Heterocyclidene-acetamide-derivative-containing composition subjected to electron beam sterilization treatment

Abstract

The present disclosure provides an aqueous liquid agent having exceptional stability. The present disclosure provides an aqueous liquid agent containing electron-beam-treated (E)-2-(7-trifluoromethylchroman-4-yldene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmacologically acceptable salt or solvate thereof. In particular, the present disclosure relates to technology for improving the stability of a suspension that contains a heterocyclidene acetamide derivative, and formulation technology based thereupon.

Description

Composition containing heterocyclideneacetamide derivatives sterilized by electron beam

[0001] The present disclosure relates to the fields of medicine, healthcare, biology, biotechnology, etc. In particular, the present disclosure relates to improving the stability of aqueous liquid preparations containing heterocyclideneacetamide derivatives, and to formulation techniques based thereon.

[0002] The number of dry eye patients in Japan is estimated to be at least 8 million, and the number is estimated to be approximately 22 million, including potential patients who use over-the-counter eye drops without visiting a doctor. It is estimated that there are over 1 billion dry eye patients worldwide. In modern society, the use of television, computers, mobile devices, and other devices increases the frequency of staring at screens, reducing the number of blinks. Furthermore, the use of air conditioners and other devices dries the air, resulting in increased tear evaporation and leading to dry eye. Furthermore, refractive surgery and the use of contact lenses can result in dry eye. Symptoms associated with dry eye include ocular discomfort, dryness, burning, and irritation of the ocular surface.

[0003] When dry eye occurs, the above symptoms appear as subjective symptoms, and treatment requires regular eye drops over a long period of time. Therefore, many of the currently commercially available dry eye treatments are of the frequent administration type. For example, Diquas (registered trademark) eye drops usually need to be instilled six times a day, Hyalein (registered trademark) eye drops usually need to be instilled five to six times a day, and Mucosta (registered trademark) eye drops usually need to be instilled four times a day.

[0004] A composition containing (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, or use thereof for treating dry eye has been disclosed (Patent Document 1).

[0005] An aqueous suspension containing (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, a cellulose-based polymer, and a nonionic surfactant has been disclosed (Patent Document 2).

[0006] Patent Document 1: International Publication No. 2021 / 066144 Pamphlet Patent Document 2: International Publication No. 2022 / 210784 Pamphlet

[0007] (Item 1) An aqueous solution comprising electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. (Item 2) The aqueous solution according to the above items, wherein the electron beam treatment is a treatment within a sterilization process. (Item 3) The aqueous solution according to any one of the above items, further comprising a non-ionic surfactant. (Item 4) An aqueous solution comprising electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a non-ionic surfactant. (Item 5) The aqueous liquid formulation according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 10 kGy to about 60 kGy. (Item 6) The aqueous liquid formulation according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 15 kGy to about 45 kGy. (Item 7) The aqueous liquid formulation according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 20 kGy to about 30 kGy. (Item 8) The aqueous liquid formulation according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 10 kGy or more. (Item 9) The aqueous liquid formulation according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 15 kGy or more. (Item 10) The aqueous liquid formulation according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 20 kGy or more. (Item 11) The aqueous liquid preparation according to any one of the above items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 60 kGy or less. (Item 12) The aqueous liquid preparation according to any one of the above items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 50 kGy or less. (Item 13) The aqueous liquid preparation according to any one of the above items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 40 kGy or less. (Item 14) The aqueous liquid preparation according to any one of the above items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 30 kGy or less.(Item 15) The aqueous liquid formulation according to any one of the preceding items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 25 kGy. (Item 16) The aqueous liquid formulation according to any one of the preceding items, wherein the electron beam treatment comprises treatment with an electron beam intensity of about 100 keV to about 5 MeV. (Item 17) The aqueous liquid formulation according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous liquid formulation is about 0.0001 w / v% to about 1 w / v%. (Item 18) The aqueous liquid formulation according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous liquid formulation is about 0.001 w / v% to about 0.5 w / v%. (Item 19) The aqueous liquid formulation according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous liquid formulation is about 0.01 w / v% to about 0.05 w / v%. (Item 20) The aqueous liquid preparation according to any one of the preceding items, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil. (Item 21) The aqueous liquid preparation according to any one of the preceding items, wherein the nonionic surfactant is tyloxapol. (Item 22) An aqueous liquid preparation comprising electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and tyloxapol. (Item 23) The aqueous solution according to any one of the preceding items, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous solution is about 0.001 w / v % to about 5 w / v %. (Item 24) The aqueous solution according to any one of the preceding items, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous solution is about 0.3 w / v % to about 1 w / v %.(Item 25) An aqueous liquid preparation comprising electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a non-ionic surfactant, wherein the electron beam treatment is performed at an irradiation dose of about 10 kGy to about 60 kGy, the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous liquid preparation is about 0.001 w / v % to about 5 w / v %, and the concentration of the non-ionic surfactant in the aqueous liquid preparation is about 0.01 w / v % to about 0.05 w / v %. (Item 26) The aqueous liquid preparation according to any one of the preceding items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide. (Item 27) The aqueous liquid preparation according to any one of the preceding items, wherein the concentration of dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof in the aqueous liquid preparation is about 0.01 w / v % or less. (Item 28) The aqueous liquid preparation according to any one of the preceding items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof in a dissolved state in the aqueous liquid preparation is greater than 0 w / v % and not more than about 0.01 w / v %.(Item 29) The aqueous liquid preparation according to any one of the preceding items, wherein the stability of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous liquid preparation is improved. (Item 30) The aqueous liquid preparation according to any one of the preceding items, wherein the improved stability is such that the remaining rate of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, when stored at about 60°C for 2 weeks is about 90% or more. (Item 31) The aqueous liquid preparation according to any one of the preceding items, wherein the remaining rate is about 95% or more. (Item 32) The aqueous liquid preparation according to any one of the preceding items, wherein the stability of the dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous liquid preparation is improved. (Item 33) The aqueous liquid preparation according to any one of the preceding items, wherein the improved stability is such that the remaining rate of the dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous liquid preparation is about 90% or more when the aqueous liquid preparation is stored at about 60°C for 2 weeks. (Item 34) The aqueous liquid preparation according to any one of the preceding items, wherein the remaining rate of the dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, is about 95% or more. (Item 35) The aqueous liquid preparation according to any one of the preceding items, wherein the pH of the aqueous liquid preparation is about 4 to about 8. (Item 36) The aqueous liquid preparation according to any one of the preceding items, wherein the aqueous liquid preparation is contained in a plastic container.(Item 37) The aqueous solution according to any one of the above items, wherein the plastic container is made of polyethylene or polypropylene. (Item 38) The aqueous solution according to any one of the above items, wherein the aqueous solution is an ophthalmic solution. (Item 39) The aqueous solution according to any one of the above items, wherein the aqueous solution is an aqueous suspension. (Item 40) The aqueous solution according to any one of the above items, wherein the aqueous solution is a suspension ophthalmic solution. (Item 41) A method for producing an aqueous liquid formulation, wherein the aqueous liquid formulation contains (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of: treating the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with an electron beam; and mixing the electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with a solvent. (Item 42) A method for stabilizing an aqueous liquid formulation, wherein the aqueous liquid formulation contains (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, the method comprising the steps of: treating the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with an electron beam; and mixing the electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with a solvent.(Item 43) A method for producing stabilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, comprising treating (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with electron beam irradiation. (Item 44) A method for stabilizing (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in an aqueous liquid preparation, comprising the steps of: treating (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with an electron beam; and mixing the electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with a solvent. (Item 45) A method for electron beam sterilization of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. (Item 46) The method according to any one of the preceding items, further comprising the step of adding a nonionic surfactant. (Item 47) The method according to any one of the preceding items, wherein the solvent comprises a nonionic surfactant. (Item 48) The method according to any one of the preceding items, wherein the solvent has been sterile filtered. (Item 49) The method according to any one of the preceding items, wherein the electron beam treatment comprises an electron beam irradiation dose of about 10 kGy to about 60 kGy. (Item 50) The method according to any one of the preceding items, wherein the electron beam treatment comprises an electron beam irradiation dose of about 15 kGy to about 45 kGy.(Item 51) The method according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 20 kGy to about 30 kGy. (Item 52) The method according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 25 kGy. (Item 52-1) The method according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 10 kGy or more. (Item 52-2) The method according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 15 kGy or more. (Item 52-3) The method according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 20 kGy or more. (Item 52-4) The method according to any one of the above items, wherein the electron beam treatment involves a treatment with an electron beam irradiation dose of about 60 kGy or less. (Item 52-5) The method according to any one of the preceding items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 50 kGy or less. (Item 52-6) The method according to any one of the preceding items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 40 kGy or less. (Item 52-7) The method according to any one of the preceding items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 30 kGy or less. (Item 52-8) The method according to any one of the preceding items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 25 kGy. (Item 52-9) The method according to any one of the preceding items, wherein the electron beam treatment comprises treatment with an electron beam intensity of about 100 keV to about 5 MeV. (Item 53) The method according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous liquid formulation is about 0.0001 w / v % to about 1 w / v %. (Item 54) The method according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous liquid preparation is about 0.001 w / v % to about 0.5 w / v %. (Item 55) The method according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous liquid preparation is about 0.01 w / v % to about 0.05 w / v %.(Item 56) The method according to any one of the preceding items, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil. (Item 57) The method according to any one of the preceding items, wherein the nonionic surfactant is tyloxapol. (Item 58) The method according to any one of the preceding items, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof in the aqueous solution is from about 0.001 w / v % to about 5 w / v %. (Item 59) The method according to any one of the preceding items, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous solution is about 0.3 w / v % to about 1 w / v %. (Item 60) The method according to any one of the preceding items, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in a dissolved state in the aqueous solution is about 0.01 w / v % or less. 61. The method according to any one of the preceding items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof in a dissolved state in the aqueous liquid formulation is greater than 0 w / v % and not more than about 0.01 w / v %. 62. The method according to any one of the preceding items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.(Item 63) The method according to any one of the preceding items, wherein the aqueous liquid preparation is an eye drop. (Item 64) The method according to any one of the preceding items, wherein the aqueous liquid preparation is an aqueous suspension. (Item 65) The method according to any one of the preceding items, wherein the aqueous liquid preparation is a suspension eye drop. (Item 66) Electron beam treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. (Item 67) Electron beam treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. (Item 68) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 10 kGy to about 60 kGy. (Item 69) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 15 kGy to about 45 kGy. (Item 70) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 20 kGy to about 30 kGy. (Item 71) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 10 kGy or more. (Item 72) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 15 kGy or more. (Item 73) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 20 kGy or more. (Item 74) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 60 kGy or less.(Item 75) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 50 kGy or less. (Item 76) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 40 kGy or less. (Item 77) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 30 kGy or less. (Item 78) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 25 kGy. (Item 79) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the electron beam treatment comprises treatment at an electron beam intensity of about 100 keV to about 5 MeV. (Item 80) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, for use in stabilizing an aqueous liquid formulation. (Item 81) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the aqueous liquid formulation further comprises a non-ionic surfactant. (Item 82) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the concentration of the non-ionic surfactant in the aqueous liquid formulation is about 0.0001 w / v % to about 1 w / v %. (Item 83) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the concentration of the nonionic surfactant in the aqueous solution is about 0.001 w / v % to about 0.5 w / v %. (Item 84) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the concentration of the nonionic surfactant in the aqueous solution is about 0.01 w / v % to about 0.05 w / v %.(Item 85) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil. (Item 86) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the nonionic surfactant is tyloxapol. (Item 87) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof in the aqueous solution is about 0.001 w / v % to about 5 w / v %. (Item 88) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous solution is about 0.3 w / v % to about 1 w / v %. (Item 89) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in a dissolved state in the aqueous solution is about 0.01 w / v % or less. (Item 90) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the concentration of the dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous liquid preparation is greater than 0 w / v % and not more than about 0.01 w / v %.(Item 91) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the stability of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof in the aqueous liquid preparation is improved. (Item 92) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the improved stability is such that the remaining rate of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, is about 90% or more when the aqueous liquid preparation is stored at about 60°C for 2 weeks. (Item 93) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the residual rate is about 95% or more. (Item 94) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the stability of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof in a dissolved state in the aqueous liquid preparation is improved. (Item 95) The improved stability of the compound or pharmaceutically acceptable salt or solvate thereof according to any one of the preceding items is such that the remaining percentage of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or pharmaceutically acceptable salt or solvate thereof in a dissolved state is about 90% or more when an aqueous solution formulation is stored at about 60° C. for 2 weeks. (Item 96) The compound or pharmaceutically acceptable salt or solvate thereof according to any one of the preceding items is such that the remaining percentage of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or pharmaceutically acceptable salt or solvate thereof in a dissolved state is about 95% or more.(Item 97) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the aqueous solution has a pH of about 4 to about 8. (Item 98) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the aqueous solution is housed in a plastic container. (Item 99) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the plastic container is made of polyethylene or polypropylene. (Item 100) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the aqueous solution is an ophthalmic solution. (Item 101) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the aqueous solution is an aqueous suspension. (Item 102) The compound according to any one of the preceding items, or a pharmaceutically acceptable salt or solvate thereof, wherein the aqueous solution is an ophthalmic suspension. (Item 103) Use of electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicine. (Item 104) Use of electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicine. (Item 105) The use according to any one of the preceding items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 10 kGy to about 60 kGy. (Item 106) The use according to any one of the above items, wherein the electron beam treatment comprises a treatment with an electron beam irradiation dose of about 15 kGy to about 45 kGy. (Item 107) The use according to any one of the above items, wherein the electron beam treatment comprises a treatment with an electron beam irradiation dose of about 20 kGy to about 30 kGy. (Item 108) The use according to any one of the above items, wherein the electron beam treatment comprises a treatment with an electron beam irradiation dose of about 10 kGy or more.(Item 109) The use according to any one of the above items, wherein the electron beam treatment comprises a treatment with an electron beam irradiation dose of about 15 kGy or more. (Item 110) The use according to any one of the above items, wherein the electron beam treatment comprises a treatment with an electron beam irradiation dose of about 20 kGy or more. (Item 111) The use according to any one of the above items, wherein the electron beam treatment comprises a treatment with an electron beam irradiation dose of about 60 kGy or less. (Item 112) The use according to any one of the above items, wherein the electron beam treatment comprises a treatment with an electron beam irradiation dose of about 50 kGy or less. (Item 113) The use according to any one of the above items, wherein the electron beam treatment comprises a treatment with an electron beam irradiation dose of about 40 kGy or less. (Item 114) The use according to any one of the above items, wherein the electron beam treatment comprises a treatment with an electron beam irradiation dose of about 30 kGy or less. (Item 115) The use according to any one of the above items, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 25 kGy. (Item 116) The use according to any one of the above items, wherein the electron beam treatment comprises treatment with an electron beam intensity of about 100 keV to about 5 MeV. (Item 117) The use according to any one of the above items, wherein the use is used to stabilize an aqueous liquid formulation. (Item 118) The use according to any one of the above items, wherein the aqueous liquid formulation further comprises a nonionic surfactant. (Item 119) The use according to any one of the above items, wherein the concentration of the nonionic surfactant in the aqueous liquid formulation is about 0.0001 w / v% to about 1 w / v%. (Item 120) The use according to any one of the above items, wherein the concentration of the nonionic surfactant in the aqueous liquid formulation is about 0.001 w / v% to about 0.5 w / v%. (Item 121) The use according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous liquid is about 0.01 w / v % to about 0.05 w / v %. (Item 122) The use according to any one of the preceding items, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil.(Item 123) The use according to any one of the preceding items, wherein the nonionic surfactant is tyloxapol. (Item 124) The use according to any one of the preceding items, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous solution is about 0.001 w / v % to about 5 w / v %. (Item 125) The use according to any one of the preceding items, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous solution is about 0.3 w / v % to about 1 w / v %. (Item 126) The use according to any one of the preceding items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in a dissolved state in the aqueous liquid formulation is about 0.01 w / v % or less. (Item 127) The use according to any one of the preceding items, wherein the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in a dissolved state in the aqueous liquid formulation is greater than 0 w / v % and about 0.01 w / v % or less. (Item 128) The use according to any one of the preceding items, wherein the stability of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous liquid formulation is improved.(Item 129) The use according to any one of the preceding items, wherein the improved stability is such that the remaining rate of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, is about 90% or more when the aqueous liquid preparation is stored at about 60° C. for 2 weeks. (Item 130) The use according to any one of the preceding items, wherein the remaining rate is about 95% or more. (Item 131) The use according to any one of the preceding items, wherein the stability of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in a dissolved state in the aqueous liquid preparation is improved. (Item 132) The use according to any one of the preceding items, wherein the improved stability is such that the remaining percentage of the dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, is about 90% or more when the aqueous liquid formulation is stored at about 60° C. for two weeks. (Item 133) The use according to any one of the preceding items, wherein the remaining percentage of the dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, is about 95% or more. (Item 134) The use according to any one of the preceding items, wherein the aqueous liquid formulation has a pH of about 4 to about 8. (Item 135) The use according to any one of the above items, wherein the aqueous solution is contained in a plastic container. (Item 136) The use according to any one of the above items, wherein the plastic container is made of polyethylene or polypropylene. (Item 137) The use according to any one of the above items, wherein the aqueous solution is an ophthalmic solution. (Item 138) The use according to any one of the above items, wherein the aqueous solution is an aqueous suspension.(Item 139) The use according to any one of the preceding items, wherein the aqueous liquid preparation is a suspension eye drop.

[0008] In the present disclosure, it is intended that one or more of the above-described features may be provided in combination in addition to the combinations explicitly stated. Further embodiments and advantages of the present disclosure will be recognized by those skilled in the art upon reading and understanding the following detailed description as necessary. Features and significant actions and effects of the present disclosure other than those described above will become clear to those skilled in the art upon reference to the following description of the preferred embodiments of the present invention and the drawings.

[0009] According to the present disclosure, an aqueous liquid preparation having excellent stability can be provided.

[0010] The present disclosure will be described below. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the relevant field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present specification (including definitions) will prevail.

[0011] (Definitions) In this specification, unless otherwise specified, the term "about" means ±10% of the following numerical value.

[0012] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same applies to "or" and "alternative." In this specification, when it is specified that "within" "a range of two values," the range includes the two values ​​themselves.

[0013] In this specification, the term "aqueous liquid preparation" is used in the same sense as the term is commonly used in this field, and refers to any liquid preparation containing at least a portion of water. Aqueous liquid preparations include solutions in which the components to be mixed are dissolved, those in which the components to be mixed are suspended, and those in which the components to be mixed are partially dissolved and partially suspended.

[0014] As used herein, the term "aqueous suspension" is used in the same sense as the term is commonly used in this field, and refers to a liquid agent containing at least a portion of water, in which the ingredients to be mixed are suspended and solid particles are present in the liquid. Since (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof has extremely low solubility in water, in the aqueous suspension of the present disclosure, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is in the form of suspended particles, although some of the particles remain dissolved.

[0015] As used herein, "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic or organic acid addition salts, or inorganic or organic base addition salts of compounds of the present disclosure.

[0016] As used herein, the term "stability" refers to the degree to which the content of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof dissolved and / or suspended in an aqueous liquid formulation is maintained without being altered by decomposition or the like, when the formulation is stored for a certain period of time under certain conditions. In addition, as used herein, "stability" refers to the content retention rate, which is the ratio of the content of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof in an aqueous liquid preparation stored under certain conditions for a certain period of time after preparation to the content of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof in the aqueous liquid preparation immediately after preparation. Alternatively, the content retention rate of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof in a dissolved state in the aqueous liquid preparation can also be used as an index. Storage for a certain period under certain conditions means, for example, storing an aqueous liquid formulation at about 60°C for two weeks.

[0017] As used herein, "improved stability" means that the stability is improved when the retention rate of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, is high in comparison with any formulation.

[0018] As used herein, the term "solvate" refers to a compound of the present disclosure or a pharmaceutically acceptable salt thereof interacting with any solvent to form a group, including, for example, solvates with organic solvents (e.g., solvates with alcohols (ethanol, etc.)), hydrates, etc. When a hydrate is formed, it may be coordinated with any number of water molecules. Examples of hydrates include monohydrates, dihydrates, etc.

[0019] In this specification, the term "nonionic surfactant" is also referred to as a nonionic surfactant, and refers to a surfactant in which the hydrophilic group portion is nonionic. Whether a surfactant is nonionic or not can be easily determined by a person skilled in the art, and can be determined by confirming that a surfactant does not ionize (does not exhibit ionicity) when dissolved in water. Examples of nonionic surfactants include tyloxapol, polyoxyl stearates (polyethylene glycol monostearate, polyethylene glycol 40 monostearate (MYS-40), polyethylene glycol 400 monostearate, etc.), polyoxyethylene sorbitan fatty acid esters (polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, etc.), and polyoxyethylene hydrogenated castor oils (polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 (HCO-60), etc.).

[0020] As used herein, "electron beam treatment" refers to the application of electron beams to a solid or liquid object, essentially irradiating the object with electron beams. When electron beam treatment is carried out as a sterilization process, it may be referred to as "electron beam sterilization treatment." Alternatively, when it is a treatment within a sterilization process, it may be referred to as electron beam treatment within a sterilization process. In this case, sterilization is achieved by the electron beam treatment, and it is understood that the electron beam treatment is carried out under such conditions. The intensity of the electron beam in the electron beam treatment may refer to the absorbed dose (Gy) for the object, or may be the intensity set in the device used to apply the electron beam or the intensity displayed on a display. The duration of the intensity treatment may refer to the time required for a target object to be irradiated with an electron beam to reach a predetermined intensity (e.g., about 10 kGy to about 60 kGy, about 15 kGy to about 45 kGy, about 20 kGy to about 30 kGy, about 35 kGy to about 45 kGy, about 30 kGy to about 40 kGy, or about 25 kGy, etc.), or may refer to the time set in an apparatus used for irradiating the electron beam or the time displayed on a display. In the present disclosure, the electron beam treatment may be performed at an electron beam intensity of about 100 keV to about 5 MeV. The electron beam treatment may be performed on a solid form of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. More specifically, electron beam treatment can be performed on a powder of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. The term "powder" refers to a granular material (composed of solid particles having a given particle size distribution, with interactions such as electrostatic forces and van der Waals forces acting between the individual particles).

[0021] As used herein, "sterilization" or "sterilization treatment" refers to the substantial removal, sterilization, or inactivation of viruses, microorganisms, etc. present in a solid or liquid object. Examples of sterilization include electron beam sterilization, gamma ray sterilization, dry heat sterilization, and autoclave sterilization. Therefore, "electron beam sterilization treatment" as used in this disclosure refers to the sterilization of a substance or molecule by irradiating the object with an electron beam. In this disclosure, sterilization or sterilization treatment refers to treatment of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, itself. The electron beam sterilization treatment can be performed on a solid form of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. More specifically, the electron beam sterilization treatment can be performed on a powder form of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

[0022] In this specification, the term "solvent" is used to encompass water, organic solvents, and mixtures of water and organic solvents, and may be sterilized by filtration or other sterilization treatments, and these sterilized solvents are also encompassed by the term "solvent" in this specification. In addition to water, organic solvents, or mixtures of water and organic solvents, solvents may contain any additives dissolved therein, such as thickeners, stabilizers, pH adjusters, buffers, and preservatives (antiseptics), and these additive-containing solvents are also encompassed by the term "solvent" in this specification.

[0023] (Preferred Embodiments) Preferred embodiments of the present disclosure will be described below. The embodiments provided below are provided for a better understanding of the present disclosure, and the scope of the present disclosure should not be limited to the following description. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description herein. In addition, the following embodiments of the present disclosure can be used alone or in combination.

[0024] Electron Beam Treated (E)-2-(7-Trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide In one aspect of the present disclosure, an aqueous liquid formulation comprising electron beam treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, may be provided.

[0025] In another aspect of the present disclosure, there may be provided an aqueous liquid formulation comprising electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a non-ionic surfactant.

[0026] In one aspect of the present disclosure, there can be provided an aqueous suspension comprising electron beam treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

[0027] In another aspect of the present disclosure, there may be provided an aqueous suspension comprising electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a non-ionic surfactant.

[0028] In another aspect, the present disclosure provides e-beam treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

[0029] In one aspect of the present disclosure, there may be provided a method for producing an aqueous liquid formulation, wherein the aqueous liquid formulation comprises (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and the method comprises the steps of treating the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with an electron beam; and mixing the electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with a solvent.

[0030] In one aspect of the present disclosure, there can be provided a method for producing an aqueous suspension, the aqueous suspension containing (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, comprising the steps of: treating the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with an electron beam; and mixing the electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with a solvent.

[0031] In another aspect, the present disclosure provides a method for stabilizing an aqueous liquid formulation, wherein the aqueous liquid formulation comprises (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, the method comprising the steps of: treating the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with an electron beam; and mixing the electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with a solvent.

[0032] In another aspect, the present disclosure provides a method for stabilizing an aqueous suspension, wherein the aqueous suspension comprises (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, the method comprising the steps of: treating the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with an electron beam; and mixing the electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with a solvent.

[0033] In one embodiment, the aqueous liquid formulation of the present disclosure may be an aqueous suspension, an emulsion, an eye drop solution, etc. Preferably, it is an aqueous suspension or an eye drop solution, and more preferably, it is an aqueous suspension.

[0034] In one embodiment, the aqueous solution of the present disclosure may further comprise a non-ionic surfactant.

[0035] In another embodiment, the solvent of the present disclosure comprises a non-ionic surfactant.

[0036] In another embodiment, the solvents used in the aqueous solutions of the present disclosure are sterile filtered or otherwise sterilized.

[0037] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide includes the R-form (CAS No. 920332-28-1), the S-form (CAS No. 920332-29-2), or the racemic form (CAS No. 920332-27-0), and more preferably the R-form ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (also referred to as compound (1) in the present disclosure)).

[0038] The pharmaceutically acceptable salt of the compound of the present disclosure is not particularly limited as long as it is a pharmaceutically acceptable salt, and specific examples thereof include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, and mandelic acid; aromatic monocarboxylic acids such as benzoic acid and salicylic acid; aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, and tartaric acid; and citric acid. and organic sulfonic acids such as aliphatic sulfonic acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, etc., and aromatic sulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid, etc.; inorganic base addition salts with metals such as alkali metals or alkaline earth metals, such as sodium, potassium, magnesium, calcium, etc.; and organic base addition salts with methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine, ornithine, etc.

[0039] These salts can be obtained by a conventional method, for example, by mixing a solution containing an equivalent amount of a compound of the present disclosure and the desired acid or base, and collecting the desired salt by filtration or by distilling off the solvent. In addition, the compound of the present disclosure or a salt thereof can form a solvate with a solvent such as water or ethanol.

[0040] (E)-2-(7-Trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide has excellent Transient Receptor Potential Vanilloid 1 (hereinafter referred to as "TRPV1." TRPV1 is also called "Transient Receptor Potential Vanilloid 1" or "Vanilloid Receptor 1 (VR1)") antagonistic activity.

[0041] The R-isomer (compound (1)), S-isomer, or racemic form of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide is described in International Publication No. WO 2007 / 010383, Japanese Patent No. 4754566, Japanese Patent No. 6230743, International Publication No. WO 2018 / 221543, Japanese Patent No. 6830569, International Publication No. WO 2021 / 038889, and International Publication No. WO 2021 / 039023. The R-isomer (compound (1)), S-isomer, or racemic form can be produced by the production methods described in these publications. The contents of these publications are incorporated herein by reference in their entirety.

[0042] TRPV1 was cloned from the dorsal root ganglion (DRG) as a capsaicin-responsive cation channel. It is also sensitive to heat above 43°C and protons, and is a TRP channel that has been studied as a key molecule in nociception (Biochemistry, Vol. 85, No. 7: 561-565). TRPV1 activity is known to increase during inflammation and tissue injury, inducing hyperalgesia. Therefore, TRPV1 has attracted attention as a potential drug target for pain treatment.

[0043] TRPV1 antagonists have been reported to be effective against various pain models, such as inflammatory pain, neuropathic pain, and osteoarthritis pain (Biochemistry, Vol. 85, No. 7: 561-565).

[0044] In one embodiment of the present disclosure, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, is subjected to electron beam treatment, and the electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof is mixed with a solvent to form an aqueous liquid formulation (e.g., an aqueous suspension), thereby improving the stability of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof in the aqueous liquid formulation.

[0045] In one embodiment of the present disclosure, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, can be present in the aqueous liquid preparation (e.g., aqueous suspension) of the present disclosure at a concentration of generally about 0.001 w / v % to about 5 w / v %, preferably about 0.1 w / v % to about 3 w / v %, more preferably about 0.2 w / v % to about 2 w / v %, particularly preferably about 0.2 w / v % to about 1.5 w / v %, and even more preferably about 0.3 w / v % to about 1.0 w / v %.

[0046] In one embodiment of the present disclosure, when (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof is used, it can be present in the composition of the present disclosure (e.g., aqueous suspension) at a concentration of generally about 0.001 w / v % to about 5 w / v %, preferably about 0.1 w / v % to about 3 w / v %, more preferably about 0.2 w / v % to about 2 w / v %, particularly preferably about 0.2 w / v % to about 1.5 w / v %, and even more preferably about 0.3 w / v % to about 1.0 w / v %.

[0047] In one embodiment of the present disclosure, the electron beam treatment of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, can be carried out as a treatment within a sterilization process of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and the electron beam intensity of the electron beam treatment is not limited as long as a sterilization effect can be confirmed, and is typically about 100 keV to about 5 MeV. For example, the upper limit may be about 5 MeV, about 4 MeV, about 3 MeV, about 2 MeV, about 1 MeV, etc., and the lower limit may be about 100 keV, about 110 keV, about 120 keV, about 130 keV, about 140 keV, about 150 keV, about 200 keV, about 300 keV, about 400 keV, about 500 keV, etc.

[0048] In one embodiment of the present disclosure, the time for electron beam treatment of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, is not limited as long as a sterilization effect can be confirmed, and the treatment is typically performed for about 10 minutes to about 24 hours, more preferably about 30 minutes to about 12 hours, particularly preferably about 30 minutes to about 8 hours, and even more preferably about 30 minutes to about 5 hours. The irradiation time is appropriately selected depending on the intensity of the selected electron beam.

[0049] In one embodiment of the present disclosure, electron beam sterilization of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, can be performed as a treatment within the sterilization process of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof. The electron beam irradiation dose in the electron beam sterilization treatment may be any dose as long as a sterilization effect is confirmed, but typically may be about 10 kGy to about 60 kGy. From the viewpoint of achieving sterilization, the electron beam irradiation dose is preferably about 15 kGy or more, and more preferably about 20 kGy or more. From the viewpoint of stability, it is preferably about 50 kGy or less, and more preferably about 40 kGy or less. From the viewpoint of sterility and stability, treatment at about 25 kGy is particularly preferred.

[0050] In one embodiment of the present disclosure, the nonionic surfactant is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include tyloxapol, polyoxyl stearates (polyethylene glycol monostearate, polyethylene glycol 40 monostearate (MYS-40), polyethylene glycol 400 monostearate, etc.), polyoxyethylene sorbitan fatty acid esters (polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, etc.), and polyoxyethylene hydrogenated castor oils (polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 (HCO-60), etc.). These nonionic surfactants may be used alone or in combination of two or more. When the aqueous liquid preparation is an aqueous suspension, the nonionic surfactant is preferably tyloxapol, polysorbate, polyethylene glycol monostearate, or polyoxyethylene hydrogenated castor oil, more preferably tyloxapol, polysorbate, or polyethylene glycol monostearate, and even more preferably tyloxapol, from the viewpoint of redispersibility or stability of the aqueous suspension.

[0051] In one embodiment of the present disclosure, the nonionic surfactant can be present in the aqueous liquid formulation of the present disclosure at a concentration of about 0.0001 w / v % to about 1 w / v %, preferably about 0.0005 w / v % to about 0.5 w / v %, more preferably about 0.001 w / v % to about 0.5 w / v %, particularly preferably about 0.005 w / v % to about 0.1 w / v %, and even more preferably about 0.01 w / v % to about 0.05 w / v %.

[0052] In one embodiment, the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in a dissolved state in the aqueous liquid formulation of the present disclosure is generally about 0.01 w / v % or less, and preferably, for example, less than about 0.01 w / v %, less than about 0.009 w / v %, less than about 0.009 w / v %, or less than about 0.008 w / v% or less, less than about 0.008 w / v%, about 0.007 w / v% or less, less than about 0.007 w / v%, about 0.006 w / v% or less, less than about 0.006 w / v%, about 0.005 w / v% or less, less than about 0.005 w / v%, about 0.004 w / v% or less, less than about 0.004 w / v%, about 0.003 w / v% or less, less than about 0.003 w / v%, about 0.002 w / v% or less, less than about 0.002 w / v%, about 0.001 w / v% or less , less than about 0.001 w / v%, about 0.0009 w / v% or less, less than about 0.0009 w / v%, about 0.0008 w / v% or less, less than about 0.0008 w / v%, about 0.0007 w / v% or less, less than about 0.0007 w / v%, about 0.0006 w / v% or less, less than about 0.0006 w / v%, about 0.0005 w / v% or less, less than about 0.0005 w / v%, about 0.0001 w / v% or less, less than about 0.0001 w / v%, about 0.00009 w / v %, less than about 0.00009 w / v%, less than about 0.00008 w / v%, less than about 0.00008 w / v%, less than about 0.00007 w / v%, less than about 0.00007 w / v%, less than about 0.00006 w / v%, less than about 0.00006 w / v%, less than about 0.00005 w / v%, less than about 0.00005 w / v%, less than about 0.00001 w / v%, less than about 0.00001 w / v%, or may be greater than 0 w / v%.

[0053] For example, in the case of an aqueous liquid preparation containing 0.3 w / v % (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide usually dissolves at about 0.01 w / v % or less, and the remaining (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide exists as suspended particles.The concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof in a dissolved state in the aqueous liquid preparation of the present disclosure is greater than 0 w / v % and usually about 0.01 w / v % or less, preferably, for example, less than about 0.01 w / v %, about 0.009 w / v % or less, about 0.009 less than about 0.008 w / v% or less, less than about 0.008 w / v%, less than about 0.007 w / v% or less, less than about 0.007 w / v%, less than about 0.006 w / v% or less, less than about 0.006 w / v%, less than about 0.005 w / v% or less, less than about 0.005 w / v%, less than about 0.004 w / v% or less, less than about 0.004 w / v%, less than about 0.003 w / v% or less, less than about 0.003 w / v%, less than about 0.002 w / v% or less, less than about 0.002 w / v%, About 0.001 w / v% or less, less than about 0.001 w / v%, about 0.0009 w / v% or less, less than about 0.0009 w / v%, about 0.0008 w / v% or less, less than about 0.0008 w / v%, about 0.0007 w / v% or less, less than about 0.0007 w / v%, about 0.0006 w / v% or less, less than about 0.0006 w / v%, about 0.0005 w / v% or less, less than about 0.0005 w / v%, about 0.0001 w / v% or less, about 0.0001 w / v% less than about 0.00009 w / v%, less than about 0.00009 w / v%, less than about 0.00008 w / v%, less than about 0.00008 w / v%, less than about 0.00007 w / v%, less than about 0.00007 w / v%, less than about 0.00006 w / v%, less than about 0.00006 w / v%, less than about 0.00005 w / v%, less than about 0.00005 w / v%, less than about 0.00001 w / v%, less than about 0.00001 w / v%.

[0054] In one embodiment, the stability of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in an aqueous liquid formulation of the present disclosure is improved. In another embodiment, the stability of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in a dissolved state in an aqueous liquid formulation of the present disclosure is improved.

[0055] As used herein, the term "improved stability of the compound ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof) to which the term "dissolved" is added means that the compound is stable in a dissolved state in an aqueous liquid preparation. On the other hand, as used herein, when the term "dissolved state" is not added, unless otherwise specified, it is intended that the aqueous liquid preparation as a whole is stable.

[0056] As used herein, "stable" means that the target compound or the like is maintained without decomposition, and stability can be confirmed by the methods exemplified in the Examples. The method for confirming stability can be appropriately selected depending on whether or not the compound is in a dissolved state. For example, stability can be confirmed by confirming that the remaining percentage of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof after storage at about 60°C for two weeks is about 90% or more, more preferably about 95% or more.

[0057] In one embodiment, the concentration of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof in a dissolved state in the aqueous liquid formulation of the present disclosure may be about 0.01 w / v % or less.

[0058] In another embodiment, the stability of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in a dissolved state in the aqueous liquid preparation of the present disclosure is improved. In this case, stability can be confirmed by the fact that, when the aqueous liquid preparation is stored at about 60°C for 2 weeks, the remaining percentage of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in a dissolved state is about 90% or more, preferably about 95% or more. A substance in a dissolved state is generally less stable than a substance in a solid state, and in an aqueous liquid preparation containing (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, the dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, typically decomposes, resulting in a decrease in the content retention rate over time. The aqueous liquid preparation of the present disclosure improves the stability of the dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, thereby contributing to an overall improvement in the stability of the aqueous liquid preparation. For example, such stability can be confirmed by filtering the liquid portion of the suspension and extracting the dissolved portion, and the stability can be confirmed as an indicator thereof, but is not limited to this.

[0059] In one specific embodiment, the present disclosure provides an aqueous solution comprising electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a non-ionic surfactant, wherein the electron beam treatment comprises treatment with an electron beam irradiation dose of about 10 kGy to about 60 kGy, the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous solution is about 0.01 w / v % to about 5 w / v %, and the concentration of the non-ionic surfactant in the aqueous solution is about 0.01 w / v % to about 0.05 w / v %. Preferably, the aqueous solution is an aqueous suspension.

[0060] In one embodiment, the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof in the aqueous solution of the present disclosure can be used in a crystalline form, and the crystalline form is not particularly limited as long as it does not affect stability. For example, in the present disclosure, Type I crystals, Type II crystals, Type III crystals, or mixtures thereof of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide disclosed in WO 2018 / 221543, Japanese Patent No. 6230743, etc. can be used. Preferably, Type I crystals are used.

[0061] (Dosage Form) In one embodiment of the present disclosure, the aqueous liquid preparation may be an eye drop. For example, the eye drop may be provided in the form of a suspension in which the active ingredient is suspended in an aqueous solvent (e.g., phosphate buffered saline) or in the form of a solution in which the active ingredient is dissolved.

[0062] In one embodiment of the present disclosure, the aqueous liquid preparation may be an aqueous suspension. For example, the aqueous suspension may be provided in the form of a suspension in which the active ingredient is suspended in an aqueous solvent (e.g., phosphate buffered saline) or in the form of a solution in which the active ingredient is dissolved.

[0063] In one embodiment of the present disclosure, the aqueous solution is an ophthalmic suspension, which is also referred to as a suspension eye drop, and may be provided as an ophthalmic injection solution, eye drops, or ophthalmic irrigation solution. For example, an ophthalmic suspension may be provided in the form of a suspension in which the active ingredient is suspended or dissolved in an aqueous solvent (e.g., phosphate buffered saline).

[0064] The aqueous solution formulations of the present disclosure can be administered by any appropriate route as determined by one of ordinary skill in the art, and may be formulated to be suitable for administration by a route selected from, but not limited to, ocular injection, topical application (including application to the eye), eye drops, intravenous injection, infusion, oral, parenteral, transdermal, etc.

[0065] (Additives and / or excipients) The aqueous liquid formulation of the present disclosure may contain any pharmaceutically acceptable additives and / or excipients known in the art, including, but not limited to, thickeners, stabilizers, pH adjusters, buffers, and preservatives.

[0066] The thickening agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, etc.; cellulose-based polymers such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, etc. These thickening agents may be used alone or in combination of two or more.

[0067] The stabilizer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyvinylpyrrolidone, monoethanolamine, cyclodextrin, dextran, ascorbic acid, tocopherol, dibutylhydroxytoluene, sulfite, sodium edetate, etc., and the content thereof is preferably about 0.001 w / v % to about 1 w / v % based on the total amount of the aqueous liquid preparation.

[0068] The pH adjuster is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid; alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, and sodium carbonate; and the content thereof is, for example, 0 w / v % to about 20 w / v % relative to the total amount of the aqueous liquid preparation.

[0069] In one embodiment of the present disclosure, the aqueous liquid preparation of the present disclosure can be mixed with the above-mentioned pH adjuster as needed to adjust the pH to generally about 4 to about 8, preferably about 5.0 to about 8.0, more preferably about 6.0 to about 8.0, particularly preferably about 7.0 to about 8.0, and even more preferably about 7.2 to about 7.8.

[0070] The buffer used in the aqueous liquid preparation of the present disclosure is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include borate buffer, phosphate buffer, Tris buffer, citrate buffer, tartrate buffer, acetate buffer, amino acid buffer, etc. However, when the aqueous liquid preparation is a suspension, from the viewpoint of stability, borate buffer or phosphate buffer is preferred, and borate buffer is particularly preferred.

[0071] The concentration of the buffering agent may be appropriately set within a range that can impart the desired buffering ability to the aqueous liquid preparation, and may be, for example, about 0.1 w / v % to about 10 w / v %, and from the viewpoint of improving redispersibility or stability, preferably about 1 w / v % to about 5 w / v %, more preferably about 1 w / v % to about 3 w / v %.

[0072] The boric acid buffer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include boric acid and / or its salts. The boric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, tetraboric acid, etc. The salt of boric acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and aluminum salt; and organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, and pyrrolidine. Boric acid or its salts may be used alone or in combination of two or more. Furthermore, a preferred embodiment of the boric acid buffer is a combination of boric acid and borax.

[0073] When boric acid and borax are used in combination, the ratio of boric acid to borax is not particularly limited, but examples thereof include about 10 to about 300 parts by mass, preferably about 10 to about 250 parts by mass, more preferably about 30 to about 100 parts by mass, and particularly preferably about 40 to about 60 parts by mass of borax per about 100 parts by mass of boric acid.

[0074] Specific examples of phosphate buffers include phosphoric acid and / or its salts. Phosphate salts are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. Phosphate salts may also be in the form of solvates such as hydrates, for example, disodium hydrogen phosphate may be in the form of a dodecahydrate, and sodium dihydrogen phosphate may be in the form of a dihydrate. Phosphate buffers may be selected from phosphoric acid and its salts and used alone or in combination of two or more. Among phosphoric acid and its salts, preferred are phosphates, more preferably at least one of dialkali metal hydrogen phosphates and alkali metal dihydrogen phosphates, and particularly preferably at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0075] Examples of Tris buffers include Tris (also known as trishydroxymethylaminomethane) and / or its salts. The Tris salts are not particularly limited as long as they are pharmaceutically acceptable, and examples include acetate, hydrochloride, maleate, sulfonate, and the like. As the Tris acid buffer, one selected from Tris and its salts may be used alone, or two or more may be used in combination. In another embodiment, specific examples of Tris buffers include trometamol and / or its salts. As the salt of trometamol, there are no particular limitations, as long as it is pharmaceutically acceptable, and examples include organic acid salts such as acetate; and inorganic acid salts such as hydrochloride and sulfonate. As the Tris acid buffer, one selected from trometamol and its salts may be used alone, or two or more may be used in combination. Among trometamol and its salts, trometamol is preferred.

[0076] Specific examples of citrate buffers include citric acid and / or its salts. The citric acid salts are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt. The citric acid salt may also be in the form of a solvate such as a hydrate. As the citrate buffer, one selected from citric acid and its salts may be used alone, or two or more may be used in combination. Among citric acid and its salts, preferred are citric acid salts, more preferred are alkali metal citric acid salts, and particularly preferred is sodium citrate.

[0077] Specific examples of tartaric acid buffers include tartaric acid and / or its salts. The salts of tartaric acid are not particularly limited as long as they are pharmaceutically acceptable, and include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts. The salts of tartaric acid may also be in the form of solvates such as hydrates. As the tartaric acid buffer, one selected from tartaric acid and its salts may be used alone, or two or more may be used in combination.

[0078] Specific examples of acetate buffers include acetic acid and / or its salts. The salts of acetic acid are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts. Furthermore, the salts of acetic acid may be in the form of a solvate such as a hydrate. Acetic acid and its salts may be used singly or in combination as the acetate buffer.

[0079] Specific examples of the amino acid buffer include acidic amino acids and / or their salts. Specific examples of the acidic amino acids include aspartic acid and glutamic acid. The salts of acidic amino acids are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts. As the amino acid buffer, one kind selected from acidic amino acids and their salts may be used alone, or two or more kinds may be used in combination.

[0080] The preservative is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include sorbic acid, potassium sorbate, parahydroxybenzoic acid esters such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate, chlorhexidine gluconate, quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, and chlorhexidine, and the content thereof can be appropriately varied depending on the type, and can be, for example, about 0.0001 w / v % to about 0.2 w / v % of the total amount of the aqueous liquid.

[0081] When preparing eye drops, for example, the desired components described above can be dissolved or suspended in an aqueous solvent such as sterilized purified water, physiological saline, or a buffer solution (e.g., phosphate buffer, citrate buffer, or acetate buffer), or in a non-aqueous solvent such as a vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil, and the like, and the resulting solution is adjusted to a predetermined osmotic pressure and subjected to a sterilization treatment such as filtration sterilization.

[0082] (Container) The container for storing the aqueous liquid preparation of the present disclosure is not particularly limited, and examples thereof include glass containers and plastic containers. Plastic containers can be made of any material, such as polyester (polyethylene terephthalate, polyarylate), polycarbonate, polyethylene, polypropylene, a mixture thereof, or a mixture of these with other materials. The container used in the present disclosure may be one used in the medical field or may be other.

[0083] The container to be used may have any shape, and generally, any shape can be used as long as it is suitable for the application of the present disclosure (for example, for eye drops).

[0084] In one embodiment, the aqueous solution of the present disclosure can be filled into any eye dropper container commonly used in the medical field. Examples of eye dropper containers include plastic containers, such as polyethylene (preferably low-density polyethylene) or polypropylene, preferably colorless polypropylene. In one embodiment, the container can be made of any material that meets the "Standards for Plastic Containers for Eye Drops" in Japan or other equivalent standards.

[0085] (General Techniques) The molecular biological, biochemical and microbiological techniques used herein are well known and commonly used in the art, and are described, for example, in Sambrook J. et al. (1989). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor and its 3rd Ed. (2001); Ausubel, F. M. (1987). Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Ausubel, F. M. (1989). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Green Pub. Associates and Wiley-Interscience; Innis, M. A. (1990). PCR Protocols: A Guide to Methods and Applications, Academic Press; Ausubel, F. M. (1992). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Green Pub. Associates; Ausubel, F. M. (1995). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Green Pub. Associates; Innis, M. A. et al. (1995). PCR Strategies, Academic Press;Ausubel, F. M. (1999). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Wiley, and annual updates; Sninsky, J. J. et al. (1999). PCR Applications: Protocols for Functional Genomics, Academic Press, Gait, M. J. (1985). Oligonucleotide Synthesis: A Practical Approach, IRL Press; Gait, M. J. (1990). Oligonucleotide Synthesis: A Practical Approach, IRL Press; Eckstein, F. (1991). Oligonucleotides and Analogues: A Practical Approach, IRL Press; Adams, R. L. et al. (1992). The Biochemistry of the Nucleic Acids, Chapman & Hall; Shabarova, Z. et al. (1994). Advanced Organic Chemistry of Nucleic Acids, Weinheim; Blackburn, G.; M. et al. (1996). Nucleic Acids in Chemistry and Biology, Oxford University Press; Hermanson, G. T. (I996). These methods are described in Bioconjugate Techniques, Academic Press, Special Edition of Experimental Medicine, "Gene Transfer & Expression Analysis Experimental Methods," Yodosha, 1997, etc. The relevant portions (possibly in their entirety) of these are incorporated herein by reference.

[0086] All references cited herein, including scientific literature, patents, patent applications, and the like, are incorporated by reference in their entirety to the same extent as if each were specifically set forth.

[0087] The present disclosure has been described above by showing preferred embodiments for ease of understanding. Hereinafter, the present disclosure will be described based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the scope of the claims.

[0088] (Test Example 1: Stability of Dissolved State of Compound (1) Treated with Electron Beam)

[0089] Sterilization of Compound (1) (Electron Beam Sterilization) Compound (1) was placed in a colorless, transparent bag and irradiated with electron beams. The irradiation was stopped when the irradiation dose reached 25 kGy, and a sterilized compound (1) was obtained.

[0090] Preparation of aqueous solutions: Base solutions were prepared according to the compositions shown in Table 1, and compound (1) was dissolved by stirring to obtain each aqueous solution. Tyloxapol was manufactured by AMRI Rensselaer (Curia Global, Inc.), and boric acid and borax were manufactured by Merck KGaA. The above-mentioned type I crystal was used as compound (1). In Comparative Example 2, compound (1) irradiated with approximately 25 kGy of gamma rays (cobalt 60) was used.

[0091] 5 mL of the prepared solution was collected and filled into eye drop containers. The eye drop containers used were colorless polyethylene containers (the same containers used for GatiFlo ophthalmic solution 0.3% (manufactured and sold by Senju Pharmaceutical Co., Ltd.)).

[0092] The aqueous solution was placed in a temperature test chamber (Nagano Science Co., Ltd., model number: CH24-12M) and stored at 60°C for 2 weeks (2W), and the content of compound (1) in the solution was measured using a liquid chromatography apparatus (Shimadzu Corporation) under the following conditions. The content retention rate was calculated as the ratio (%) of the measured content after storage to the amount of compound (1) used in the preparation.

[0093] (Measurement conditions) Column: InertSustain C18 5 μm, 4.6 × 150 mm (GL Sciences Inc.) Detector: UV-visible spectrophotometric detector Detection wavelength: 250 nm Column temperature: 40°C Mobile phase: Acetonitrile / aqueous sodium dihydrogen phosphate mixture (2:3)

[0094] Measurement Results The results are shown in Table 1. The content retention rate of the electron beam-treated compound (1) after storage at 60° C. for 2 W was 100%, and the compound was stable.

[0095]

[0096] (Example 2: Stability of aqueous liquid preparation containing electron beam-treated compound (1))

[0097] Sterilization of Compound (1) (Electron Beam Sterilization) The same procedure as in Test Example 1 was carried out.

[0098] Preparation of aqueous solution A base solution was prepared according to the composition shown in Table 2, and compound (1) was stirred and dispersed to obtain a suspension. The concentration of dissolved compound (1) in this suspension was 0.00101%. Tyloxapol was manufactured by AMRI Rensselaer (Curia Global, Inc.), and boric acid and borax were manufactured by Merck KGaA. The above-mentioned type I crystal was used as compound (1).

[0099] Placement in a container was carried out in the same manner as in Test Example 1.

[0100] The suspension was stored at 60°C for 2 weeks (2W), and the content of compound (1) in the suspension was measured using a liquid chromatography device (Shimadzu Corporation) under the following conditions. The content retention rate was calculated as the ratio (%) of the measured content after storage to the amount of compound (1) used in the preparation.

[0101] (Measurement conditions) Column: InertSustain C18 5 μm, 4.6 × 150 mm (GL Sciences Inc.) Detector: UV-visible spectrophotometric detector Detection wavelength: 250 nm Column temperature: 40°C Mobile phase: Acetonitrile / aqueous sodium dihydrogen phosphate mixture (2:3)

[0102] Measurement Results The results are shown in Table 2. The content retention rate of the electron beam-treated aqueous liquid preparation containing compound (1) after storage at 60°C for 2W was 100%, and the aqueous liquid preparation was stable.

[0103]

[0104] (Note) As described above, the present disclosure has been illustrated using preferred embodiments thereof, but it is understood that the scope of the present disclosure should be interpreted solely by the claims. It is understood that the patents, patent applications, and other documents cited in this specification are incorporated by reference into this specification as if the contents themselves were specifically set forth herein. This application claims priority to Japanese Patent Application No. 2024-054893, filed on March 28, 2024, with the Japan Patent Office, and it is understood that the entire contents of the specification and claims thereof are incorporated by reference.

[0105] The present disclosure is applicable to fields such as medicine, pharmaceuticals, healthcare, biology, and biochemistry.

Claims

1. An aqueous liquid preparation comprising electron beam treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof.

2. The aqueous liquid preparation according to claim 1, wherein the electron beam treatment is a treatment within a sterilization process.

3. The aqueous liquid preparation according to claim 1 or 2, further comprising a nonionic surfactant.

4. An aqueous liquid preparation according to any one of claims 1 to 3, wherein the irradiation dose of the electron beam treatment includes treatment with about 10 kGy to about 60 kGy.

5. The aqueous liquid preparation according to claim 3 or 4, wherein the concentration of the nonionic surfactant in the aqueous liquid preparation is about 0.0001 w / v % to about 1 w / v %.

6. The aqueous liquid preparation according to any one of claims 3 to 5, wherein the nonionic surfactant is tyloxapol.

7. The aqueous liquid preparation according to any one of claims 1 to 6, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof in the aqueous liquid preparation is from about 0.001 w / v % to about 5 w / v %.

8. The aqueous liquid preparation according to any one of claims 1 to 7, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.

9. An aqueous liquid preparation comprising electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, wherein the stability of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof in the aqueous liquid preparation is improved.

10. The aqueous liquid preparation according to any one of claims 1 to 9, wherein the concentration of dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, in the aqueous liquid preparation is about 0.01 w / v % or less.

11. An aqueous liquid preparation comprising electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, wherein the stability of the dissolved (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof in the aqueous liquid preparation is improved.

12. The aqueous liquid preparation according to any one of claims 1 to 11, wherein the aqueous liquid preparation is an aqueous suspension.

13. A method for producing an aqueous liquid preparation, wherein the aqueous liquid preparation contains (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, the method comprising the steps of: treating the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with an electron beam; and mixing the electron beam-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharmaceutically acceptable salt or solvate thereof, with a solvent.

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