Suspension containing heterocyclidene acetamide derivative

Abstract

To provide suspension eye drops having superior re-dispersibility.SOLUTION: The present disclosure provides an aqueous suspension agent that contains (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, a cellulose-based polymer, and a nonionic surfactant.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to the fields of medicine, healthcare, 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 to be at least 8 million, and the number is estimated to be approximately 22 million if potential patients who use over-the-counter eye drops without visiting a doctor are included. It is estimated that there are over 1 billion dry eye patients worldwide. In modern society, the use of television, computers, and mobile 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 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. For this reason, many of the dry eye medications currently on the market are frequently administered. For example, Diquas eye drops usually need to be administered six times a day, Hyalein eye drops five to six times a day, and Mucosta eye drops usually four times a day. Summary of the Invention [Means for solving the problem]

[0004] The present disclosure provides an aqueous suspension having excellent redispersibility, which contains (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide, which is a heterocyclideneacetamide derivative, or a pharmaceutically acceptable salt or solvate thereof.

[0005] Thus, the present disclosure provides: (Item 1) An aqueous suspension comprising (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 non-ionic surfactant. (Item 2) The aqueous suspension according to the preceding item, wherein the concentration of the cellulose polymer in the aqueous suspension is about 0.00007 w / v % to about 0.01 w / v %. (Item 2a) The aqueous suspension according to the preceding item, wherein the concentration of the cellulose polymer in the aqueous suspension is about 0.00007 w / v % to about 0.007 w / v %. (Item 3) The aqueous suspension according to any one of the preceding items, wherein the concentration of the cellulose polymer in the aqueous suspension is about 0.0001 w / v % to about 0.008 w / v %. (Item 3a) The aqueous suspension according to any one of the preceding items, wherein the concentration of the cellulose polymer in the aqueous suspension is about 0.0001 w / v % to about 0.005 w / v %. (Item 4) The aqueous suspension according to any one of the preceding items, wherein the cellulose-based polymer is at least one selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose. (Item 5) 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 0.5 w / v %. (Item 6) 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 6a) 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 7) 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 80, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil. (Item 8) 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 pharmaceutically acceptable salt or solvate thereof in the aqueous suspension is about 0.01 w / v% to about 5 w / v%. (Item 9) Item 10. The aqueous suspension of any one of the preceding items, further comprising a zinc salt or a silver salt. (Item 10) The aqueous suspension according to any one of the preceding items, wherein the concentration of the zinc salt or silver salt in the aqueous suspension is about 0.0001 w / v % to about 0.05 w / v %. (Item 11) Item 10. The aqueous suspension of any one of the preceding items, wherein the zinc salt is zinc chloride or zinc sulfate. (Item 11a) Item 10. The aqueous suspension of any one of the preceding items, wherein the silver salt is silver nitrate. (Item 12) 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 13) Item 10. The aqueous suspension of any one of the preceding items, further comprising a borate buffer. (Item 14) The aqueous suspension according to any one of the preceding items, wherein the pH of the aqueous suspension is about 4 to about 8. (Item 15) The aqueous suspension 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 pharmaceutically acceptable salt or solvate thereof, in the aqueous suspension is improved. (Item 16) Item 10. The aqueous suspension according to any one of the preceding items, wherein the improved redispersibility is such that the suspended particles are redispersed after about 15 or fewer shakings, as assessed by shaking. (Item 17) 2. The aqueous suspension according to claim 1, wherein the improved redispersibility is such that the suspended particles redisperse after about 40 or fewer inversions, as assessed by inversion. (Item 18) The aqueous suspension according to any one of the preceding items, wherein the stability of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or its pharmaceutically acceptable salt or solvate in the aqueous suspension is improved. (Item 19) The aqueous suspension 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 pharmaceutically acceptable salt or solvate thereof in the aqueous suspension is improved, and 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 suspension is improved. (Item 20) The aqueous suspension according to any one of the preceding items, wherein the average particle size 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 suspension is about 1 μm to about 5 μm. (Item 21) 2. The aqueous suspension according to any one of the preceding items, wherein the aqueous suspension is contained in a plastic container. (Item 22) Item 10. The aqueous suspension according to any one of the preceding items, wherein the plastic container is made of polyethylene or polypropylene. (Item 23) An aqueous suspension comprising (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 cellulosic polymer, and a non-ionic surfactant, the concentration of the cellulose polymer in the aqueous suspension is about 0.0001 w / v% to about 0.005 w / v%, the cellulose-based polymer is at least one selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.05 w / v %, the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, and polyethylene glycol monostearate; 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 suspension is about 0.01 w / v% to about 5 w / v%. Aqueous suspension. (Item 24) An aqueous suspension comprising (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 cellulosic polymer, and a non-ionic surfactant, the concentration of the cellulose polymer in the aqueous suspension is about 0.0001 w / v% to about 0.005 w / v%, the cellulose-based polymer is at least one selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.05 w / v %, the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, and polyethylene glycol monostearate; further comprising a zinc salt or a silver salt, and a borate buffer; the zinc salt or silver salt is at least one selected from the group consisting of zinc chloride, zinc sulfate, and silver nitrate; the concentration of the zinc salt or silver salt in the aqueous suspension is about 0.0005 w / v% to about 0.01 w / v%, the pH of the aqueous suspension is about 4 to about 8; 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 suspension is about 0.01 w / v% to about 5 w / v%. Aqueous suspension. (Item 25) An aqueous suspension comprising (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 cellulosic polymer, and a non-ionic surfactant, the concentration of the cellulose polymer in the aqueous suspension is about 0.0001 w / v% to about 0.005 w / v%, the cellulosic polymer is methylcellulose; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.05 w / v %, the nonionic surfactant is tyloxapol; Further containing zinc chloride and borate buffer, the concentration of the zinc chloride in the aqueous suspension is about 0.0005 w / v% to about 0.01 w / v%, the pH of the aqueous suspension is about 4 to about 8; 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 suspension is about 0.01 w / v% to about 5 w / v%. Aqueous suspension. (Item 26) An aqueous suspension comprising (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 cellulosic polymer, and a non-ionic surfactant, the concentration of the cellulose polymer in the aqueous suspension is about 0.0005 w / v% to about 0.003 w / v%, the cellulosic polymer is methylcellulose; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.03 w / v %, the nonionic surfactant is tyloxapol; Further, it contains a borate buffer, the pH of the aqueous suspension is about 6.0 to about 8.0; 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 suspension is about 0.3 w / v % to about 1.0 w / v %; 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; Aqueous suspension. (Item 27) An aqueous suspension comprising (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 cellulosic polymer, and a non-ionic surfactant, the concentration of the cellulose polymer in the aqueous suspension is about 0.0005 w / v% to about 0.003 w / v%, the cellulosic polymer is methylcellulose; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.03 w / v %, the nonionic surfactant is tyloxapol; Further containing zinc chloride and borate buffer, the concentration of the zinc chloride in the aqueous suspension is about 0.001 w / v% to about 0.005 w / v%, the pH of the aqueous suspension is about 6.0 to about 8.0; 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 suspension is about 0.3 w / v % to about 1.0 w / v %; 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, The aqueous suspension is contained in a plastic container. Aqueous suspension. (Item A1) An aqueous suspension comprising (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 B1) An aqueous suspension comprising (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 non-ionic surfactant, and a zinc salt or a silver salt. (Item B2) 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 0.5 w / v %. (Item B2a) 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 B3) 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 B4) 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 80, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil. (Item B5) 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 pharmaceutically acceptable salt or solvate thereof in the aqueous suspension is about 0.01 w / v% to about 5 w / v%. (Item B6) The aqueous suspension according to any one of the preceding items, wherein the concentration of the zinc salt or silver salt in the aqueous suspension is about 0.0001 w / v % to about 0.05 w / v %. (Item B7) Item 10. The aqueous suspension of any one of the preceding items, wherein the zinc salt is zinc chloride or zinc sulfate. (Item B7a) Item 10. The aqueous suspension of any one of the preceding items, wherein the silver salt is silver nitrate. (Item B8) Item 10. The aqueous suspension of any one of the preceding items, further comprising a cellulosic polymer. (Item B9) The aqueous suspension according to the preceding item, wherein the concentration of the cellulose polymer in the aqueous suspension is about 0.00007 w / v % to about 0.01 w / v %. (Item B9a) The aqueous suspension according to the preceding item, wherein the concentration of the cellulose polymer in the aqueous suspension is about 0.00007 w / v % to about 0.007 w / v %. (Item B10) The aqueous suspension according to any one of the preceding items, wherein the concentration of the cellulose polymer in the aqueous suspension is about 0.0001 w / v % to about 0.008 w / v %. (Item B10a) The aqueous suspension according to any one of the preceding items, wherein the concentration of the cellulose polymer in the aqueous suspension is about 0.0001 w / v % to about 0.005 w / v %. (Item B11) The aqueous suspension according to any one of the preceding items, wherein the cellulose-based polymer is at least one selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose. (Item B12) 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 B13) Item 10. The aqueous suspension of any one of the preceding items, further comprising a borate buffer. (Item B14) The aqueous suspension according to any one of the preceding items, wherein the pH of the aqueous suspension is about 4 to about 8. (Item B15) The aqueous suspension 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 pharmaceutically acceptable salt or solvate thereof, in the aqueous suspension is improved. (Item B16) Item 10. The aqueous suspension according to any one of the preceding items, wherein the improved redispersibility is such that the suspended particles are redispersed after about 15 or fewer shakings, as assessed by shaking. (Item B17) 2. The aqueous suspension according to claim 1, wherein the improved redispersibility is such that the suspended particles redisperse after about 40 or fewer inversions, as assessed by inversion. (Item B18) The aqueous suspension according to any one of the preceding items, wherein the stability of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or its pharmaceutically acceptable salt or solvate in the aqueous suspension is improved. (Item B19) The aqueous suspension 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 pharmaceutically acceptable salt or solvate thereof in the aqueous suspension is improved, and 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 suspension is improved. (Item B20) The aqueous suspension according to any one of the preceding items, wherein the average particle size 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 suspension is about 1 μm to about 5 μm. (Item B21) 2. The aqueous suspension according to any one of the preceding items, wherein the aqueous suspension is contained in a plastic container. (Item B22) Item 10. The aqueous suspension according to any one of the preceding items, wherein the plastic container is made of polyethylene or polypropylene. (Item B23) 1. An aqueous suspension comprising (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 non-ionic surfactant, and a zinc salt or a silver salt, the concentration of the nonionic surfactant in the aqueous suspension is about 0.0001 w / v % to about 0.5 w / v %, the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, and polyethylene glycol monostearate; the concentration of the zinc salt or silver salt in the aqueous suspension is about 0.0005 w / v% to about 0.01 w / v%, the zinc salt or silver salt is at least one selected from the group consisting of zinc chloride, zinc sulfate, and silver nitrate; 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 suspension is about 0.01 w / v% to about 5 w / v%. Aqueous suspension. (Item B24) 1. An aqueous suspension comprising (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 non-ionic surfactant, and a zinc salt or a silver salt, the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.05 w / v %, the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, and polyethylene glycol monostearate; the concentration of the zinc salt or silver salt in the aqueous suspension is about 0.0005 w / v% to about 0.01 w / v%, the zinc salt or silver salt is at least one selected from the group consisting of zinc chloride, zinc sulfate, and silver nitrate; 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 suspension is about 0.01 w / v% to about 5 w / v%. Aqueous suspension. (Item B25) 1. An aqueous suspension comprising (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 non-ionic surfactant, and a zinc salt; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.03 w / v %, the nonionic surfactant is tyloxapol; the concentration of the zinc salt in the aqueous suspension is about 0.001 w / v % to about 0.005 w / v %, the zinc salt is zinc chloride; Further, it contains a borate buffer, the pH of the aqueous suspension is about 6.0 to about 8.0; 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 suspension is about 0.3 w / v % to about 1.0 w / v %; 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, The aqueous suspension is contained in a plastic container. Aqueous suspension. (Item C1) An aqueous suspension comprising (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 D1a) 1. A method for improving the redispersibility of an aqueous suspension comprising (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: A method comprising the step of preparing an aqueous suspension by mixing (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 cellulosic polymer, and a non-ionic surfactant. (Item D1b) 1. A method for improving the redispersibility of an aqueous suspension comprising (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: A method comprising the step of adding a cellulosic polymer and a nonionic surfactant to 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. (Item D2) The method according to the preceding items, wherein the concentration of the cellulose-based polymer in the aqueous suspension is about 0.00007 w / v % to about 0.01 w / v %. (Item D2a) The method according to the preceding items, wherein the concentration of the cellulose-based polymer in the aqueous suspension is about 0.00007 w / v % to about 0.007 w / v %. (Item D3) The method according to any one of the preceding items, wherein the concentration of the cellulose-based polymer in the aqueous suspension is about 0.0001 w / v % to about 0.008 w / v %. (Item D3a) The method according to any one of the preceding items, wherein the concentration of the cellulose-based polymer in the aqueous suspension is about 0.0001 w / v % to about 0.005 w / v %. (Item D4) The method according to any one of the preceding items, wherein the cellulose-based polymer is at least one selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose. (Item D5) 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 0.5 w / v %. (Item D6) 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 0.1 w / v %. (Item D6a) 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 D7) 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 80, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil. (Item D8) 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 suspension is about 0.01 w / v% to about 5 w / v%. (Item D9) The method of any one of the preceding items, further comprising the step of mixing a zinc salt or a silver salt. (Item D10) The method according to any one of the preceding items, wherein the concentration of the zinc salt or silver salt in the aqueous suspension is about 0.0001 w / v % to about 0.05 w / v %. (Item D11) The method of any one of the preceding items, wherein the zinc salt is zinc chloride or zinc sulfate. (Item D11a) Item 10. The method of any one of the preceding items, wherein the silver salt is silver nitrate. (Item D12) 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 D13) The method according to any one of the preceding items, further comprising the step of mixing a borate buffer. (Item D14) The method according to any one of the preceding items, wherein the aqueous suspension has a pH of about 4 to about 8. (Item D15) 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 pharmaceutically acceptable salt or solvate thereof, in the aqueous suspension is improved. (Item D16) The method according to any one of the preceding items, wherein the improved redispersibility comprises the suspended particles being redispersed after about 15 or fewer shakings, as assessed by shaking. (Item D17) Item 10. The method of any one of the preceding items, wherein the improved redispersibility comprises redispersing the suspended particles after about 40 or fewer inversions, as assessed by inversion. (Item D18) The method according to any one of the preceding items, wherein the stability of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or its pharmaceutically acceptable salt or solvate in the aqueous suspension is improved. (Item D19) 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 pharmaceutically acceptable salt or solvate thereof in the aqueous suspension is improved, and 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 suspension is improved. (Item D20) 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 its pharmaceutically acceptable salt or solvate in the aqueous suspension is about 1 μm to about 5 μm. (Item D21) Item 10. The method of any one of the preceding items, wherein the aqueous suspension is contained in a plastic container. (Item D22) The method according to any one of the preceding items, wherein the plastic container is made of polyethylene or polypropylene. (Item D23) 1. A method for improving the redispersibility of an aqueous suspension comprising (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: preparing an aqueous suspension by mixing (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 cellulosic polymer, and a nonionic surfactant; the concentration of the cellulose polymer in the aqueous suspension is about 0.0001 w / v% to about 0.005 w / v%, the cellulose-based polymer is at least one selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.05 w / v %, the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, and polyethylene glycol monostearate; 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 suspension is about 0.01 w / v% to about 5 w / v%. method. (Item D24) 1. A method for improving the redispersibility of an aqueous suspension comprising (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: preparing an aqueous suspension by mixing (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 cellulosic polymer, and a nonionic surfactant; further comprising the step of combining a zinc salt or a silver salt and a borate buffer; the concentration of the cellulose polymer in the aqueous suspension is about 0.0001 w / v% to about 0.005 w / v%, the cellulose-based polymer is at least one selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.05 w / v %, the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, and polyethylene glycol monostearate; the zinc salt or silver salt is at least one selected from the group consisting of zinc chloride, zinc sulfate, and silver nitrate; the concentration of the zinc salt or silver salt in the aqueous suspension is about 0.0005 w / v% to about 0.01 w / v%, the pH of the aqueous suspension is about 4 to about 8; 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 suspension is about 0.01 w / v% to about 5 w / v%. method. (Item D25) 1. A method for improving the redispersibility of an aqueous suspension comprising (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: preparing an aqueous suspension by mixing (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 cellulosic polymer, and a nonionic surfactant; further comprising the step of mixing zinc chloride and a borate buffer; the concentration of the cellulose polymer in the aqueous suspension is about 0.0001 w / v% to about 0.005 w / v%, the cellulosic polymer is methylcellulose; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.05 w / v %, the nonionic surfactant is tyloxapol; the concentration of the zinc chloride in the aqueous suspension is about 0.0005 w / v% to about 0.01 w / v%, the pH of the aqueous suspension is about 4 to about 8; 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 suspension is about 0.01 w / v% to about 5 w / v%. method. (Item D26) 1. A method for improving the redispersibility of an aqueous suspension comprising (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: preparing an aqueous suspension by mixing (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 cellulosic polymer, and a nonionic surfactant; further comprising the step of mixing a borate buffer; the concentration of the cellulose polymer in the aqueous suspension is about 0.0005 w / v% to about 0.003 w / v%, the cellulosic polymer is methylcellulose; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.03 w / v %, the nonionic surfactant is tyloxapol; the pH of the aqueous suspension is about 6.0 to about 8.0; 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 suspension is about 0.3 w / v % to about 1.0 w / v %; The method, 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 D27) 1. A method for improving the redispersibility of an aqueous suspension comprising (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: preparing an aqueous suspension by mixing (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 cellulosic polymer, and a nonionic surfactant; further comprising the step of mixing zinc chloride and a borate buffer; the concentration of the cellulose polymer in the aqueous suspension is about 0.0005 w / v% to about 0.003 w / v%, the cellulosic polymer is methylcellulose; the concentration of the nonionic surfactant in the aqueous suspension is about 0.01 w / v % to about 0.03 w / v %, the nonionic surfactant is tyloxapol; the concentration of the zinc chloride in the aqueous suspension is about 0.001 w / v% to about 0.005 w / v%, the pH of the aqueous suspension is about 6.0 to about 8.0; 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 suspension is about 0.3 w / v % to about 1.0 w / v %; 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, The aqueous suspension is contained in a plastic container. (Item E1) 1. A method for improving the redispersibility of an aqueous suspension comprising (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: A method comprising the step of preparing an aqueous suspension by mixing (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 non-ionic surfactant. (Item F1) 1. A method for improving the redispersibility of an aqueous suspension comprising (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: A method comprising the step of preparing an aqueous suspension by mixing (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 non-ionic surfactant, and a zinc salt or a silver salt. (Item G1) 1. A method for improving the stability of 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, comprising: A method comprising the step of mixing (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 tyloxapol to prepare an aqueous suspension. [Effects of the Invention]

[0006] According to the present disclosure, an aqueous suspension having excellent redispersibility can be provided.

[0007] By providing the above-mentioned features, the present disclosure can suppress the phenomenon of non-uniform dispersion of suspended particles, enable stable administration of the required amount of active ingredient, and realize stable and sufficient exertion of pharmacological effects, thereby contributing to improved patient adherence and convenience. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 is a graph showing the transmittance at each wavelength of each bottle (colorless PE, colorless PP, brown PE). DETAILED DESCRIPTION OF THE INVENTION

[0009] 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 art 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.

[0010] (definition) In this specification, unless otherwise specified, the term "about" means ±10% of the following numerical value.

[0011] 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." When "within a range" of "two values" is specified in this specification, the range includes the two values ​​themselves.

[0012] As used herein, the term "aqueous suspension" is used in the same sense as the term is used in the art, and refers to a liquid agent containing at least a portion 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 is in the form of suspended particles, but some of it is in a dissolved state.

[0013] 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.

[0014] 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 single 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.

[0015] As used herein, "redispersibility" refers to the ease with which particles that have settled in the solvent of a liquid containing particles, such as a suspension (also referred to as "suspended particles"), can be dispersed again uniformly throughout the liquid by storing the liquid for a certain period of time. As used herein, "redispersibility" is evaluated by a test using a shaking or inversion procedure.

[0016] As used herein, "shaking" refers to the act of holding a container filled with an "aqueous suspension" and shaking it up and down by hand. The "shaking" operation involves shaking the container up and down in a 10-15 cm increment, then shaking it up and back down to its original position, counting as one shaking session, with five shaking sessions at a speed of 1.1 seconds per set. Tests of redispersibility by "shaking" are performed on 3-5 samples per formulation, and the average number of sets required for each sample to be redispersed is calculated. This average number is then used as the number of shaking sessions.

[0017] In this specification, "inversion" refers to the action of holding a container filled with an "aqueous suspension" and turning it upside down in one hand. The redispersibility test using "inversion" is performed on 3 to 5 specimens per formulation, and one inversion is defined as the operation of inverting the container 180° upside down at a rate of 1 second, then inverting it again 180° to return it to the upright position.

[0018] In this specification, "improved redispersibility" means 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 "shaking operations" or "inversion operations" described above is reduced, it can be said that redispersibility has been improved.

[0019] 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 suspension is maintained without being altered by decomposition or the like after storage for a certain period of time. Furthermore, in this specification, "stability" is evaluated by 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 suspension that has been prepared and stored for a certain period of time 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 suspension immediately after preparation. Typically, this evaluation is determined by evaluating 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 suspension.

[0020] In this specification, "improved stability" means that the stability is improved when the content retention rate is high in comparison with any formulation.

[0021] 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 pharmaceutically acceptable salt or solvate thereof. 50 ) and is a value measured using a laser diffraction particle size distribution analyzer.

[0022] As used herein, the term "cellulose-based polymer" refers to a type of water-soluble polymer, a cellulose derivative in which the hydroxyl groups of cellulose have been partially converted to other substituents. Examples of cellulose-based polymers include methyl cellulose (hereinafter sometimes referred to as "MC"), hydroxypropyl methyl cellulose, carboxymethyl cellulose (hereinafter sometimes referred to as "CMC"), ethyl cellulose, propyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and sulfonated cellulose derivatives.

[0023] 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. 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.), 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.).

[0024] In this specification, the term "zinc salt" refers to a compound having zinc ions (Zn 2+(compounds of zinc with organic or inorganic acids) or zinc oxides. Examples include zinc halides such as zinc chloride, zinc bromide, and zinc fluoride, zinc sulfate, zinc acetate, zinc phosphate, zinc carbonate, zinc hydroxide, zinc citrate, zinc lactate, zinc gluconate, zinc oxide, and hydrates thereof.

[0025] In this specification, the term "silver salt" refers to a silver salt having silver ions (Ag + Silver oxide refers to a salt (a compound of silver with an organic or inorganic acid) containing silver, or a silver oxide. Examples include silver nitrate, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate, silver protein, and their hydrates.

[0026] (aqueous suspension) The present disclosure may provide an aqueous suspension comprising (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.

[0027] The present disclosure may provide an aqueous suspension comprising (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 non-ionic surfactant.

[0028] The present disclosure may provide an aqueous suspension comprising (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 nonionic surfactant, and a zinc salt or a silver salt.

[0029] The present disclosure may provide an aqueous suspension comprising (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, a nonionic surfactant, and a zinc salt or a silver salt.

[0030] In one aspect of the present disclosure, there may be provided a method for improving the redispersibility of suspended particles 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 method comprising the step of mixing (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 nonionic surfactant to prepare an aqueous suspension.

[0031] In yet another aspect, there can be provided a method for improving the redispersibility of suspended particles 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 method comprising the step of preparing an aqueous suspension by mixing (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.

[0032] In yet another aspect, there can be provided a method for improving the redispersibility of suspended particles 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 method comprising the step of mixing (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 nonionic surfactant, and a zinc salt or a silver salt to prepare an aqueous suspension.

[0033] In yet another aspect, there can be provided a method for improving the redispersibility of suspended particles 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 method comprising the step of preparing an aqueous suspension by mixing (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, a nonionic surfactant, and a zinc salt or a silver salt.

[0034] In another aspect of the present disclosure, there may be provided a method for improving the redispersibility of an aqueous suspension comprising (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 step of adding a cellulosic polymer to an aqueous suspension comprising (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.

[0035] In another aspect of the present disclosure, there may be provided a method for improving the redispersibility of an aqueous suspension comprising (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 step of adding a nonionic surfactant to an aqueous suspension comprising (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.

[0036] In another aspect of the present disclosure, there may be provided a method for improving the redispersibility of an aqueous suspension comprising (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 step of adding a zinc salt or a silver salt to an aqueous suspension comprising (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.

[0037] In another aspect of the present disclosure, there may be provided a method for improving the redispersibility of an aqueous suspension comprising (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 step of adding a cellulose-based polymer and a nonionic surfactant to an aqueous suspension comprising (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.

[0038] In another aspect of the present disclosure, there may be provided a method for improving the redispersibility of an aqueous suspension comprising (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 step of adding a nonionic surfactant and a zinc salt or a silver salt to an aqueous suspension comprising (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.

[0039] In another aspect of the present disclosure, there may be provided a method for improving the redispersibility of an aqueous suspension comprising (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 step of adding a cellulose-based polymer and a zinc salt or a silver salt to an aqueous suspension comprising (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.

[0040] In another aspect of the present disclosure, there may be provided a method for improving the redispersibility of an aqueous suspension comprising (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 step of adding a cellulose-based polymer, a nonionic surfactant, and a zinc salt or a silver salt to an aqueous suspension comprising (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.

[0041] (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 is 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)).

[0042] 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.

[0043] 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 also form a solvate with a solvent such as water or ethanol.

[0044] (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.

[0045] 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.

[0046] 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, causing hyperalgesia. Therefore, TRPV1 has attracted attention as a potential drug target for pain treatment.

[0047] 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).

[0048] In 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 mixed with a cellulose-based polymer and a nonionic surfactant 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 pharmaceutically acceptable salt or solvate thereof.

[0049] In another aspect of the present disclosure, a composition for improving the redispersibility of an aqueous suspension 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 provided, the composition comprising a nonionic surfactant.

[0050] In another aspect of the present disclosure, a composition for improving the redispersibility of an aqueous suspension 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 provided, the composition comprising a cellulosic polymer.

[0051] In another aspect of the present disclosure, a composition for improving the redispersibility of an aqueous suspension 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 provided, the composition comprising a cellulose-based polymer and a nonionic surfactant.

[0052] In another aspect of the present disclosure, there can be provided a composition for improving the redispersibility of an aqueous suspension 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 composition comprising a cellulose-based polymer and a zinc salt or a silver salt.

[0053] In yet another aspect of the present disclosure, there can be provided a composition for improving the redispersibility of an aqueous suspension 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 composition comprising a nonionic surfactant and a zinc salt or a silver salt.

[0054] In another aspect of the present disclosure, there can be provided a composition for improving the redispersibility of an aqueous suspension 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 composition comprising a cellulose-based polymer, a nonionic surfactant, and a zinc salt or a silver salt.

[0055] 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 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.

[0056] 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 pharmaceutically acceptable salt or solvate thereof is used, it can 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.

[0057] In one embodiment of the present disclosure, the cellulose-based polymer is not particularly limited as long as it is pharmaceutically acceptable, and may include methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, ethyl cellulose, propyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sulfonated cellulose derivatives, or pharmaceutically acceptable salts thereof. These cellulose-based polymer compounds may be used alone or in combination of two or more. From the viewpoint of redispersibility of aqueous suspensions, methyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose are preferred as the cellulose-based polymer.

[0058] Cellulose-based polymers are linear, water-soluble polymers with glucose as a basic unit. When a cellulose-based polymer is blended into an aqueous suspension containing compound (1), the cellulose-based polymer is appropriately distributed around the suspended particles in the presence of a nonionic surfactant. It is also known that cellulose molecules in cellulose-based polymers form a sheet structure. Without being bound by theory, it is believed that the presence of this sheet structure covering the suspended particles maintains an appropriate distance between the particles, contributing to the formation of a bulky sedimentation layer. It is also believed that, without being bound by theory, when the suspended particles settle, adjusting the concentration of the cellulose-based polymer relative to the suspended particles provides an appropriate steric hindrance, forming a bulky sedimentation layer and enabling the preparation of an aqueous suspension with good redispersibility. Therefore, in one embodiment of the present disclosure, the use of a cellulose-based polymer is expected to enable the preparation of an aqueous suspension with excellent redispersibility.

[0059] On the other hand, carboxyvinyl polymers and polyvinylpyrrolidone have main chain structures of acrylic acid and N-vinyl-2-pyrrolidone, respectively, and are water-soluble polymers that do not form a three-dimensional structure such as a sheet. When these water-soluble polymers are distributed around suspended particles, they are thought to be less effective at maintaining the distance between suspended particles than cellulose-based polymers.

[0060] In one embodiment of the present disclosure, the methyl cellulose used is not particularly limited, and any methyl cellulose with different methoxy group substitution rates, molecular weights, viscosities, etc. may be used, either alone or in combination. The methoxy group substitution rate of methyl cellulose is typically in the range of about 20 to about 40%, preferably 26 to 33%. Furthermore, the viscosity of methyl cellulose (referring to the viscosity of a 2 wt% aqueous solution at 20°C) is typically 1 to 10,000 mPa·s, preferably 3 to 3,000 mPa·s, more preferably 4 to 1,500 mPa·s, particularly preferably 3 to 50 mPa·s, and even more preferably 10 to 20 mPa·s. Commercially available products include, for example, Metolose SM-4, Metolose SM-15, Metolose SM-25, SM-100, SM-400, Metolose SM-1500, and SM-4000 (Shin-Etsu Chemical Co., Ltd.).

[0061] In one embodiment of the present disclosure, the cellulose-based polymer can be present in the aqueous suspension of the present disclosure at a concentration of typically about 0.00007 w / v% to about 0.01 w / v%, preferably about 0.0001 w / v% to about 0.008 w / v%, more preferably about 0.0005 w / v% to about 0.005 w / v%, particularly preferably about 0.0006 w / v% to about 0.003 w / v%, even more preferably about 0.0007 w / v% to about 0.002 w / v%, and most preferably about 0.0008 w / v% to about 0.001 w / v%.

[0062] In another embodiment of the present disclosure, the cellulose-based polymer can be present in the aqueous suspension of the present disclosure at a concentration of typically about 0.00007 w / v% to about 0.007 w / v%, preferably about 0.0001 w / v% to about 0.005 w / v%, more preferably about 0.0003 w / v% to about 0.004 w / v%, particularly preferably about 0.0005 w / v% to about 0.003 w / v%, even more preferably about 0.0007 w / v% to about 0.001 w / v%, and most preferably about 0.001 w / v%.

[0063] In one embodiment of the present disclosure, when methylcellulose is used as the cellulose-based polymer, it can be present in the aqueous suspension of the present disclosure at a concentration of typically about 0.00007 w / v% to about 0.007 w / v%, preferably about 0.0001 w / v% to about 0.005 w / v%, more preferably about 0.0003 w / v% to about 0.004 w / v%, particularly preferably about 0.0005 w / v% to about 0.003 w / v%, even more preferably about 0.0007 w / v% to about 0.001 w / v%, and most preferably about 0.001 w / v%.

[0064] 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. From the viewpoint of redispersibility or stability of the aqueous suspension, the nonionic surfactant is preferably tyloxapol, polysorbate 80, polyethylene glycol monostearate, or polyoxyethylene hydrogenated castor oil 60, more preferably tyloxapol, polysorbate 80, or polyethylene glycol monostearate, and even more preferably tyloxapol.

[0065] 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 0.5 w / v%, preferably about 0.0001 w / v% to about 0.1 w / v%, and more preferably about 0.01 w / v% to about 0.005 w / v%.

[0066] In other embodiments 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 0.5 w / v%, preferably about 0.005 w / v% to about 0.1 w / v%, more preferably about 0.01 w / v% to about 0.05 w / v%, and particularly preferably about 0.01 w / v% to about 0.03 w / v%.

[0067] In one embodiment of the present disclosure, when tyloxapol is used as the nonionic surfactant, it can be present in the aqueous suspension of the present disclosure at a concentration of about 0.0001 w / v% to about 0.5 w / v%, preferably about 0.005 w / v% to about 0.1 w / v%, more preferably about 0.01 w / v% to about 0.05 w / v%, and particularly preferably about 0.01 w / v% to about 0.03 w / v%.

[0068] In one embodiment of the present disclosure, zinc salts that can be added to the aqueous suspension of the present disclosure include zinc halides such as zinc chloride, zinc bromide, or zinc fluoride, zinc sulfate, zinc acetate, zinc phosphate, zinc carbonate, zinc hydroxide, zinc citrate, zinc lactate, zinc gluconate, zinc oxide, or hydrates thereof.

[0069] In one embodiment of the present disclosure, the zinc salt can be present in the aqueous suspension of the present disclosure at a concentration of about 0.0001 w / v% to about 0.05 w / v%, more preferably about 0.0005 w / v% to about 0.01 w / v%, and particularly preferably about 0.001 w / v% to about 0.005 w / v%.

[0070] In one embodiment of the present disclosure, when zinc chloride is used as the zinc salt, it can be present in the aqueous suspension of the present disclosure at a concentration of about 0.0001 w / v% to about 0.05 w / v%, more preferably about 0.0005 w / v% to about 0.01 w / v%, and particularly preferably about 0.001 w / v% to about 0.005 w / v%.

[0071] In one embodiment of the present disclosure, silver salts that can be added to the aqueous suspension of the present disclosure include silver nitrate, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate, silver protein, or hydrates thereof.

[0072] In one embodiment of the present disclosure, the silver salt can be present in the aqueous suspension of the present disclosure at a concentration of about 0.0001 w / v% to about 0.05 w / v%, more preferably about 0.0005 w / v% to about 0.01 w / v%, and particularly preferably about 0.001 w / v% to about 0.005 w / v%.

[0073] (Redispersibility) (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 low solubility in water, and in the absence of a dispersing agent 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 dispersing agent other than a nonionic surfactant is used, the dispersing agent must be added at a concentration substantially exceeding the pharmaceutically acceptable concentration, making it 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 adding a desired amount of a cellulose-based polymer, even in the presence of a nonionic surfactant as a dispersing agent.

[0074] In one embodiment of the present disclosure, an aqueous suspension having improved redispersibility can be provided by further blending a cellulose-based polymer and / or a zinc salt or a silver salt with 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 and a nonionic surfactant.

[0075] In one embodiment, the redispersibility can be determined to be improved when the number of shakings required for the redispersion is generally about 15 times or less, preferably about 13 times or less, more preferably about 12 times or less, particularly preferably about 11 times or less, and even more preferably about 10 times or less.

[0076] Measurements using the falling operation can be said to reproduce the evaluation when used by patients whose hands have weakened due to some kind of disability or symptom, making it difficult to redisperse the tablet by shaking, and therefore can also be said to evaluate the redispersibility when used by these patients and elderly people.

[0077] In one embodiment, the redispersibility can be determined to be improved when the number of inversion operations required for the redispersion described above is generally about 40 times or less, preferably about 35 times or less, more preferably about 30 times or less, particularly preferably about 25 times or less, and even more preferably about 20 times or less.

[0078] 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.

[0079] 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 pharmaceutically acceptable salt or solvate thereof in an aqueous suspension of the present disclosure.50 ) is not particularly limited, but can usually be about 0.1 μm to about 50 μm, preferably about 0.5 μm to about 10 μm, particularly preferably about 1 μm to about 10 μm, and even more preferably about 1 μm to about 5 μm. By setting the average particle size in this range, redispersibility can be improved.

[0080] 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 suspension of the present disclosure can be used in a crystalline form. The crystalline form is not particularly limited as long as it does not affect redispersibility. 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 International Publication No. 2018 / 221543 and Japanese Patent No. 6230743 can be used. Preferably, Type I crystals are used.

[0081] (stability) 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 a portion thereof is dissolved in the aqueous solution. 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 suspended in an aqueous solution containing tyloxapol, thereby suppressing decomposition 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 solution, thereby improving the stability of the aqueous suspension.

[0082] Therefore, in another aspect of the present disclosure, there can be provided a composition for 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 an aqueous suspension, the composition comprising tyloxapol.

[0083] In yet another aspect, there is provided a method for 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 an aqueous suspension, the method comprising the step of mixing (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 tyloxapol to prepare an aqueous suspension.

[0084] In one embodiment of the present disclosure, stability can be evaluated by the content retention rate (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, dissolved and / or suspended in an aqueous suspension after storage for a certain period of time. Therefore, stability is preferably evaluated by dissolving (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 solution containing an excess amount of a nonionic surfactant, and using the content retention rate in the resulting aqueous solution as an index.

[0085] Because eye drops are administered directly to the ocular mucosa, ensuring high safety is essential, necessitating the suppression of the formation of degradation products during storage. In particular, in the development of prescription drugs, if the concentration of degradation products generated during storage exceeds a certain level, the structure of the degradation products must be identified and a safety report must be submitted (Notification No. 0624001 of the Pharmaceutical and Medical Devices Agency, "Revision of the Guidelines on Impurities in Pharmaceutical Preparations Containing New Active Ingredients"). In the development of eye drops, this obligation typically arises when the concentration of degradation products exceeds 1.0%. Therefore, the formation of degradation products during storage must be sufficiently suppressed during the formulation of eye drops. Furthermore, in aqueous suspensions, the stability of dissolved compounds is generally more sensitive than that of solid-state (suspended particle) compounds, making it important to evaluate the stability of the dissolved state from the perspective of pharmaceutical quality control.

[0086] (Dosage form) In one embodiment of the present disclosure, the aqueous suspension is an ophthalmic suspension, which may be provided as an ophthalmic injection, eye drop, or ophthalmic irrigation solution. For example, the ophthalmic 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.

[0087] 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 ocular discomfort, and requires long-term and regular treatment. In addition, since dry eye treatments are generally administered frequently, there is a strong demand for formulations that are easy to use and that facilitate patient adherence. Furthermore, in the case of a suspension with poor redispersibility, there is a concern that the suspended particles may not be uniformly dispersed, the desired active ingredient may not be administered, and the pharmacological effect may not be fully exerted. From these perspectives, redispersibility is a major issue in eye drops for treating dry eye, and the provision of an aqueous suspension with excellent redispersibility according to the present disclosure is of great value.

[0088] The 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.

[0089] (additives and / or excipients) Aqueous suspensions of the present disclosure may contain any pharmaceutically acceptable additives and / or excipients known in the art, including, but not limited to, stabilizers, pH adjusting agents, buffers, and preservatives.

[0090] The stabilizer is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include polyvinylpyrrolidone, monoethanolamine, cyclodextrin, dextran, ascorbic acid, tocopherol, dibutylhydroxytoluene, sulfites, etc., and the content thereof is preferably about 0.001 w / v% to about 1 w / v% of the total amount of the composition.

[0091] 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 can be, for example, 0 to about 20 w / v % based on the total amount of the aqueous suspension.

[0092] In one embodiment of the present disclosure, the aqueous suspension of the present disclosure can be mixed with a pH adjuster as described above, if necessary, 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.

[0093] The buffer used in the aqueous suspension 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., 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.

[0094] The concentration of the buffering agent may be appropriately set within a range that can impart the desired buffering capacity 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%.

[0095] 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, and tetraboric acid. 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. A preferred embodiment of the boric acid buffer is a combination of boric acid and borax.

[0096] When boric acid and borax are used in combination, the ratio of boric acid to borax is not particularly limited, but examples thereof include 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.

[0097] 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 examples include 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.

[0098] Examples of Tris buffers include Tris (also known as trishydroxymethylaminomethane) and / or salts thereof. The Tris salts are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include acetate, hydrochloride, maleate, sulfonate, and the like. The Tris acid buffer may be one selected from Tris and its salts and used alone, or two or more may be used in combination. In another embodiment, specific examples of Tris buffers include trometamol and / or salts thereof. The salts of trometamol are not particularly limited as long as they are pharmaceutically acceptable, and examples include organic acid salts such as acetate; and inorganic acid salts such as hydrochloride and sulfonate. The Tris acid buffer may be one selected from trometamol and its salts and used alone, or two or more may be used in combination. Among trometamol and its salts, trometamol is preferred.

[0099] 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 examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and the like. The citric acid salts may also be in the form of solvates such as hydrates. 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.

[0100] 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 examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and the like. Furthermore, the salts of tartaric acid may 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.

[0101] 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 alone or in combination as the acetate buffer.

[0102] Specific examples of amino acid buffers include acidic amino acids and / or their salts. Specific examples of acidic amino acids include aspartic acid and glutamic acid. Examples of salts of acidic amino acids include, but are not limited to, alkali metal salts such as sodium salts and potassium salts, as long as they are pharmaceutically acceptable. As the amino acid buffer, one selected from acidic amino acids and their salts may be used alone, or two or more may be used in combination.

[0103] 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, quaternary ammonium salts such as chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, and chlorhexidine. The content can be varied appropriately depending on the type of preservative, and can be, for example, about 0.0001 w / v% to about 0.2 w / v% of the total amount of the aqueous suspension.

[0104] When preparing eye drops, for example, the desired components 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, followed by sterilization treatment such as filtration sterilization.

[0105] (container) The container for housing the aqueous suspension 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, mixtures thereof, or mixtures of these with other materials. Containers used in the present disclosure may be those used in the medical field or other fields. In one embodiment, the container can be made of any material that meets the "Standards for Plastic Containers for Ophthalmic Solutions" in Japan or other equivalent standards.

[0106] The shape of the container to be used may be any shape, and generally any shape suitable for eye drops can be used.

[0107] In certain embodiments, the aqueous suspension of the present disclosure can be filled into any eye drop container commonly used in the medical field, for example, a polyethylene (preferably low-density polyethylene) or polypropylene, preferably a colorless polypropylene container.

[0108] (General technology) The molecular biological, biochemical, and microbiological techniques used herein are well known and commonly used in the art, and are described in, for example, 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 Transfer & Expression Analysis Experimental Methods," Yodosha, 1997. These are incorporated herein by reference in their entirety (perhaps in their entirety).

[0109] 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.

[0110] 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. [Example]

[0111] (Test Example 1: Change in redispersibility depending on methylcellulose concentration) Preparation of suspension A base solution was prepared according to the composition shown in Table 1, and compound (1) was dispersed in it by stirring to obtain a suspension. Tyloxapol manufactured by AMRI Rensselaer (Curia Global, Inc.) and methylcellulose manufactured by Shin-Etsu Chemical Co., Ltd. were used. SM-15 was used as the methylcellulose. The above-mentioned type I crystals were used as compound (1).

[0112] Containment in a container The prepared suspension was stirred with a stirrer and 5 mL aliquots were filled into eye dropper containers. The eye dropper containers used were colorless polyethylene containers (the same containers used for GatiFlo ophthalmic solution 0.3% (manufactured and sold by Senju Pharmaceutical Co., Ltd.)).

[0113] Redispersibility evaluation It was confirmed that the suspended particles in the suspension filled in the eye drop container had completely settled. Five shakings constituted one set, and the shaking operation was repeated until the precipitate had disappeared from the bottom and walls of the eye drop container. The shaking operation was performed in an up and down direction of 10 to 15 cm, with one shaking being from shaking down to returning to the original position, at a speed of 1.1 seconds per set. The test was performed on 3 to 5 specimens per formulation, and the average number of sets required for redispersion for each specimen was calculated and converted into the number of shakings. Redispersion was judged to be good when the number of shakings was 15 or less (e.g., for a set of 1, the number of shakings was 1.0 seconds). 5 times, or 10 times for sets 2).

[0114] Particle size measurement After shaking the sample until the precipitate was redispersed, approximately 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 median diameter (D 50 ) was taken as the particle size.

[0115] Surface tension measurement After shaking the sample until the precipitate was redispersed, approximately 10 mL of the sample was dropped onto a glass petri dish. The petri dish was placed in a surface tensiometer, and the surface tension was measured using the plate method.

[0116] Test results The results are shown in Table 1. At methylcellulose concentrations of 0.0001 w / v% to 0.005 w / v%, the number of shaking cycles was 15 or less. The number of shaking cycles was lowest at 8.3 when 0.001 w / v% methylcellulose was added. The surface tension of a separately prepared base (a formulation excluding compound (1) and tyloxapol) was 54.6 mN / m, and there was no correlation between redispersibility and surface tension. [Table 1]

[0117] (Test Example 2: Comparative study of cellulose derivatives) A suspension having the composition shown in Table 2 was prepared, and the number of shaking cycles required for redispersion was determined in the same manner as in Test Example 1. Hydroxypropyl methylcellulose (HPMC) manufactured by Shin-Etsu Chemical Co., Ltd. and carboxymethyl cellulose (CMC) manufactured by Dai-ichi Kogyo Seiyaku Co., Ltd. were used. Hydroxypropyl methylcellulose 60SH-4000 and carboxymethyl cellulose Cellogen PR-S were used. The above-mentioned type I crystals were used as compound (1).

[0118] Test results The results are shown in Table 2. By blending 0.0005 w / v% to 0.003 w / v% HPMC, the number of shaking cycles was 15 or less. The number of shaking cycles was lowest at 11.7 when 0.001 w / v% HPMC was blended. The number of shaking cycles was 11.7 when 0.001 w / v% CMC was blended. [Table 2]

[0119] (Test Example 3: Comparative study of nonionic surfactants) Suspensions having the compositions shown in Table 3 were prepared, and the number of shaking cycles required for redispersion was determined in the same manner as in Test Example 1. Polysorbate 80 manufactured by NOF Corp. and polyethylene glycol monostearate 40 (MYS-40) manufactured by Nippon Surfactant Kogyo Co., Ltd. were used. The above-mentioned type I crystals were used as compound (1).

[0120] Test results The results are shown in Table 3. The suspensions containing tyloxapol, polysorbate 80, and MYS-40 required 15 or fewer shaking cycles. [Table 3]

[0121] (Test Example 4: Comparative study of water-soluble polymers other than cellulose) Suspensions having the compositions shown in Table 4 were prepared, and the number of shaking cycles required for redispersion was determined in the same manner as in Test Example 1. Polyvinylpyrrolidone (PVP) manufactured by BASF Japan, xanthan gum manufactured by DSP Gokyo Food & Chemical, and carboxyvinyl polymer (CVP) manufactured by Lubrizol were used. Kollidon 30 was used as polyvinylpyrrolidone, and 974P was used as carboxyvinyl polymer. The above-mentioned type I crystals were used as compound (1).

[0122] Test results The results are shown in Table 4. The suspension containing PVP, xanthan gum, and CVP was shaken 15 times or more. [Table 4]

[0123] (Test Example 5: Change in redispersibility due to addition of zinc chloride) A suspension having the composition shown in Table 5 was prepared and filled into an eye dropper. Zinc chloride manufactured by Merck KGaA was used. The above-mentioned type I crystal was used as Compound (1).

[0124] Redispersibility evaluation It was confirmed that the suspended particles in the suspension filled in the eye dropper container had completely settled. The container was inverted and repeated until the precipitate had disappeared from the bottom and walls of the container and redispersed. The number of inversions required to redisperse was counted. The test was conducted on 3 to 5 samples per formulation, and the average number of inversions was calculated.

[0125] Test results The results are shown in Table 5. When methylcellulose was added to Formulation 28, the number of inversions decreased from 47.3 to 24.7. When zinc chloride was added to Formulation 28, the number of inversions increased to 32.3. When both methylcellulose and zinc chloride were added, the number of inversions decreased to 16.0. [Table 5]

[0126] Test Example 6: Stability of Compound (1) in a Nonionic Surfactant Solution Preparation of aqueous solutions A base solution was prepared according to the composition shown in Table 6, and Compound (1) was dissolved therein to obtain an aqueous solution. 2 mL of the prepared aqueous solution was collected and filled into glass ampoules. Tyloxapol manufactured by Ruger was used. The above-mentioned Form I crystals were used as Compound (1).

[0127] Stability evaluation The aqueous solution was stored at 25°C for 1 month (1M), and the compound (1) content in the solution was measured using a liquid chromatography system (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.

[0128] (Measurement conditions) Column: X Bridge Phenyl 3.5 μm, 4.6 × 150 mm, 3.5 μm (Waters) Detector: UV-visible spectrophotometric detector Detection wavelength: 220nm Column temperature: 40℃ Mobile phase: Water / acetonitrile / trifluoroacetic acid mixture (50:50:0.02)

[0129] Measurement results The results are shown in Table 6. The content retention rate of compound (1) after storage at 25°C at 1 M was 100%, and compound (1) was stable in the aqueous solution containing tyloxapol. [Table 6]

[0130] (Test Example 7: Change in redispersibility due to addition of each metal) Suspensions having the compositions shown in Tables 7 to 9 were prepared, and the number of inversion operations required for redispersion was determined in the same manner as in Test Example 5. Zinc sulfate manufactured by Merck KGaA, silver nitrate manufactured by Fujifilm Wako Pure Chemical Industries, sodium chloride manufactured by Manac, potassium chloride manufactured by Manac, calcium chloride manufactured by Fujifilm Wako Pure Chemical Industries, and magnesium chloride manufactured by Nacalai Tesque were used. The above-mentioned type I crystal was used as compound (1).

[0131] [Table 7]

[0132] [Table 8]

[0133] [Table 9]

[0134] The results are shown in Tables 7 to 9. By incorporating 0.0005 w / v to 0.01 w / v of zinc chloride, good redispersibility was observed. Furthermore, when zinc sulfate or silver nitrate was incorporated, good redispersibility was also observed. On the other hand, when sodium chloride, potassium chloride, calcium chloride, or magnesium chloride was incorporated, good redispersibility was not observed.

[0135] (Test Example 8: Change in redispersibility of 0.3 w / v% Compound (1)) A suspension having the composition shown in Table 10 was prepared, and the number of shaking cycles required for redispersion was determined in the same manner as in Test Example 1.

[0136] [Table 10]

[0137] At methylcellulose concentrations of 0.0005 w / v% to 0.003 w / v%, the number of shaking cycles was 15 or less. The number of shaking cycles was lowest at 6.7 when 0.001 w / v% methylcellulose was added. Furthermore, when redispersibility by inversion was evaluated when 0.001 w / v% methylcellulose was added, the number of shaking cycles was 17.0 for Formulation 6 and 12.7 for Formulation 41 (not shown in the table), confirming good redispersibility even when measured by the number of inversion cycles.

[0138] (Test Example 9: Change in redispersibility due to addition of zinc chloride) A suspension having the composition shown in Table 11 was prepared, and the number of inversion operations required for redispersion was determined in the same manner as in Test Example 5.

[0139] [Table 11]

[0140] When zinc chloride was added to Formulation 44, the number of inversions decreased from 40.7 to 23.0. When methylcellulose and zinc chloride were added together, the number of inversions decreased to 11.3. Furthermore, when redispersibility was evaluated as a function of the number of shakings when methylcellulose and zinc chloride were added together, the number of shakings was 5.0 (not shown in the table), confirming good redispersibility regardless of the number of shakings.

[0141] (Manufacturing example) High-quality eye drops can be produced by preparing aqueous suspensions having the compositions shown in Tables 12 to 14. The amounts of compound (1) and each additive are expressed in g / 100 mL.

[0142] [Table 12]

[0143] [Table 13]

[0144] [Table 14]

[0145] Tyloxapol (cloud point: 90-100°C) is manufactured by AMRI Rensselaer (Curia Global, Inc.), methylcellulose is Metolose SM-15 manufactured by Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose (HPMC) is 60SH-4000 manufactured by Shin-Etsu Chemical Co., Ltd., carboxymethylcellulose (CMC) is Cellogen PR-S manufactured by Daiichi Kogyo Seiyaku Co., Ltd., and lifitegrast is manufactured by Shanghai Sumway Pharmaceutical Technology Co., Ltd. Compound (1) is used as a type I crystal.

[0146] Specifications of each container Each container consists of a bottle (colorless PE, colorless PP, or brown PP), a nozzle (PE), and a cap (PP). The appearance, lightness, chromaticity, saturation, and transmittance at each wavelength of the bottle body of each container are as specified in Table 15 and Figure 1. Each container is shrink-wrapped with a product label.

[0147] [Table 15]

[0148] Bottle shape The bottle measures approximately 23 mm x 17 mm x 50 mm, and weighs approximately 3 g of resin. Its shape is similar to that of the bottle of Softia (registered trademark) 0.02% eye drops (manufactured and sold by Senju Pharmaceutical Co., Ltd.).

[0149] Bottle Material The polyethylene is low-density polyethylene. The polypropylene is a propylene-ethylene copolymer with a propylene / ethylene ratio of 50 / 50 to 99.9 / 0.1, and is the same material as the bottle of Softia (registered trademark) eye drops 0.02% (manufactured and sold by Senju Pharmaceutical Co., Ltd.).

[0150] Method for measuring the lightness, saturation, and transmittance of a bottle body The side of the bottle (wider side, 1.0 cm x 2.0-3.0 cm) was cut out from the body of the bottle and measured for lightness (L * value) and chromaticity (a * value, b * value) is measured. Also, the formula: ((a * value) 2 +(b * value) 2 ) 1 / 2 According to * Furthermore, the transmittance (%) of light in the range of 200 to 800 nm was measured for this side surface using an ultraviolet-visible spectrophotometer ("UV-2450 model", manufactured by Shimadzu Corporation).

[0151] How to sterilize bottles EB (electron beam sterilization): Eye drop bottles are sterilized by irradiating them with electron beams at 10 to 60 kGy. EOG (ethylene oxide gas sterilization): Eye drop bottles are sterilized under the following conditions: ethylene oxide concentration 400-700 mg / L, temperature 40-50°C, relative humidity 45-85%, and processing time 3 hours or more. VHP (Vaporous Hydrogen Peroxide): Eye drop bottles are sterilized by spraying 3% VHP at a temperature of 20-50°C, a relative humidity of 30-90%, and for approximately one hour. Gamma rays (gamma ray sterilization): Bottles are sterilized by irradiating them with gamma rays at 20 to 60 kGy.

[0152] 50L scale manufacturing method for eye drops (No. 11) Purified water and the specified amounts of boric acid, borax, sodium chloride, and zinc chloride are added to a 30L stainless steel container and stirred. A specified amount of tyloxapol aqueous solution is prepared in a 1L stainless steel container and this aqueous solution is added to the 30L stainless steel container. Furthermore, a specified amount of methylcellulose is dispersed in hot water (50-90°C) in another 1L stainless steel container, cooled, and this methylcellulose aqueous solution is added to the 30L stainless steel container. After confirming that all additives have dissolved in the 30L stainless steel container, purified water is added to make a 1.5x concentrated base solution, and the weight is adjusted to a measuring tape. This base solution is sterilized by filtration, and the weight is adjusted to a measuring tape with purified water (including rinsing) to prepare the specified amount of base solution. Compound (1) is added to this base solution and dispersed by stirring to prepare a suspension. After confirming that compound (1) has dispersed in the liquid, the suspension is gently stirred to defoam. Thereafter, the suspension is roughly filtered using a filter with a pore size of 75 μm, and the suspension is filled into a bottle while being stirred, and then a nozzle and a cap are attached to the bottle.

[0153] (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 herein are incorporated by reference in their entirety as if the contents themselves were specifically set forth herein. This application claims priority to Japanese Patent Application No. 2021-57713, filed on March 30, 2021, with the Japan Patent Office, the contents of which are incorporated by reference in their entirety as if they constitute the contents of this application. [Industrial Applicability]

[0154] The present disclosure is applicable to fields such as medicine, pharmaceuticals, healthcare, biology, and biochemistry.

Claims

1. 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, a water-soluble cellulose-based polymer, and a non-ionic surfactant.

2. The aqueous suspension formulation of claim 1, wherein the water-soluble cellulose polymer is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

3. 3. The aqueous suspension according to claim 1, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate, and polyoxyethylene hydrogenated castor oil.

4. 4. An aqueous suspension according to any one of claims 1 to 3, further comprising a zinc salt or a silver salt.

5. 5. The aqueous suspension of claim 4, wherein the zinc salt is zinc chloride or zinc sulfate.

6. 5. The aqueous suspension of claim 4, wherein the silver salt is silver nitrate.

7. The aqueous suspension according to any one of claims 1 to 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.

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