount of hydrolysates (%) were calculated as a percentage of the mass of cepetaprost contained in the test formulation, taken as 100%.

[0110] (3) Test Results and Discussion The test results are shown in Figure 2. Figure 2A is a bar graph showing the total amount (%) of related substances for each test formulation after 4 weeks of storage, and Figure 2B is a bar graph showing the amount (%) of hydrolysates for each test formulation after 4 weeks of storage. As shown in Figure 2, Test Formulations 8 and 9, which contain 0.05% (w / v) or more of sodium edetate, suppressed the production of cepetaprost related substances and hydrolysates compared to Test Formulation 5, which does not contain sodium edetate. In particular, Test Formulation 9, which contains 0.1% (w / v) of sodium edetate, suppressed the production of cepetaprost related substances and hydrolysates by approximately 80% compared to Test Formulation 5, which does not contain sodium edetate. These results demonstrate that the stability of sepetaprost is enhanced by incorporating sodium edetate in an ophthalmic composition containing sepetaprost at a concentration of more than 0.01% (w / v), particularly 0.05% (w / v) or more.

[0111] Test Example 3 A preservative effectiveness test was carried out on various ophthalmic compositions containing cepetaprost.

[0112] (1) Preparation of Test Formulations 10 to 13 Test Formulations 10 to 13 were prepared according to the same method as for Test Formulation 1, as shown in Table 3.

[0113]

[0114] (2) Test Method The preservative effectiveness test was conducted in accordance with the preservative effectiveness test methods of the 17th edition of the Japanese Pharmacopoeia and the 8th edition of the European Pharmacopoeia. In this test, Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus brasiliensis (A. brasiliensis) were used as test bacteria. The bacterial solution concentration in the test sample consisting of each test preparation was 10 ５ ~10 ６ The test sample was inoculated with the inoculum so that the total number of inoculum was 10 cfu / mL (for all five bacterial species). ７ ~10 ８An inoculum was prepared so that the inoculum had a density of 10 cfu / mL. ５ ~10 ６ Each test sample was inoculated to a concentration of 0.01 cfu / mL and mixed uniformly to prepare a sample. These samples were stored at 20-25°C in the dark, and at each sampling point (6 hours, 24 hours, 7 days, 14 days, or 28 days), 1 mL of each sample was taken with a micropipette and the viable bacterial count was measured. At each sampling point, the lid of the sample solution was opened, sampling was performed, and the lid was then closed.

[0115] (3) Test Results and Discussion The test results are shown in Table 4. The test results in Table 4 are expressed as common logarithmic values ​​of the ratio (B / A) of the number of bacteria measured at the time of sampling (A) to the number of bacteria at the time of inoculation (B). For example, a value of "1" indicates that the number of live bacteria at the time of sampling was reduced to 10% of the number of bacteria inoculated.

[0116] The pass / fail result of the preservative effectiveness test was judged according to the standards of the 17th edition of the Japanese Pharmacopoeia and the 8th edition of the European Pharmacopoeia.

[0117]

[0118] As shown in Table 4, all of the test preparations 10 to 13 conformed to the preservative effectiveness tests of the Japanese Pharmacopoeia and the European Pharmacopoeia, and had sufficient preservative effectiveness.

[0119] Test Example 4 The influence of the type of isotonic agent on bacterial growth in an ophthalmic composition containing sepetaprost was examined.

[0120] (1) Preparation of Test Formulations 14 to 16 Test Formulations 14 to 16 were prepared as shown in Table 5 according to the same method as for Test Formulation 1.

[0121]

[0122] (2) Test Method In this test, Aspergillus brasiliensis (A. brasiliensis) was used as the test bacterium. Test preparations 14 to 16 were each placed in a test tube to serve as test samples. The bacterial solution concentration in the test sample consisting of each test preparation was 2.5 x 10 ５The test sample was inoculated with the inoculum so that the inoculum was 2.5 × 10 cfu / mL. ７ An inoculum was prepared so that the inoculum was 2.5 x 10 cfu / mL. ５ Each test sample was inoculated with the test bacteria so that the total cfu / mL was 10 ...

[0123] (3) Test Results and Discussion The test results are shown in Figure 3. Figure 3 is a photograph showing the appearance of each test sample 21 days after inoculation with the test bacteria. As shown in Figure 3, Test Formulation 14, which contains sodium chloride as a tonicity agent, remained clear even 21 days after inoculation with the test bacteria, and no growth of the test bacteria (A. brasiliensis) was observed. On the other hand, Test Formulation 15, which contains mannitol as a tonicity agent, and Test Formulation 16, which contains glycerin as an isotonicity agent, both showed the presence of white floating matter in the solution 21 days after inoculation with the test bacteria, confirming the growth of the test bacteria (A. brasiliensis). This suggests that the ionic tonicity agent can impart preservative efficacy to the ophthalmic composition.

[0124] Test Example 5 A preservative effectiveness test was carried out on various ophthalmic compositions containing cepetaprost.

[0125] (1) Preparation of Test Formulations 17 to 23 Test Formulations 17 to 23 were prepared as shown in Table 6 according to the same method as for Test Formulation 1.

[0126]

[0127] (2) Test Method The preservative effectiveness test was conducted in accordance with the preservative effectiveness test methods of the 15th edition of the Japanese Pharmacopoeia, the 33rd edition of the United States Pharmacopoeia, and the 7th edition of the European Pharmacopoeia. In this test, Esherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus brasiliensis (A. brasiliensis) were used as test bacteria. The bacterial solution concentration in the test sample consisting of each test preparation was 10 ５ ~10 ６ The test sample was inoculated with the inoculum so that the total number of inoculum was 10 cfu / mL (for all five bacterial species). ７ ~10 ８ An inoculum was prepared so that the inoculum had a density of 10 cfu / mL. ５ ~10 ６ Each test sample was inoculated to a concentration of 0.01 cfu / mL and mixed uniformly to prepare a sample. These samples were stored at 20-25°C in the dark, and at each sampling point (6 hours, 24 hours, 7 days, 14 days, or 28 days), 1 mL of each sample was taken with a micropipette and the viable bacterial count was measured. At each sampling point, the lid of the sample solution was opened, sampling was performed, and the lid was then closed.

[0128] (3) Test Results and Discussion The test results are shown in Table 7. Table 7 shows the pass / fail results of the preservative effectiveness test, which was determined in accordance with the standards of the Japanese Pharmacopoeia, 15th Edition, the United States Pharmacopoeia, 33rd Edition, and the European Pharmacopoeia, 7th Edition.

[0129]

[0130] As shown in Table 7, Test Formulations 18-23 all passed the preservative effectiveness tests of the Japanese Pharmacopoeia, the United States Pharmacopoeia, and the European Pharmacopoeia, demonstrating sufficient preservative effectiveness. On the other hand, Test Formulation 17 failed the preservative effectiveness tests of the Japanese Pharmacopoeia, the United States Pharmacopoeia, and the European Pharmacopoeia. Comparing the test results of Test Formulations 17 and 19, it was found that when benzalkonium chloride was used as the preservative and a non-ionic tonicity agent was used as the isotonicity agent, sufficient preservative effectiveness was obtained, but when an ionic tonicity agent was used instead of the non-ionic tonicity agent, the preservative effectiveness was insufficient. This finding demonstrates that the inclusion of an ionic tonicity agent in the presence of benzalkonium chloride reduces preservative effectiveness, while the inclusion of a non-ionic tonicity agent maintains preservative effectiveness.

[0131] The above results suggest that the stability of sepetaprost can be improved by adjusting the pH to 5 to 8 and adding edetic acid or a salt thereof to an ophthalmic composition containing sepetaprost. Furthermore, it was suggested that adding an ionic tonicity agent to an ophthalmic composition containing sepetaprost can enhance its preservative effectiveness, while adding an ionic tonicity agent in the presence of benzalkonium chloride reduces the preservative effectiveness, and adding a nonionic tonicity agent can maintain the preservative effectiveness.

[0132] Test Example 6 An ophthalmic composition containing sepetaprost was sterilized, and the stability of sepetaprost in the composition was examined.

[0133] (1) Test Formulation A test formulation (total volume 100 mL, pH 6.5; ingredients: cepetaprost 0.002 g, sodium citrate hydrate 0.3 g, polysorbate 80 0.1 g, sodium chloride 0.75 g, sodium edetate hydrate 0.12 g, pH adjuster (sodium hydroxide or dilute hydrochloric acid) appropriate amount, water for injection appropriate amount) was prepared according to a conventional method in the technical field.

[0134] (2) Test Method The prepared test formulations were sterilized by filter filtration or filled into unit dose eye drop containers or PFMD containers (OSD bottles manufactured by Aptar) and then sterilized by gamma irradiation to obtain sterile formulations. The content of cepetaprost in the test formulations after sterilization was quantified using high performance liquid chromatography, and its percentage relative to the labeled amount was calculated.

[0135] (3) Results Table 8 shows the content of cepetaprost (% of the labeled amount) in the test preparations subjected to each sterilization treatment.

[0136]

[0137] The test results confirmed that the content of cepetaprost was reduced in the preparation subjected to gamma ray sterilization.On the other hand, it was confirmed that the reduction of the content of cepetaprost was effectively suppressed in the preparation subjected to filter sterilization.As a result, it was shown that the ophthalmic composition of the present invention can maintain higher storage stability in the preparation after sterilization by subjecting to filter sterilization.

[0138] [Formulation Examples] Representative formulation examples using the ophthalmic composition of the present invention are shown below, but the present invention is not limited to these formulation examples. In the formulation examples below, the amount of each component (% (w / v)) is the content (g) in 100 mL of the ophthalmic composition.

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146] According to the present invention, it is possible to provide an ophthalmic composition that can increase the stability of sepetaprost in the ophthalmic composition and maintain its stability even when exposed to high temperatures during distribution or storage. Furthermore, in addition to maintaining the stability of sepetaprost, the present invention also provides an ophthalmic composition that can maintain its preservative effectiveness by using an appropriate type of isotonic agent. Furthermore, in the present invention, it is possible to provide an ophthalmic composition that can maintain high storage stability of sepetaprost in the ophthalmic composition by selecting a sterilization method for the ophthalmic composition containing sepetaprost.

Claims

1. An ophthalmic composition containing sepetaprost at a concentration of 0.0001 to 0.003% (w / v) and having a pH in the range of 5 to 8.

2. The ophthalmic composition according to claim 1, further containing edetate or a salt thereof at a concentration of more than 0.01% (w / v).

3. The ophthalmic composition according to claim 2, wherein the concentration of edetate or its salt is 0.05% (w / v) or more.

4. The ophthalmic composition according to claim 2, wherein the concentration of edetate or its salt is 0.05 to 0.5% (w / v).

5. The ophthalmic composition according to claim 2, wherein the concentration of edetate or its salt is 0.05 to 0.2% (w / v).

6. The ophthalmic composition according to claim 1, wherein the pH is in the range of 6 to 7.

7. The ophthalmic composition according to claim 1, wherein the pH is 6.

5.

8. The ophthalmic composition according to claim 1, further containing an isotonic agent.

9. The ophthalmic composition according to claim 8, wherein the isotonic agent is an ionic isotonic agent.

10. The ophthalmic composition according to claim 9, which does not contain benzalkonium chloride.

11. The ophthalmic composition according to claim 9, which does not contain a preservative.

12. The ophthalmic composition according to claim 9, which does not contain a nonionic isotonic agent.

13. The ophthalmic composition according to claim 8, wherein the isotonic agent is a nonionic isotonic agent.

14. The ophthalmic composition according to claim 13, further containing benzalkonium chloride.

15. The ophthalmic composition according to claim 13, which does not contain an ionic isotonic agent.

16. An ophthalmic composition containing sepetaprost at a concentration of 0.0001 to 0.003% (w / v), a nonionic isotonic agent, and benzalkonium chloride, with a pH in the range of 5 to 8.

17. The ophthalmic composition according to claim 16, which does not contain an ionic isotonic agent.

18. An ophthalmic composition containing 0.0001 to 0.003% (w / v) of sepetaprost and an ionic isotonic agent, without benzalkonium chloride, and with a pH in the range of 5 to 8.

19. An ophthalmic composition according to claim 18, which does not contain a preservative.

20. Sepetaprost at a concentration of 0.0001–0.003% (w / v), Edetate or its salts at concentrations exceeding 0.01% (w / v) and It contains an ionic isotonic agent, It does not contain nonionic isotonic agents and benzalkonium chloride. An ophthalmic composition having a pH in the range of 5 to 8.

21. Sepetaprost at a concentration of 0.0001–0.003% (w / v), Edetate or its salts at concentrations exceeding 0.01% (w / v) and It contains a nonionic isotonic agent and benzalkonium chloride, It does not contain ionic isotonic agents. An ophthalmic composition having a pH in the range of 5 to 8.

22. The ophthalmic composition according to any one of claims 12 to 17, 20, and 21, wherein the nonionic isotonic agent is at least one selected from the group consisting of mannitol, glycerin, propylene glycol, polyethylene glycol, sorbitol, trehalose, maltose, and sucrose.

23. The ophthalmic composition according to claim 22, wherein the nonionic isotonic agent is mannitol.

24. The ophthalmic composition according to any one of claims 9 to 12, 15 and 17 to 21, wherein the ionic isotonic agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

25. The ophthalmic composition according to claim 24, wherein the ionic isotonic agent is sodium chloride.

26. The ophthalmic composition according to any one of claims 1 to 21, further containing a buffering agent.

27. The ophthalmic composition according to any one of claims 1 to 21, further containing a surfactant.

28. An ophthalmic composition according to any one of claims 1 to 21, which is a sterilized ophthalmic composition.

29. The ophthalmic composition according to claim 28, wherein the sterilization process is filter filtration sterilization.

30. Sepetaprost at a concentration of 0.0001–0.003% (w / v), Polysorbate 80 at a concentration of 0.05-0.3% (w / v), Sodium citrate hydrate at a concentration of 0.1-0.5% (w / v), Sodium edetate in a concentration of 0.05–0.5% (w / v), and Sodium chloride at a concentration of 0.5–1% (w / v) It contains, It does not contain benzalkonium chloride. An ophthalmic composition with a pH of 6 to 7.

31. Sepetaprost at a concentration of 0.0001–0.003% (w / v), Polysorbate 80 at a concentration of 0.05-0.3% (w / v), Sodium citrate hydrate at a concentration of 0.1-0.5% (w / v), Sodium edetate at a concentration of 0.05–0.5% (w / v), Mannitol in concentrations of 1-6% (w / v), and Benzalkonium chloride at concentrations of 0.001 to 0.0075% (w / v) It contains, An ophthalmic composition with a pH of 6 to 7.

32. Sepetaprost at a concentration of 0.0001–0.003% (w / v), Polysorbate 80 at a concentration of 0.05-0.3% (w / v), Sodium citrate hydrate at a concentration of 0.1-0.5% (w / v), Sodium edetate in a concentration of 0.05–0.5% (w / v), and Sodium chloride at a concentration of 0.5–1% (w / v) It contains, It does not contain benzalkonium chloride. An ophthalmic composition with a pH of 6.

5.

33. Sepetaprost at a concentration of 0.0001–0.003% (w / v), Polysorbate 80 at a concentration of 0.05-0.3% (w / v), Sodium citrate hydrate at a concentration of 0.1-0.5% (w / v), Sodium edetate at a concentration of 0.05–0.5% (w / v), Mannitol in concentrations of 1-6% (w / v), and Benzalkonium chloride at concentrations of 0.001 to 0.0075% (w / v) It contains, An ophthalmic composition with a pH of 6.

5.

34. An ophthalmic composition according to any one of claims 1 to 21 and 30 to 33, wherein the concentration of sepetaprost is 0.001 to 0.003% (w / v).

35. An ophthalmic composition according to any one of claims 1 to 21 and 30 to 33, wherein the concentration of sepetaprost is 0.002 to 0.003% (w / v).

36. An ophthalmic composition according to any one of claims 1 to 21 and 30 to 33, wherein the concentration of sepetaprost is 0.002% (w / v).

37. An ophthalmic composition containing sepetaprost at a concentration of 0.002-0.003% (w / v) and having a pH in the range of 6-7.

38. An ophthalmic composition containing 0.002% (w / v) sepetaprost and having a pH in the range of 6 to 7.

39. The ophthalmic composition according to any one of claims 1 to 21, 30 to 33, 37 and 38, wherein the ophthalmic composition is an eye drop.

40. An ophthalmic composition according to any one of claims 1 to 21, 30 to 33, 37 and 38, contained in a unit dose eye drop container.

41. An ophthalmic composition according to any one of claims 1 to 21, 30 to 33, 37 and 38, contained in a multi-dose eye drop container.

42. An ophthalmic composition according to any one of claims 1 to 21, 30 to 33, 37 and 38, contained in a plastic eye drop container.

43. An ophthalmic composition according to any one of claims 1 to 21, 30 to 33, 37 and 38, for preventing or treating glaucoma or ocular hypertension.

44. A method for stabilizing sepetaprost in an ophthalmic composition, characterized by adjusting the pH to a range of 5 to 8 in an ophthalmic composition containing sepetaprost at a concentration of 0.0001 to 0.003% (w / v).

45. The method according to claim 44, wherein the pH of an ophthalmic composition containing sepetaprost at a concentration of 0.002 to 0.003% (w / v) is adjusted to a range of 6 to 7.

46. The method according to claim 44 or 45, wherein an ophthalmic composition containing sepetaprost at a concentration of 0.002% (w / v) is adjusted to a pH in the range of 6 to 7.