Sterilized heterocyclidene-acetamide-derivative-containing suspension

Abstract

To provide a suspension-type ophthalmic solution having excellent re-dispersibility.SOLUTION: The present disclosure provides a water-based suspension preparation containing heat-treated (E)-2-(7-trifluoromethylchroman-4-yldene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof. In particular, the present disclosure relates to technology for improving the re-dispersibility of a suspension that contains a heterocyclidene acetamide derivative or to formulation technology based thereupon.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to the fields of medicine, health care, biology, biotechnology, etc. In particular, the present disclosure relates to a technology for improving the redispersibility of a suspension containing a heterocyclideneacetamide derivative, and a formulation technology based thereon. [Background technology]

[0002] The number of dry eye patients in Japan is estimated at at least 8 million, and the number is estimated to be about 22 million if potential patients who use over-the-counter eye drops without visiting a hospital are included, and it is said that there are more than 1 billion people with dry eye worldwide. In modern society, the use of television, computers, mobile devices, etc. increases the number of times people stare at screens, which reduces the number of times they blink, and the use of air conditioners, etc., dries the air, which ultimately increases the evaporation of tears and is widely known to cause dry eye. In addition, refractive surgery and the use of contact lenses can result in dry eye. Symptoms associated with dry eye include ocular discomfort, dryness, burning sensation, and irritation on the ocular surface.

[0003] When dry eye occurs, the above symptoms appear as subjective symptoms, and long-term regular eye drops are required for treatment. Therefore, many of the currently commercially available dry eye treatment drugs are of the frequent administration type, for example, Diquas (registered trademark) eye drops are usually instilled 6 times a day, Hyalein (registered trademark) eye drops are usually instilled 5 to 6 times a day, and Mucosta (registered trademark) eye drops are usually instilled 4 times a day.

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

[0005] Patent Document 1: International Publication No. 2021 / 066144 Brochure Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides an aqueous suspension having excellent redispersibility, comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, which is a heterocyclideneacetamide derivative, or a pharma- ceutically acceptable salt or solvate thereof.

[0007] Thus, the present disclosure provides: (Item 1) An aqueous suspension comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof. (Item 1-1) The aqueous suspension according to the preceding paragraph, wherein the heat treatment is a dry heat treatment. (Item 2) The aqueous suspension according to the above item, wherein the heat treatment is a treatment during a sterilization process. (Item 2-1) The aqueous suspension preparation according to the above item, wherein the treatment in the sterilization step is a dry heat sterilization treatment. (Item 3) Item 11. An aqueous suspension according to any one of the preceding items, further comprising a non-ionic surfactant. (Item 4) Item 11. The aqueous suspension of any one of the preceding items, wherein the heat treatment comprises a heat treatment at a temperature below about 180°C. (Item 5) The aqueous suspension according to any one of the preceding items, wherein the heat treatment comprises a heat treatment at about 100 to about 175°C. (Item 6) The aqueous suspension according to any one of the preceding items, wherein the heat treatment comprises a heat treatment at about 100 to about 170°C. (Item 7) The aqueous suspension according to any one of the preceding items, wherein the heat treatment comprises a heat treatment at about 150 to about 170°C. (Item 8) The aqueous suspension according to any one of the preceding items, wherein the heat treatment is carried out for about 30 minutes to about 5 hours. (Item 9) The aqueous suspension according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is about 0.0001 w / v% to about 1 w / v%. (Item 10) The aqueous suspension according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is about 0.001 w / v% to about 0.5 w / v%. (Item 11) The aqueous suspension according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v% to about 0.05 w / v%. (Item 12) The aqueous suspension 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 13) 2. The aqueous suspension of claim 1, wherein the nonionic surfactant is tyloxapol. (Item 14) The aqueous suspension 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 pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension is about 0.01 w / v% to about 5 w / v%. (Item 15) The aqueous suspension 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 pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension is about 0.3 w / v% to about 1 w / v%. (Item 16) 1. An aqueous suspension comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and a non-ionic surfactant, the heat treatment comprises a heat treatment at a temperature below about 180° C.; The heat treatment is carried out for about 30 minutes to about 5 hours. the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, has a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension; The aqueous suspension has a concentration of the nonionic surfactant in the aqueous suspension of about 0.01 w / v % to about 0.05 w / v %. (Item 17) The aqueous suspension 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 18) An aqueous suspension comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, in the aqueous suspension, redisperses suspended particles after less than about 35 shakes, as assessed by a shaking procedure. (Item 19) An aqueous suspension comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, in the aqueous suspension, redisperses suspended particles after less than about 50 inversions, as assessed by an inversion procedure. (Item 20) 1. An aqueous suspension comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, wherein the aqueous suspension has improved redispersibility of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma-ceutically acceptable salt or solvate thereof. (Item 21) 2. The aqueous suspension according to claim 1, wherein the improved redispersibility is such that the suspended particles are redispersed with less than about 35 shakings, as assessed by shaking. (Item 22) 2. The aqueous suspension of claim 1, wherein the improved redispersibility is redispersibility of the suspended particles after less than about 50 inversions, as assessed by inversion. (Item 23) An aqueous suspension comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, wherein the average particle size (D50) of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma-ceutically acceptable salt or solvate thereof in the aqueous suspension is about 1 μm to about 10 μm. (Item 24) 1. A method for producing an aqueous suspension comprising the steps of: heat treating (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof; mixing the heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, with a solvent; method. (Item 25) Heat treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof. (Item 26) The aqueous suspension according to any one of the preceding items, wherein the aqueous suspension has a pH of about 4 to about 8. (Item 27) 2. The aqueous suspension according to any one of the preceding claims, wherein the aqueous suspension is contained in a plastic container. (Item 28) 2. The aqueous suspension according to any one of the preceding claims, wherein the plastic container is made of polyethylene or polypropylene. (Item B1) An aqueous suspension comprising gamma ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof. (Item B2) Item 11. An aqueous suspension according to any one of the preceding items, further comprising a non-ionic surfactant. (Item B3) An aqueous suspension comprising gamma ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and a non-ionic surfactant. (Item B4) The aqueous suspension according to any one of the preceding items, wherein the gamma ray sterilization treatment comprises gamma ray treatment at about 10 to about 50 kGy. (Item B5) Item 11. The aqueous suspension of any one of the preceding items, wherein the gamma sterilization treatment comprises gamma sterilization at about 25 kGy. (Item B6) The aqueous suspension according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is about 0.0001 w / v% to about 0.1 w / v%. (Item B7) The aqueous suspension according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is about 0.001 w / v% to about 0.5 w / v%. (Item B8) The aqueous suspension according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v% to about 0.05 w / v%. (Item B9) The aqueous suspension 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 B10) 2. The aqueous suspension of claim 1, wherein the nonionic surfactant is tyloxapol. (Item B11) The aqueous suspension 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 pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension is about 0.01 w / v% to about 5 w / v%. (Item B12) The aqueous suspension 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 pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension is about 0.3 w / v% to about 1 w / v%. (Item B13) 1. An aqueous suspension comprising gamma ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and a non-ionic surfactant, The gamma ray sterilization treatment includes gamma ray treatment at about 10 to about 50 kGy; the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, has a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension; The aqueous suspension has a concentration of the nonionic surfactant in the aqueous suspension of about 0.01 w / v % to about 0.05 w / v %. (Item B14) The aqueous suspension 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 B15) An aqueous suspension comprising gamma-ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, in the aqueous suspension, redisperses suspended particles after less than about 35 shakes, as assessed by shaking. (Item B16) An aqueous suspension comprising gamma-ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, in the aqueous suspension, redisperses suspended particles after less than about 50 inversions, when evaluated by inversion. (Item B17) 1. An aqueous suspension comprising gamma-ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, wherein the aqueous suspension has improved redispersibility of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma-ceutically acceptable salt or solvate thereof. (Item B18) 2. The aqueous suspension according to claim 1, wherein the improved redispersibility is such that the suspended particles are redispersed after about 35 or fewer shakings, as assessed by shaking. (Item B19) 2. The aqueous suspension according to any one of the preceding items, wherein the improved redispersibility is such that the suspended particles redisperse after about 50 or fewer inversions as assessed by inversion. (Item B20) Gamma ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof. (Item B21) The aqueous suspension according to any one of the preceding items, wherein the aqueous suspension has a pH of about 4 to about 8. (Item B22) 2. The aqueous suspension according to any one of the preceding claims, wherein the aqueous suspension is contained in a plastic container. (Item B23) 2. The aqueous suspension according to any one of the preceding claims, wherein the plastic container is made of polyethylene or polypropylene. (Item A1) 1. A method for producing an aqueous suspension comprising the steps of: heat treating (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof; mixing the heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, with a solvent. (Item A1-1) Item 10. The method according to any one of the preceding items, wherein the heat treatment is a dry heat treatment. (Item A2) The method according to any one of the preceding claims, wherein the heat treatment is a treatment within a sterilization process. (Item A2-2) The method according to any one of the preceding claims, wherein the treatment in the sterilization step is a dry heat sterilization treatment. (Item A3) The method of any one of the preceding claims, further comprising the step of mixing a non-ionic surfactant. (Item A4) 2. The method of any one of the preceding claims, wherein the heat treatment comprises a heat treatment at a temperature below about 180° C. (Item A5) The method according to any one of the preceding items, wherein the heat treatment comprises a heat treatment at about 100 to about 175°C. (Item A6) The method according to any one of the preceding items, wherein the heat treatment comprises a heat treatment at about 100 to about 170°C. (Item A7) The method according to any one of the preceding items, wherein the heat treatment comprises a heat treatment at about 150 to about 170°C. (Item A8) The method according to any one of the preceding items, wherein the heat treatment is carried out for about 30 minutes to about 5 hours. (Item A9) The method according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is about 0.0001 w / v% to about 1 w / v%. (Item A10) The method according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is about 0.001 w / v% to about 0.5 w / v%. (Item A11) The method according to any one of the preceding items, wherein the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v% to about 0.05 w / v%. (Item A12) 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 A13) The method of any one of the preceding claims, wherein the nonionic surfactant is tyloxapol. (Item A14) 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 pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension is about 0.01 w / v% to about 5 w / v%. (Item A15) 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 pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension is about 0.3 w / v% to about 1 w / v%. (Item A16) The method according to any one of the above 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 A17) The method according to any one of the preceding items, wherein the aqueous suspension has a pH of about 4 to about 8. (Item A18) The method according to any one of the preceding items, wherein the heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension redisperses suspended particles in less than about 35 shakes, as assessed by a shaking procedure. (Item A19) The method according to any one of the preceding items, wherein the heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension redisperses suspended particles in less than about 50 inversions, as assessed by an inversion procedure. (Item A20) The method according to any one of the preceding items, wherein the redispersibility of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension is improved. (Item A21) The method according to any one of the preceding items, wherein the improved redispersibility is such that the suspended particles are redispersed with about 35 or fewer shakes as assessed by a shaking operation. (Item A22) The method according to any one of the preceding items, wherein the improved redispersibility is such that the suspended particles are redispersed after about 50 or fewer inversions as assessed by inversion. (Item A23) The method according to any one of the preceding items, wherein the average particle size of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension is about 1 μm to about 10 μm. (Item A24) 2. The method of any one of the preceding claims, wherein the aqueous suspension is contained in a plastic container. (Item A25) The method according to any one of the preceding claims, wherein the plastic container is made of polyethylene or polypropylene. (Item C1) 1. A method for producing an aqueous suspension comprising the steps of: subjecting (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, to gamma radiation; mixing the gamma-ray treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, with a solvent; A method comprising: Effect of the Invention

[0008] According to the present disclosure, it is possible to provide an aqueous suspension having excellent redispersibility.

[0009] By providing the above-mentioned features, the present disclosure suppresses the phenomenon in which suspended particles are not uniformly dispersed, enables stable administration of a required amount of active ingredient, and realizes stable and sufficient exertion of pharmacological effects, thereby contributing to improved adherence and convenience for patients. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present disclosure will be described below. Throughout this specification, the singular expression should be understood to include the concept of the plural form, unless otherwise specified. Therefore, the singular article (for example, in the case of English, "a", "an", "the", etc.) should be understood to include the concept of the plural form, unless otherwise specified. In addition, it should be understood that the terms used in this specification are used in the sense commonly used in the field, unless otherwise specified. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In case of conflict, the present specification (including definitions) shall prevail.

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

[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 "alternative" 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 suspension" is used in the same sense as the term is generally used in this field, and refers to a liquid agent containing at least a part of water, in which the components 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 its pharmaceutically acceptable salt or solvate 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 its pharmaceutically acceptable salt or solvate becomes suspended particles, but some of them are dissolved.

[0014] 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.

[0015] As used herein, the term "solvate" refers to a group formed by interaction between the compound of the present disclosure or a pharma- ceutically acceptable salt thereof and any solvent, including, for example, a solvate with an organic solvent (e.g., an alcohol (ethanol, etc.) solvate), a hydrate, etc. When a hydrate is formed, it may be coordinated with any number of water molecules. Examples of the hydrate include a monohydrate, a dihydrate, etc.

[0016] In this specification, "redispersibility" refers to the ease with which particles that have settled in the solvent of a liquid containing particles (in the case of a suspension, they are also called "suspended particles"), such as a suspension, can be dispersed again uniformly throughout the liquid by storing the liquid for a certain period of time. In this specification, "redispersibility" is evaluated by a test using a shaking operation or a tumbling operation.

[0017] In this specification, the term "shaking operation" refers to the action of holding a container filled with an "aqueous suspension" and shaking it up and down by hand. The "shaking operation" is performed by shaking the container up and down in a range of 10 to 15 cm, and then shaking it up and back to the original position, with one shaking being counted as one set of five shakings at a speed of 1.1 seconds / set. The redispersibility test by the "shaking operation" is performed on three samples per formulation, and the average number of sets is calculated from the number of sets required for redispersion for each sample, and the number converted into the number of shakings is used.

[0018] In this specification, "inversion" refers to the action of holding a container filled with "aqueous suspension" and turning it upside down by hand. The redispersibility test by "inversion" is performed on three samples per formulation, and one inversion is defined as the operation of inverting the container 180° upside down at a speed of one second, then inverting it 180° again to the upright state.

[0019] In this specification, "improved redispersibility" refers to the fact that particles that have settled in a liquid containing particles, such as a suspension, become easier to disperse again. In a comparison of any formulation, if the number of operations of the above-mentioned "shaking operation" or "tipping operation" is reduced, it can be said that the redispersibility is improved.

[0020] As used herein, the term "average particle size of suspended particles" refers to the median particle size (D) of particles of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof. 50 ) and is a value measured using a laser diffraction particle size distribution measuring device.

[0021] 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 or not a surfactant is nonionic 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. For example, 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.), 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.).

[0022] In this specification, "heat treatment" refers to the application of heat to a target substance or molecule, aqueous suspension, or composition, and may be any treatment that substantially heats the substance or molecule, aqueous suspension, or composition. "Heat treatment" includes, for example, dry heat treatment, moist heat treatment, and high-pressure steam treatment. The temperature of the heat treatment may mean the temperature of the target substance or molecule, aqueous suspension, or composition, or may be the temperature set in the device used for applying heat or the temperature displayed on the display. The time of the heat treatment may mean the time during which the target substance or molecule, aqueous suspension, or composition is maintained at a predetermined temperature as an average temperature after the temperature reaches a predetermined temperature when heat is applied to the target substance or molecule, aqueous suspension, or composition, or may be the time set in the device used for applying heat or the time displayed on the display. In the present disclosure, heat treatment (e.g., dry heat treatment, moist heat treatment, high-pressure steam treatment) means that the heat treatment is applied to (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, itself. The dry heat treatment may be applied to a powder of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof. The term "powder" refers to a granular material (a material consisting of solid particles having any particle size distribution, in which interactions such as electrostatic forces and van der Waals forces exist between individual particles).

[0023] In this specification, "sterilization" or "sterilization treatment" refers to substantially removing, killing, or inactivating viruses, microorganisms, etc. present in a target substance or molecule, aqueous suspension, or composition. Examples of sterilization include gamma ray sterilization, dry heat sterilization, and autoclave sterilization. Therefore, "gamma ray sterilization treatment" refers to sterilizing a target substance or molecule, aqueous suspension, or composition by irradiating the substance or molecule with gamma rays. In addition, "dry heat sterilization" refers to a treatment of sterilization by heating in a dry state. In the present disclosure, sterilization or sterilization treatment refers to treatment performed on (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof. The gamma radiation sterilization treatment may be applied to a powder of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof.

[0024] In this specification, the term "solvent" is used to mean water, an organic solvent, and a mixture of water and an organic solvent, and may be sterilized by filtration or other sterilization treatment, and these sterilized solvents are also included in the "solvent" of this specification. In addition to water, an organic solvent, or a mixture of water and an organic solvent, the solvent may be in a state in which any additive such as a thickener, a stabilizer, a pH regulator, a buffer, and a preservative (antiseptic) is dissolved, and these additive-containing solvents are also included in the "solvent" of this specification.

[0025] (Preferred embodiment) Preferred embodiments of the present disclosure are 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 a person skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description in this specification. In addition, the following embodiments of the present disclosure can be used alone or in combination.

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

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

[0028] In one aspect of the present disclosure, there may be provided an aqueous suspension comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, which has been heat-treated at about 150°C to about 170°C.

[0029] In another aspect of the present disclosure, there may be provided an aqueous suspension comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide heat-treated at about 150° C. to about 170° C., or a pharma- ceutically acceptable salt or solvate thereof, and a nonionic surfactant.

[0030] In one aspect of the present disclosure, there may be provided an aqueous suspension comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, which has been sterilized by heat treatment at about 100°C to about 170°C.

[0031] In another aspect of the present disclosure, there may be provided an aqueous suspension comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, which has been sterilized by heat treatment at about 100°C to about 170°C, and a nonionic surfactant.

[0032] In one aspect of the present disclosure, there may be provided an aqueous suspension comprising gamma ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof.

[0033] In another aspect of the present disclosure, there may be provided an aqueous suspension comprising gamma-sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and a non-ionic surfactant.

[0034] In one aspect of the present disclosure, there may be provided a method for producing an aqueous suspension, the method comprising the steps of heat-treating (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and mixing the heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, with a solvent.

[0035] In another aspect of the present disclosure, there may be provided a method for producing an aqueous suspension, the method comprising the steps of gamma ray sterilizing (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and mixing the gamma ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, with a solvent.

[0036] In one aspect of the disclosure, there may be provided heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof.

[0037] In one aspect of the present disclosure, there may be provided (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, which has been heat-treated at about 150°C to about 170°C.

[0038] In one aspect of the present disclosure, there may be provided (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, which has been sterilized by heat treatment at about 100°C to about 170°C.

[0039] In another aspect of the present disclosure, there may be provided gamma sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof.

[0040] (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).

[0041] The pharma- ceutically acceptable salt of the compound of the present disclosure is not particularly limited as long as it is a pharma- ceutically 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 tricarboxylic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, etc.; and organic sulfonic acids such as aliphatic sulfonic acids, 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.

[0042] These salts can be obtained by a conventional method, for example, by mixing a solution containing an equivalent amount of the compound of the present disclosure and the desired acid or base, and collecting the desired salt by filtration or by distilling off the solvent. The compound of the present disclosure or a salt thereof can form a solvate with a solvent such as water or ethanol.

[0043] (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.

[0044] The R form (compound (1)), S form, 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. 2007 / 010383, Japanese Patent No. 4754566, Japanese Patent No. 6230743, International Publication No. 2018 / 221543, Japanese Patent No. 6830569, International Publication No. 2021 / 038889, and International Publication No. 2021 / 039023. The R form (compound (1)), S form, or racemic form can be produced by the production method described in the publication. The contents of the publication are incorporated herein by reference in their entirety.

[0045] TRPV1 was cloned from the dorsal root ganglion (DRG) as a cation channel that responds to capsaicin, and is also sensitive to heat above 43°C and protons. It is a TRP channel that has been studied as a key molecule in nociception (Biochemistry, Vol. 85, No. 7: 561-565). TRPV1 is known to be activated during inflammation and tissue injury, causing hyperalgesia. Therefore, TRPV1 has been attracting attention as a potential drug target for pain treatment.

[0046] 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).

[0047] 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 pharma- ceutically acceptable salt or solvate thereof is heat-treated, and the heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof is mixed with a solvent to form an aqueous suspension, thereby improving the redispersibility of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof.

[0048] In another embodiment of the present disclosure, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, is subjected to gamma ray sterilization, and the gamma ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma-ceutically acceptable salt or solvate thereof is mixed with a solvent to form an aqueous suspension, thereby improving the redispersibility of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma-ceutically acceptable salt or solvate thereof.

[0049] 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 pharma- ceutically acceptable salt or solvate thereof, may be present in the aqueous suspension of the present disclosure at a concentration of typically about 0.01 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%.

[0050] In one embodiment of the present disclosure, when the R-isomer of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof is used, it can be present in the aqueous suspension of the present disclosure at a concentration of usually about 0.01 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%.

[0051] In one embodiment of the present disclosure, the heat treatment of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, can be carried out as a treatment in the sterilization process of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, and the heat treatment temperature is usually lower than about 180 ° C., preferably about 175 ° C. or less, more preferably about 100 to about 175 ° C., particularly preferably about 100 to about 170 ° C., even more preferably about 120 to about 170 ° C., even more preferably about 145 to about 175 ° C., and most preferably about 150 to about 170 ° C.

[0052] In one embodiment of the present disclosure, the heat treatment time for (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof is usually 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.

[0053] In one embodiment of the present disclosure, the gamma ray sterilization treatment of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, can be carried out 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 pharma-ceutically acceptable salt or solvate thereof, and the dose of the gamma ray sterilization treatment can be usually about 10 to about 50 kGy, more preferably about 25 kGy.

[0054] In one embodiment of the present disclosure, the nonionic surfactant is not particularly limited as long as it is pharma- ceutically acceptable, but 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.), 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. From the viewpoint of redispersibility or stability of the 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.

[0055] In one embodiment of the present disclosure, the nonionic surfactant can be present in the aqueous suspension 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%.

[0056] (Redispersibility) Since (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, has low solubility in water, in the absence of a dispersant such as a nonionic surfactant, an ionic surfactant, or a water-soluble polymer, the particles float on the water surface, making it impossible to prepare an aqueous suspension. In addition, when a dispersant other than a nonionic surfactant is used, it is necessary to add a dispersant at a concentration substantially exceeding the pharma- ceutically acceptable concentration, so that it is essential to add a nonionic surfactant to the aqueous suspension. According to the present disclosure, an aqueous suspension having improved redispersibility can be provided by subjecting (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma-ceutically acceptable salt or solvate thereof, to heat treatment in the presence of a nonionic surfactant as a dispersant.

[0057] In another aspect of the present disclosure, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, can be sterilized by gamma radiation to provide an aqueous suspension having improved redispersibility.

[0058] In one embodiment, the redispersibility can be determined to be improved when the number of shaking cycles required for the above-mentioned redispersion is usually less than about 35 times, preferably about 30 times or less, more preferably about 25 times or less, and particularly preferably about 20 times or less.

[0059] Measurements during the falling operation can be said to reproduce the evaluation of patients whose hands have weakened due to some disability or condition and who have difficulty redispersing by shaking, and therefore can also be said to evaluate the redispersibility when used by such patients and elderly people.

[0060] In one embodiment, the redispersibility can be determined to be improved when the number of inversion operations required for the above-mentioned redispersion is usually less than about 50 times, preferably about 45 times or less.

[0061] In one embodiment, the redispersibility can be evaluated by any means, for example, by filling a container with the aqueous suspension of the present disclosure and measuring the number of times the container is shaken at any speed and / or any amplitude, or inverted, until the suspended particles are redispersed.

[0062] In one embodiment, the average particle size (D) of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharma- ceutically acceptable salt or solvate thereof in an aqueous suspension of the present disclosure is 50 ) is not particularly limited, but can be usually about 1 μm to about 10 μm, preferably about 0.5 μm to about 5 μm, particularly preferably about 2 μm to about 4 μm, further preferably about 2.3 μm to about 3.3 μm, and most preferably about 2.1 μm to about 3.3 μm. By setting the average particle size in such a range, redispersibility can be improved.

[0063] In one embodiment, the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or its pharma- ceutically acceptable salt or solvate in the aqueous suspension of the present disclosure can be used as a crystalline form, and the crystalline form is not particularly limited as long as it does not affect redispersibility. For example, in the present disclosure, the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide type I crystal, type II crystal, type III crystal, or a mixture thereof disclosed in International Publication No. 2018 / 221543, Japanese Patent No. 6230743, etc. can be used. The type I crystal is preferably used.

[0064] (Dosage form) In one embodiment of the present disclosure, the aqueous suspension is an ophthalmic suspension, which can be provided as an ophthalmic injection solution, an eye drop or an ophthalmic irrigation solution.For example, the ophthalmic suspension can 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.

[0065] In one embodiment of the present disclosure, the aqueous suspension may be an eye drop for treating dry eye. Dry eye is a disease accompanied by subjective symptoms such as eye discomfort, and requires long-term and regular treatment. In addition, since dry eye treatment drugs are generally administered many times, there is a strong demand for a formulation that is easy to adhere to and convenient for patients. Furthermore, in the case of a suspension with poor redispersibility, there is a concern that the suspended particles are not uniformly dispersed, the desired active ingredient is not administered, and the pharmacological effect is not fully exerted. From these viewpoints, redispersibility is a major issue in eye drops for treating dry eye, and the provision of an aqueous suspension having excellent redispersibility according to the present disclosure is of great value.

[0066] Aqueous suspensions of the present disclosure may be administered by any suitable route as determined by one of 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, and the like.

[0067] (additives and / or excipients) Aqueous suspensions of the present disclosure may contain any pharma- ceutically acceptable additives and / or excipients known in the art, including, but not limited to, viscosity agents, stabilizers, pH adjusting agents, buffers, and preservatives.

[0068] The thickening agent is not particularly limited as long as it is pharmacologic 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, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc. These thickening agents may be used alone or in combination of two or more. From the viewpoint of redispersibility, cellulose-based polymers are preferred, and methyl cellulose is particularly preferred.

[0069] The stabilizer is not particularly limited as long as it is pharma- ceutically acceptable, but 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 suspension.

[0070] The pH adjuster is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid; and alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, and sodium carbonate. The content of the pH adjuster is, for example, 0 to about 20 w / v % based on the total amount of the aqueous suspension.

[0071] In one embodiment of the present disclosure, the aqueous suspension of the present disclosure can be mixed with a pH adjuster as described above as necessary to adjust the pH to usually 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.

[0072] The buffer used in the aqueous suspension of the present disclosure is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include borate buffer, phosphate buffer, Tris buffer, citrate buffer, tartrate buffer, acetate buffer, amino acid buffer, etc., but from the viewpoint of redispersibility or stability of the aqueous suspension, borate buffer or phosphate buffer is preferred, and borate buffer is particularly preferred.

[0073] 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%.

[0074] The boric acid buffer is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include boric acid and / or its salts. The boric acid is not particularly limited as long as it is pharmaceutically acceptable, but 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, but 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. In addition, a preferred embodiment of the boric acid buffer is a combination of boric acid and borax.

[0075] When boric acid and borax are used in combination, the ratio of boric acid to borax is not particularly limited, but for example, 10 to 300 parts by mass, preferably 10 to 250 parts by mass, more preferably 30 to 100 parts by mass, and particularly preferably 40 to 60 parts by mass of borax per 100 parts by mass of boric acid.

[0076] 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; trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. Phosphate salts may be in the form of solvates such as hydrates, for example, dodecahydrates in the case of disodium hydrogen phosphate, and dihydrates in the case of sodium dihydrogen phosphate. Phosphate buffers may be one of phosphoric acid and its salts, and may be used alone or in combination of two or more. Among phosphoric acid and its salts, preferred are phosphates, more preferred are at least one of dialkali metal hydrogen phosphate and alkali metal dihydrogen phosphate, and particularly preferred are at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0077] Examples of the tris buffer include tris (also known as trishydroxymethylaminomethane) and / or a salt thereof. Examples of the tris salt include, but are not limited to, acetate, hydrochloride, maleate, sulfonate, and other salts, as long as they are pharmaceutically acceptable. The tris acid buffer may be used alone by selecting one from tris and its salts, or may be used in combination of two or more. In another embodiment, the tris buffer specifically includes trometamol and / or a salt thereof. Examples of the trometamol salt include, but are not limited to, pharmaceutically acceptable salts, such as organic acid salts such as acetate; and inorganic acid salts such as hydrochloride and sulfonate. The tris acid buffer may be used alone by selecting one from trometamol and its salts, or may be used in combination of two or more. Among trometamol and its salts, trometamol is preferred.

[0078] Specific examples of the citrate buffer include citric acid and / or its salts. The citrate salt is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt. The citrate salt may be in the form of a solvate such as a hydrate. As the citrate buffer, one of citric acid and its salts may be selected and used alone, or two or more of them may be used in combination. Among citric acid and its salts, preferred are citric acid salts, more preferred are alkali metal salts of citric acid, and particularly preferred is sodium citrate.

[0079] Specifically, the tartaric acid buffer includes tartaric acid and / or its salt. The salt of tartaric acid is not particularly limited as long as it is pharma- ceutically acceptable, and includes, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt. The salt of tartaric acid may also be in the form of a solvate such as a hydrate. As the tartaric acid buffer, one of tartaric acid and its salts may be selected and used alone, or two or more of them may be used in combination.

[0080] Specific examples of the acetate buffer include acetic acid and / or its salts. The acetate salt is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and ammonium salt. The acetate salt may also be in the form of a solvate such as a hydrate. As the acetate buffer, one of acetic acid and its salts may be selected and used alone, or two or more of them may be used in combination.

[0081] 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 pharmacologic acceptable, and examples of the salts include alkali metal salts such as sodium salts and potassium salts. As the amino acid buffer, one of the acidic amino acids and its salts may be selected and used alone, or two or more of them may be used in combination.

[0082] The preservative is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include sorbic acid, potassium sorbate, paraoxybenzoic acid esters such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride, as well as quaternary ammonium salts, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, and chlorhexidine. The content of the preservative can be appropriately varied depending on the type of the preservative, and may be, for example, about 0.0001 w / v% to about 0.2 w / v% based on the total amount of the aqueous suspension.

[0083] 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, adjusted to a predetermined osmotic pressure, and subjected to a sterilization treatment such as filtration sterilization.

[0084] (container) The container for containing the aqueous suspension of the present disclosure is not particularly limited, and may be, for example, a glass container or a plastic container. The plastic container may be made of any material, such as polyester (polyethylene terephthalate, polyarylate), polycarbonate, polyethylene, polypropylene, a mixture thereof, or a mixture of these and other materials. The container used in the present disclosure may be one used in the medical field or may be other than those. In one embodiment, the container may be made of any material that meets the "Standard for Plastic Containers for Eye Drops" in Japan or other equivalent standards.

[0085] The shape of the container to be used may be any shape, and generally any shape suitable for eye drops can be used.

[0086] In certain embodiments, the aqueous suspensions of the present disclosure can be filled into any eye drop container commonly used in the medical field, such as polyethylene (preferably low density polyethylene) or polypropylene, preferably colorless polypropylene containers.

[0087] (General technology) 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, FM (1987). Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Ausubel, FM (1989). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience; Innis, MA (1990). PCR Protocols: A Guide to Methods and Applications, Academic Press; Ausubel, FM (1992). Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Ausubel, FM(1995).Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Greene Pub. Associates; Innis, MA et al.(1995).PCR Strategies, Academic Press; Ausubel, FM(1999).Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, Wiley, and annual updates; Sninsky, JJet al.(1999).PCR Applications: Protocols for Functional Genomics, Academic Press, Gait, MJ(1985).Oligonucleotide Synthesis: A Practical Approach, IRL Press; Gait, MJ(1990).Oligonucleotide Synthesis: A Practical Approach, IRL Press; Eckstein, F. (1991).Oligonucleotides and Analogues: A Practical Approach, IRL Press; Adams, RL et al.(1992).The Biochemistry of the Nucleic Acids, Chapman & Hall; Shabarova, Z. et al.(1994).Advanced Organic Chemistry of Nucleic Acids, Weinheim; Blackburn, GM et al.(1996).Nucleic Acids in Chemistry and Biology, Oxford University Press; Hermanson, GT (1996). Bioconjugate Techniques, Academic Press, Special Edition of Experimental Medicine "Gene Introduction & Expression Analysis Experimental Methods" Yodosha, 1997, etc. These are incorporated herein by reference in their relevant parts (possibly in their entirety).

[0088] All references cited herein, including scientific literature, patents, patent applications, and the like, are hereby incorporated by reference in their entirety to the same extent as if each was specifically set forth.

[0089] The present disclosure has been described above by showing preferred embodiments for ease of understanding. The present disclosure will be described below based on examples, but the above description and the following examples are provided for illustrative purposes only and are not provided for the purpose of limiting the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described in this specification, but is limited only by the scope of the claims. EXAMPLES

[0090] (Test Example 1: Change in redispersibility due to heat treatment temperature of pharmaceutical ingredients) Preparation of suspension A base solution was prepared according to the composition shown in Tables 1 and 2, and compound (1) was added thereto and stirred to obtain a suspension. Tyloxapol manufactured by AMRI Rensselaer (Curia Global, Inc.) was used. Compound (1) used was the above-mentioned type I crystal.

[0091] Containment in containers The prepared suspension was stirred with a stirrer and 5 mL of each solution was dispensed into eye drop containers. The eye drop containers used were colorless polyethylene containers (containers used for GatiFlo eye drops 0.3% (manufactured and sold by Senju Pharmaceutical Co., Ltd.)).

[0092] Redispersibility evaluation Evaluation method by inversion: It was confirmed that the suspended particles in the suspension filled in the eye drop container had completely settled. The inversion operation (the action of holding the container in the hand and turning it upside down) was repeated until the precipitate disappeared from the bottom and walls of the eye drop container and was redispersed. Note that one inversion was defined as the operation of turning the container 180° upside down at a speed of 1 second, then turning it 180° again to the upright state. The number of inversion operations required until the particles were redispersed was counted. The test was performed on 3 samples per formulation, and the average number of inversion operations was calculated.

[0093] Evaluation method by shaking: It was confirmed that the suspended particles in the suspension filled in the eye drop container had completely settled. Five shakings were counted as one set, and shaking was repeated until the precipitate had disappeared from the bottom and walls of the eye drop container. The shaking was performed at a speed of 1.1 seconds / set, with a width of 10 to 5 cm up and down, and one shaking was counted as shaking from down to returning to the original position. The number of sets required until the particles were redispersed was counted, and the number of shakings was calculated.

[0094] Particle size measurement After shaking the sample until the precipitate was redispersed, about 1 mL of the sample was dropped into the dispersion tank of a laser diffraction particle size distribution analyzer (SALD-2300). After ultrasonic treatment for 2 minutes, the particle size distribution was measured, and the values ​​of D10, D50, and D90 were taken as the particle diameters.

[0095] result The results are shown in Tables 1 and 2. The aqueous suspension in which compound (1) that had been heat-treated at 150 to 170° C. was dispersed had good redispersibility.

[0096] [Table 1]

[0097] [Table 2]

[0098] (Test Example 2: Heat Treatment Time) Preparation of suspension A base solution was prepared according to the composition shown in Table 3, and compound (1) was added thereto and dispersed by stirring to obtain a suspension.

[0099] Containment in containers The test was carried out in the same manner as in Test Example 1.

[0100] Redispersibility evaluation The test was carried out in the same manner as in Test Example 1.

[0101] result The results are shown in Table 3. When the heat treatment time was from 30 minutes to 5 hours, the aqueous suspension had good redispersibility.

[0102] [Table 3]

[0103] (Test Example 3: Changes in redispersibility due to differences in surfactants) Preparation of suspension A base solution was prepared according to the composition shown in Table 4, and compound (1) was added thereto and dispersed by stirring to obtain a suspension. Tyloxapol manufactured by AMRI Rensselaer (Curia Global, Inc.), polysorbate 80 manufactured by NOF Corp., polyethylene glycol monostearate 40 (MYS-40) manufactured by Nippon Surfactant Kogyo Co., Ltd., and polyoxyethylene hydrogenated castor oil 60 manufactured by Nippon Surfactant Kogyo Co., Ltd. were used. Compound (1) was the above-mentioned type I crystal.

[0104] Containment in containers The test was carried out in the same manner as in Test Example 1.

[0105] Redispersibility evaluation The test was carried out in the same manner as in Test Example 1.

[0106] result The results are shown in Table 4. When any of the nonionic surfactants was used, the aqueous suspensions in which compound (1) that had been heat-treated at 160° C. was dispersed showed good redispersibility.

[0107] [Table 4]

[0108] (Test Example 4: Surfactant Concentration) Preparation of suspension A base solution was prepared according to the composition shown in Table 5, and compound (1) was added thereto and stirred to obtain a suspension. Tyloxapol manufactured by AMRI Rensselaer (Curia Global, Inc.) was used. Compound (1) used was the above-mentioned type I crystal.

[0109] Containment in containers The test was carried out in the same manner as in Test Example 1.

[0110] Redispersibility evaluation The test was carried out in the same manner as in Test Example 1.

[0111] result The results are shown in Table 5. When the tyloxapol concentration was in the range of 0.01% to 0.04%, the aqueous suspension had good redispersibility.

[0112] [Table 5]

[0113] (Test Example 5: Changes in redispersibility due to differences in sterilization methods) Preparation of suspension A base solution was prepared according to the composition shown in Table 6, and compound (1) was added thereto and dispersed by stirring to obtain a suspension. Tyloxapol manufactured by AMRI Rensselaer (Curia Global, Inc.) was used. The above-mentioned I-type crystal was used as compound (1). In Comparative Example 7, compound (1) irradiated with about 25 kGy of electron beam was used, and in Example 13, compound (1) irradiated with about 25 kGy of gamma ray was used. In Example 14, compound (1) sterilized by dry heat treatment at 160°C for 2 hours was used.

[0114] Containment in containers The test was carried out in the same manner as in Test Example 1.

[0115] Redispersibility evaluation The test was carried out in the same manner as in Test Example 1.

[0116] result The results are shown in Table 6. The aqueous suspension in which the gamma-ray-treated compound (1) was dispersed had good redispersibility.

[0117] [Table 6]

[0118] (Test example: Stability of formulations using dry heat drug substance) Preparation of suspension A suspension was obtained according to the composition shown in Table 7. Tyloxapol manufactured by AMRI Rensselaer (Curia Global, Inc.) was used. The above-mentioned type I crystal was used as compound (1).

[0119] [Table 7]

[0120] Containment in containers The test was carried out in the same manner as in Test Example 1.

[0121] storage The storage conditions were as follows: Storage conditions: 60±2℃ (average 60.1℃), ambient humidity Storage period: Initial, 2 weeks, 4 weeks

[0122] pH measurement The pH was measured according to the pH measurement method of the Japanese Pharmacopoeia, i.e., using a pH meter with a glass electrode.

[0123] Osmolality measurement Osmolality was measured according to the Japanese Pharmacopoeia General Test Method, Osmolality Measurement Method (Osmolality Measurement Method).

[0124] Content measurement / impurity measurement In Example 15, the sample solution was prepared by diluting the solution 2-fold with acetonitrile. In Example 16, 2 mL of this product was accurately measured, and mobile phase B was added to dissolve the solution to make exactly 20 mL, which was used as the sample solution. Separately, about 20 mg of compound (1) was accurately measured, and mobile phase B was added to dissolve the solution to make exactly 20 mL, which was used as standard solution A. 2 mL of this liquid was accurately measured, and mobile phase B was added to make exactly 20 mL, which was used as standard solution B. Standard solution B was used in Example 15, and standard solution A in Example 16. 10 μL each of the sample solution and standard solution were accurately taken and tested by liquid chromatography under the following conditions.

[0125] Test conditions Detector: Ultraviolet spectrophotometer (measurement wavelength: 250 nm) Column: A commercially available column was used, which was a stainless steel tube having an inner diameter of 4.6 mm and a length of 250 mm packed with 5 μm octadecylsilylated silica gel for liquid chromatography. Column temperature: constant temperature around 40℃ Mobile phase A: Dissolve 1.79 g of disodium hydrogen phosphate dodecahydrate in 1000 mL of water. Add phosphoric acid to this solution to adjust the pH to 6.5. Add 350 mL of acetonitrile to 650 mL of this solution and mix. Mobile phase B: Acetonitrile / water mixture (80:20) Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was controlled by the linear concentration gradient shown in the table below.

[0126] Particle size measurement The test was carried out in the same manner as in Test Example 1.

[0127] result The results of n=3 are shown in Table 8. All samples showed storage stability for 4 weeks.

[0128] [Table 8]

[0129] (Note) As described above, the present disclosure has been illustrated using preferred embodiments of the present disclosure, but it is understood that the scope of the present disclosure should be interpreted only by the claims. It is understood that the patents, patent applications and other documents cited in this specification should be incorporated by reference to this specification in the same manner as if the contents themselves were specifically described in this specification. This application claims priority to Japanese Patent Application No. 2022-156060 filed on September 29, 2022 with the Japan Patent Office, and this application is incorporated by reference in its entirety. [Industrial Applicability]

[0130] The present disclosure can be used in the fields of medicine, pharmaceuticals, healthcare, biology, biochemistry, and the like.

Claims

1. An aqueous suspension comprising gamma ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof.

2. 2. The aqueous suspension of claim 1, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, is a powder.

3. 10. The aqueous suspension of claim 1 further comprising a non-ionic surfactant.

4. 4. The aqueous suspension according to any one of claims 1 to 3, wherein the gamma sterilization treatment comprises gamma radiation treatment at about 10 to about 50 kGy.

5. 5. The aqueous suspension of claim 4, wherein the gamma sterilization treatment comprises gamma radiation treatment at about 25 kGy.

6. 1. An aqueous suspension comprising a powder of gamma ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma-ceutically acceptable salt or solvate thereof, and a non-ionic surfactant, The gamma sterilization treatment comprises gamma radiation treatment at about 10 to about 50 kGy. Aqueous suspension.

7. 7. The aqueous suspension according to claim 3 or 6, wherein the concentration of the non-ionic surfactant in the aqueous suspension is from about 0.0001% w / v to about 1% w / v.

8. 7. The aqueous suspension according to claim 3 or 6, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil.

9. The concentration of the nonionic surfactant in the aqueous suspension is about 0.0001 w / v % to about 1 w / v %; The nonionic surfactant is tyloxapol, polysorbate 80, polymonostearate ethylene glycol, and polyoxyethylene hydrogenated castor oil 7. The aqueous suspension according to claim 3 or 6, which is at least one type.

10. 7. The aqueous suspension according to claim 1, wherein the concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof in the aqueous suspension is from about 0.01% w / v to about 5% w / v.

11. The aqueous suspension according to claim 1 to 3 or 6, 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.

12. An aqueous suspension comprising gamma-ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, wherein the powder of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma-ceutically acceptable salt or solvate thereof in the aqueous suspension has an average particle size (D50) of about 1 μm to about 10 μm.

13. 1. A method for producing an aqueous suspension comprising the steps of: (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy C-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or its drug subjecting the physiologically acceptable salt or solvate to gamma sterilization; mixing the gamma ray sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, with a solvent; method.

14. 14. The method of claim 13, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, or a pharma- ceutically acceptable salt or solvate thereof, is a powder.

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