Suspensions containing sterilized heterocyclic subunit acetamide derivatives

Abstract

The present disclosure provides a suspension-type eye drop having excellent redispersibility. More specifically, the present disclosure provides an aqueous based suspension formulation containing heat treated (E)-2-(7-trifluoromethylchroman-4-subunit)-N-(7-hydroxy-5, 6, 7, 8-tetrahydronaphthalene-1-yl) acetamide, or a pharmaceutically acceptable salt or solvate thereof. In particular, the present disclosure relates to techniques for improving the redispersibility of suspensions containing heterocyclic subunit acetamide derivatives, or techniques of formulations based thereon.

Description

Technical Field

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

[0002] The number of dry eye patients in Japan is estimated to be at least about 8 million, and about 22 million if potential patients who use over-the-counter eye drops without going to the hospital are included. It is said that there are more than 1 billion dry eye patients worldwide. It is well known that in modern society, the use of televisions, computers, mobile terminals, etc. has led people to stare at screens more frequently, thereby reducing the frequency of blinking, and the use of air conditioners, etc. has made the air dry, so that tear evaporation increases and thus causes dry eyes. Refractive surgery and the use of contact lenses can also cause dry eyes. Symptoms associated with dry eyes include, for example, eye discomfort, dryness, burning sensation, and irritation of the ocular surface.

[0003] When dry eye occurs, the above symptoms are manifested as subjective symptoms, and their treatment requires long-term regular eye drops. Therefore, most dry eye treatment drugs currently on the market are usually frequently administered. For example, usually, DIQUAS (registered trademark) eye drops require 6 applications per day, HYALEIN (registered trademark) eye drops require 5 to 6 applications per day, and MUCOSTA (registered trademark) eye drops require 4 applications per day.

[0004] Disclosed is a composition 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, or use thereof for treating dry eye (PTL 1).

[0005] [Citation list]

[0006] [Patent Document]

[0007] [PTL 1]

[0008] International Publication No. WO 2021 / 066144 Summary of the invention

[0009] [Solution to the problem]

[0010] The present disclosure provides an aqueous suspension formulation with excellent redispersibility, comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (one of the heterocyclic acetamide derivatives) or a pharmaceutically acceptable salt or solvate thereof.

[0011] Therefore, the present disclosure provides the following items.

[0012] (Item 1)

[0013] An aqueous suspension preparation comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

[0014] (Item 1-1)

[0015] The aqueous suspension preparation according to the above items, wherein the heat treatment is a dry heat treatment.

[0016] (Item 2)

[0017] The aqueous suspension preparation according to the above items, wherein the heat treatment is a treatment in a sterilization step.

[0018] (Item 2-1)

[0019] The aqueous suspension preparation according to the above item, wherein the treatment in the sterilization step is a dry heat sterilization treatment.

[0020] (Item 3)

[0021] The aqueous suspension preparation according to any one of the above items, further comprising a nonionic surfactant.

[0022] (Item 4)

[0023] The aqueous suspension formulation according to any of the above items, wherein the heat treatment comprises a heat treatment performed at a temperature below about 180°C.

[0024] (Item 5)

[0025] The aqueous suspension formulation according to any one of the above items, wherein the heat treatment comprises a heat treatment performed at about 100°C to about 175°C.

[0026] (Item 6)

[0027] The aqueous suspension formulation according to any one of the above items, wherein the heat treatment comprises a heat treatment performed at about 100°C to about 170°C.

[0028] (Item 7)

[0029] The aqueous suspension formulation according to any one of the above items, wherein the heat treatment comprises a heat treatment performed at about 150°C to about 170°C.

[0030] (Item 8)

[0031] The aqueous suspension formulation according to any one of the above items, wherein the heat treatment is performed for about 30 minutes to about 5 hours.

[0032] (Item 9)

[0033] The aqueous suspension formulation according to any one of the above items, wherein the nonionic surfactant has a concentration of about 0.0001 w / v% to about 1 w / v% in the aqueous suspension formulation.

[0034] (Item 10)

[0035] The aqueous suspension formulation according to any one of the above items, wherein the nonionic surfactant has a concentration of about 0.001 w / v% to about 0.5 w / v% in the aqueous suspension formulation.

[0036] (Item 11)

[0037] The aqueous suspension formulation according to any one of the above items, wherein the nonionic surfactant has a concentration of about 0.01 w / v% to about 0.05 w / v% in the aqueous suspension formulation.

[0038] (Item 12)

[0039] The aqueous suspension preparation according to any one of the above items, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate and polyoxyethylene hydrogenated castor oil.

[0040] (Item 13)

[0041] The aqueous suspension formulation according to any one of the above items, wherein the nonionic surfactant is tyloxapol.

[0042] (Item 14)

[0043] The aqueous suspension preparation according to any one of the above items, wherein (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 a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension preparation.

[0044] (Item 15)

[0045] The aqueous suspension preparation according to any one of the above items, wherein (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 a concentration of about 0.3 w / v% to about 1 w / v% in the aqueous suspension preparation.

[0046] (Item 16)

[0047] An aqueous suspension formulation comprising:

[0048] Heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof; and

[0049] Nonionic surfactants,

[0050] The heat treatment includes heat treatment at a temperature below about 180°C,

[0051] The heat treatment is performed for about 30 minutes to about 5 hours,

[0052] (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 a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension formulation, and

[0053] The nonionic surfactant has a concentration of about 0.01 w / v% to about 0.05 w / v% in the aqueous suspension formulation.

[0054] (Item 17)

[0055] The aqueous suspension preparation according to any one of the above items, wherein (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.

[0056] (Item 18)

[0057] An aqueous suspension formulation according to any of the above items, wherein the aqueous suspension formulation comprises heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, and as assessed by shaking operation, 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 are redispersed in the aqueous suspension formulation in less than about 35 shakes.

[0058] (Item 19)

[0059] An aqueous suspension formulation according to any of the above items, wherein the aqueous suspension formulation comprises heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, and as assessed by an inversion operation, 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 are redispersed in the aqueous suspension formulation in less than about 50 inversions.

[0060] (Item 20)

[0061] An aqueous suspension formulation comprising:

[0062] The heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, and 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 in the aqueous suspension preparation is improved.

[0063] (Item 21)

[0064] The aqueous suspension formulation according to any one of the above items, wherein the improved redispersibility is the property of redispersing suspended particles in less than about 35 shakes as assessed by a shaking operation.

[0065] (Item 22)

[0066] The aqueous suspension formulation according to any one of the above items, wherein the improved redispersibility is the property of redispersing suspended particles in less than about 50 inversions as assessed by an inversion operation.

[0067] (Item 23)

[0068] An aqueous suspension formulation comprising:

[0069] The heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, (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 an average particle size (D50) of about 1 μm to about 10 μm in the aqueous suspension formulation.

[0070] (Item 24)

[0071] A method for producing an aqueous suspension formulation, the method comprising:

[0072] thermally treating (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof; and

[0073] The thus heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is mixed with a solvent.

[0074] (Item 25)

[0075] Heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

[0076] (Item 26)

[0077] The aqueous suspension formulation according to any one of the above items, wherein the aqueous suspension formulation has a pH of about 4 to about 8.

[0078] (Item 27)

[0079] The aqueous suspension formulation according to any one of the above items, wherein the aqueous suspension formulation is contained in a plastic container.

[0080] (Item 28)

[0081] The aqueous suspension formulation according to any one of the above items, wherein the plastic container is made of polyethylene or polypropylene.

[0082] (Item B1)

[0083] An aqueous suspension formulation comprising:

[0084] Gamma-sterilized (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.

[0085] (Item B2)

[0086] The aqueous suspension preparation according to any one of the above items, further comprising a nonionic surfactant.

[0087] (Item B3)

[0088] An aqueous suspension formulation comprising:

[0089] Gamma-sterilized (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

[0090] Nonionic surfactant.

[0091] (Item B4)

[0092] The aqueous suspension formulation according to any one of the above items, wherein the gamma sterilization treatment comprises a gamma treatment performed at 10 to 50 kGy.

[0093] (Item B5)

[0094] The aqueous suspension formulation according to any one of the above items, wherein the gamma sterilization treatment comprises a gamma treatment performed at 25 kGy.

[0095] (Item B6)

[0096] The aqueous suspension formulation according to any one of the above items, wherein the nonionic surfactant has a concentration of about 0.0001 w / v% to about 1 w / v% in the aqueous suspension formulation.

[0097] (Item B7)

[0098] The aqueous suspension formulation according to any one of the above items, wherein the nonionic surfactant has a concentration of about 0.001 w / v% to about 0.5 w / v% in the aqueous suspension formulation.

[0099] (Item B8)

[0100] The aqueous suspension formulation according to any one of the above items, wherein the nonionic surfactant has a concentration of about 0.01 w / v% to about 0.05 w / v% in the aqueous suspension formulation.

[0101] (Item B9)

[0102] The aqueous suspension preparation according to any one of the above items, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate and polyoxyethylene hydrogenated castor oil.

[0103] (Item B10)

[0104] The aqueous suspension formulation according to any one of the above items, wherein the nonionic surfactant is tyloxapol.

[0105] (Item B11)

[0106] The aqueous suspension preparation according to any one of the above items, wherein (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 a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension preparation.

[0107] (Item B12)

[0108] The aqueous suspension preparation according to any one of the above items, wherein (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 a concentration of about 0.3 w / v% to about 1 w / v% in the aqueous suspension preparation.

[0109] (Item B13)

[0110] An aqueous suspension formulation comprising:

[0111] Heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof; and

[0112] Nonionic surfactants,

[0113] The gamma sterilization treatment comprises a gamma treatment performed at 10 to 50 kGy,

[0114] (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 a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension formulation, and

[0115] The nonionic surfactant has a concentration of about 0.01 w / v% to about 0.05 w / v% in the aqueous suspension formulation.

[0116] (Item B14)

[0117] The aqueous suspension preparation according to any one of the above items, wherein (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.

[0118] (Item B15)

[0119] An aqueous suspension formulation according to any of the above items, wherein the aqueous suspension formulation comprises (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof that has been γ-sterilized, and as assessed by shaking operation, 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 are redispersed in the aqueous suspension formulation in less than about 35 shakes.

[0120] (Item B16)

[0121] An aqueous suspension formulation according to any of the above items, wherein the aqueous suspension formulation comprises (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof that has been γ-sterilized, and as assessed by an inversion operation, 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 are redispersed in the aqueous suspension formulation in less than about 50 inversions.

[0122] (Item B17)

[0123] An aqueous suspension formulation comprising:

[0124] (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 that has been subjected to γ ​​sterilization, and 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 in the aqueous suspension preparation is improved.

[0125] (Item B18)

[0126] The aqueous suspension formulation according to any one of the above items, wherein the improved redispersibility is a property of redispersing suspended particles in about 35 shakes or less as evaluated by a shaking operation.

[0127] (Item B19)

[0128] The aqueous suspension formulation according to any one of the above items, wherein the improved redispersibility is a property of redispersing suspended particles in about 50 inversions or less as evaluated by an inversion operation.

[0129] (Item B20)

[0130] Gamma-sterilized (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.

[0131] (Item B21)

[0132] The aqueous suspension formulation according to any one of the above items, wherein the aqueous suspension formulation has a pH of about 4 to about 8.

[0133] (Item B22)

[0134] The aqueous suspension formulation according to any one of the above items, wherein the aqueous suspension formulation is contained in a plastic container.

[0135] (Item B23)

[0136] The aqueous suspension formulation according to any one of the above items, wherein the plastic container is made of polyethylene or polypropylene.

[0137] (Project A1)

[0138] A method for producing an aqueous suspension formulation, the method comprising:

[0139] thermally treating (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof; and

[0140] The thus heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is mixed with a solvent.

[0141] (Item A1-1)

[0142] The method according to any of the above items, wherein the heat treatment is a dry heat treatment.

[0143] (Project A2)

[0144] The method according to any of the above items, wherein the heat treatment is a treatment in a sterilization step.

[0145] (Project A2-2)

[0146] The method according to any of the above items, wherein the treatment in the sterilization step is a dry heat sterilization treatment.

[0147] (Item A3)

[0148] The method according to any one of the above items, further comprising mixing with a non-ionic surfactant.

[0149] (Item A4)

[0150] The method according to any of the above items, wherein the heat treatment comprises a heat treatment performed at a temperature below about 180°C.

[0151] (Item A5)

[0152] The method according to any of the above items, wherein the heat treatment comprises a heat treatment performed at about 100°C to about 175°C.

[0153] (Item A6)

[0154] The method according to any of the above items, wherein the heat treatment comprises a heat treatment performed at about 100°C to about 170°C.

[0155] (Item A7)

[0156] The method according to any of the above items, wherein the heat treatment comprises a heat treatment performed at about 150°C to about 170°C.

[0157] (Item A8)

[0158] The method according to any of the above items, wherein the heat treatment is performed for about 30 minutes to about 5 hours.

[0159] (Item A9)

[0160] The method according to any one of the above items, wherein the nonionic surfactant has a concentration of about 0.0001 w / v% to about 1 w / v% in the aqueous suspension formulation.

[0161] (Item A10)

[0162] The method according to any one of the above items, wherein the non-ionic surfactant has a concentration of about 0.001 w / v% to about 0.5 w / v% in the aqueous suspension formulation.

[0163] (Item A11)

[0164] The method according to any one of the above items, wherein the non-ionic surfactant has a concentration of about 0.01 w / v% to about 0.05 w / v% in the aqueous suspension formulation.

[0165] (Item A12)

[0166] The method according to any one of the above items, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate and polyoxyethylene hydrogenated castor oil.

[0167] (Item A13)

[0168] The method according to any of the above items, wherein the non-ionic surfactant is tyloxapol.

[0169] (Item A14)

[0170] The method according to any one of the above items, wherein (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 a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension preparation.

[0171] (Item A15)

[0172] The method according to any one of the above items, wherein (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 a concentration of about 0.3 w / v% to about 1 w / v% in the aqueous suspension preparation.

[0173] (Item A16)

[0174] According to the method of any one of the above items, (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.

[0175] (Item A17)

[0176] The method according to any of the above items, wherein the aqueous suspension formulation has a pH of about 4 to about 8.

[0177] (Item A18)

[0178] The method according to any of the above items, wherein the suspended particles of heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof are redispersed in the aqueous suspension formulation in less than about 35 shakes as assessed by shaking operation.

[0179] (Item A19)

[0180] The method according to any of the above items, wherein the suspended particles of heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof are redispersed in the aqueous suspension formulation in less than about 50 inversions as assessed by an inversion operation.

[0181] (Item A20)

[0182] The method according to any one of the above items, wherein (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 improved redispersibility in the aqueous suspension formulation.

[0183] (Item A21)

[0184] The method according to any of the above items, wherein the improved redispersibility is the property of redispersing suspended particles in about 35 shakes or less as evaluated by a shaking operation.

[0185] (Item A22)

[0186] The method according to any of the above items, wherein the improved redispersibility is the property of redispersing suspended particles in about 50 tumblings or less as evaluated by tumbling operation.

[0187] (Item A23)

[0188] The method according to any of the above items, wherein (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 an average particle size of about 1 μm to about 10 μm in the aqueous suspension formulation.

[0189] (Item A24)

[0190] The method according to any of the above items, wherein the aqueous suspension formulation is contained in a plastic container.

[0191] (Item A25)

[0192] The method according to any of the above items, wherein the plastic container is made of polyethylene or polypropylene.

[0193] (Project C1)

[0194] A method for producing an aqueous suspension formulation, the method comprising:

[0195] gamma-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof; and

[0196] The thus gamma-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is mixed with a solvent.

[0197] [Advantageous Effects of the Invention]

[0198] The present disclosure can provide an aqueous suspension formulation having excellent redispersibility.

[0199] By providing the above features, the present invention suppresses the phenomenon that the suspended particles are not uniformly dispersed, and can achieve stable administration of the required amount of active ingredients and achieve stable and sufficient pharmacological effects. This helps to improve patient compliance and convenience. DETAILED DESCRIPTION

[0200] The present disclosure will be described. It should be understood that throughout this specification, unless otherwise stated, singular expressions also include the concept of its plural form. Therefore, it should be understood that, unless otherwise stated, singular articles (e.g., "a", "an", "the", etc. in English) also include the concept of its plural form. It should also be understood that, unless otherwise stated, the terms used herein are used in the sense commonly used in the field. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present disclosure belongs. In the event of a conflict, this specification (including definitions) shall prevail.

[0201] (definition)

[0202] As used herein, unless otherwise indicated, the term "about" means ±10% of the numerical value that follows it.

[0203] As used herein, the term "or" is used when "at least one or more" of the items listed in the context can be used. The same applies to "or". When the phrase "within the range of two values" is specified herein, the range includes the two values ​​themselves.

[0204] As used herein, the phrase "aqueous suspension preparation" is used in the same meaning as the term is generally used in the art, and refers to a liquid preparation containing water in at least a portion thereof, wherein the components to be mixed are in a suspended state and wherein solid particles are present in the liquid. Since (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is extremely difficult to dissolve in water, (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 becomes suspended particles in the aqueous suspension preparation of the present disclosure, but partially dissolves.

[0205] As used herein, the phrase "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic or organic acid addition salts or inorganic or organic base addition salts of compounds of the present disclosure.

[0206] As used herein, the term "solvate" refers to an aggregate formed by the interaction of a compound of the present disclosure or a pharmaceutically acceptable salt thereof with any solvent, and includes, for example, solvates with organic solvents (e.g., alcoholates (ethanolates, etc.) and hydrates. When a hydrate is formed, the compound of the present disclosure or a pharmaceutically acceptable salt thereof may be coordinated with any number of water molecules. Hydrates may include monohydrates and dihydrates, etc.

[0207] As used herein, the term "redispersibility" refers to the ease with which particles that have settled in a liquid containing particles, such as a solvent of a suspension (in the case of a suspension, also referred to as "suspended particles") are uniformly dispersed throughout the liquid again after the liquid is stored for a period of time. As used herein, the term "redispersibility" is evaluated by testing with an oscillating operation or a tumbling operation.

[0208] As used herein, the phrase "oscillation operation" refers to the action of holding the container containing the "aqueous suspension preparation" in the hand and oscillating it up and down. Regarding the "oscillation operation", the container was vertically oscillated 10 to 15 cm downward and then oscillated upward to its original position, which was defined as one oscillation. Five oscillations were defined as one group, and the container was oscillated at a rate of 1.1 seconds per group. The test of redispersibility using the "oscillation operation" was performed with 3 samples per preparation, and the average number of groups was calculated from the number of groups required for redispersion of each sample, and then converted into the number of oscillations.

[0209] As used herein, the phrase "inversion operation" refers to the action of holding the container containing the "aqueous suspension preparation" in the hand and turning it upside down. The test of redispersibility using the "inversion operation" was carried out with 3 samples of each preparation. The container was vertically turned 180° at a rate of 1 second / inversion and then turned 180° again to stand upright, which was defined as one inversion.

[0210] As used herein, the phrase "improved redispersibility" means that particles that have settled in a liquid containing the particles, such as a suspension, are more easily dispersed again, and if for any preparation, the number of actions of the above-mentioned "shaking operation" or "tumbling operation" is reduced in comparison, the redispersibility can be said to be improved.

[0211] As used herein, the phrase "average particle size of the suspended particles" refers to the median diameter (D) of the 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 measured by laser diffraction particle size distribution analyzer.

[0212] As used herein, the phrase "nonionic surfactant" is also referred to as a nonionic surfactant and refers to a surfactant whose hydrophilic group portion is nonionic. A person skilled in the art can easily determine whether a compound is a nonionic surfactant by checking that the compound does not ionize (exhibits ionicity) when dissolved in water. Examples of the nonionic surfactant include tyloxapol, polyethylene glycol stearates (polyethylene glycol monostearate, polyethylene glycol monostearate 40 (MYS-40), polyethylene glycol monostearate 400, 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 oil (polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 (HCO-60), etc.).

[0213] As used herein, the phrase "heat treatment" refers to applying heat to a target substance, molecule, aqueous suspension formulation or composition, and only needs to be substantially heated. "Heat treatment" includes, for example, dry heat treatment, wet heat treatment and high pressure steam treatment. The temperature of the heat treatment may refer to the temperature of the target substance, molecule, aqueous suspension formulation or composition, or may be the temperature set on the device for applying heat or the temperature displayed on the display. The time of the heat treatment may refer to the time period during which the target substance, molecule, aqueous suspension formulation or composition applies heat to reach a predetermined temperature and maintain the predetermined temperature (determined by the average temperature), or may be the time set on the device for applying heat or the time displayed on the display. In the present disclosure, heat treatment (e.g., dry heat treatment, wet heat treatment or high pressure steam treatment) is carried out on (E)-2-(7-trifluoromethylchroman-4-subunit)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl) acetamide or its pharmaceutically acceptable salt or solvate itself. The dry heat treatment can be performed on a powder of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof. The term "powder" refers to a powder or granules (made of solid particles having any particle size distribution, and in which individual particles interact with each other by, for example, electrostatic forces and van der Waals forces).

[0214] As used herein, the term "sterilization" or the phrase "sterilization treatment" refers to the basic removal, disinfection or inactivation of viruses, microorganisms, etc. present in the target substance, molecule, aqueous suspension formulation or composition. Sterilization may include, for example, γ sterilization, dry heat sterilization and autoclave sterilization. Therefore, the phrase "γ sterilization treatment" refers to sterilizing the target substance, molecule, aqueous suspension formulation or composition by irradiating the substance, molecule, etc. with γ rays. In addition, the phrase "dry heat sterilization" refers to sterilization treatment by heating in a dry state. In the present disclosure, sterilization or sterilization treatment is performed on (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or its pharmaceutically acceptable salt or solvate itself. The gamma sterilization treatment can be performed on powder of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

[0215] As used herein, the term "solvent" is used to cover water, organic solvents, and mixtures of water and organic solvents, which may be sterilized by filtration or other means. Such sterilized solvents are also included in the "solvent" herein. In addition to water, organic solvents, or mixtures of water and organic solvents, the "solvent" may also contain any additives dissolved therein, such as viscous agents, stabilizers, pH regulators, buffers, and preservatives (preservatives). Such solvents containing additives are also included in the "solvent" herein.

[0216] (Preferred Implementation)

[0217] The preferred embodiments of the present disclosure will be described. The embodiments provided below are given for a better understanding of the present disclosure, and the scope of the present disclosure should not be limited to the following description. Therefore, it is apparent that those skilled in the art can make modifications as appropriate within the scope of the present disclosure with reference to the description herein. The following embodiments of the present disclosure may also be used alone or in combination.

[0218] (Aqueous suspension preparation)

[0219] In one aspect of the present disclosure, an aqueous suspension formulation may be provided, comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

[0220] In another aspect of the present disclosure, an aqueous suspension formulation may be provided, comprising heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof; and a nonionic surfactant.

[0221] In one aspect of the present disclosure, an aqueous suspension formulation may be provided, 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 that has been heat-treated at about 150 to about 170°C.

[0222] In another aspect of the present disclosure, an aqueous suspension formulation may be provided, 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 that has been heat-treated at about 150 to about 170° C.; and a nonionic surfactant.

[0223] In one aspect of the present disclosure, an aqueous suspension formulation may be provided, 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 sterilized by heat treatment at about 100 to about 170°C.

[0224] In another aspect of the present disclosure, an aqueous suspension formulation may be provided, 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 sterilized by heat treatment at about 100 to about 170° C.; and a nonionic surfactant.

[0225] In one aspect of the present disclosure, an aqueous suspension formulation may be provided, comprising gamma-sterilized (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.

[0226] In another aspect of the present disclosure, an aqueous suspension formulation may be provided, 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 that has been γ-sterilized; and a nonionic surfactant.

[0227] In one aspect of the present disclosure, a method for producing an aqueous suspension preparation may be provided, the method comprising heat-treating (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof; and mixing the thus heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof with a solvent.

[0228] In another aspect of the present disclosure, a method for producing an aqueous suspension preparation may be provided, the method comprising sterilizing (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 γ rays; and mixing the thus sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof with a solvent.

[0229] In one aspect of the present disclosure, heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof may be provided.

[0230] In one aspect 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 subjected to heat treatment at about 150 to about 170° C. may be provided.

[0231] In one aspect 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 sterilized by heat treatment at about 100 to about 170° C. may be provided.

[0232] In another aspect of the present disclosure, there may be provided (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof that has been subjected to gamma sterilization.

[0233] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide includes its R isomer (CAS.No.920332-28-1), its S isomer (CAS.No.920332-29-2) or its racemate (CAS.No.920332-27-0), and more preferably is its R isomer ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (also referred to herein as compound (1)).

[0234] The pharmaceutically acceptable salt of the compound of the present disclosure is not particularly limited as long as it is a pharmaceutically acceptable salt. Specific examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like; organic carboxylic acids such as aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, heptanoic acid, decanoic acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, mandelic acid and the like, aromatic monocarboxylic acids such as benzoic acid, salicylic acid and the like, aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid and the like, aliphatic tricarboxylic acids such as citric acid and the like; acid addition salts with organic sulfonic acids such as aliphatic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid and the like, and aromatic sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid and the like; and inorganic base addition salts with metals such as alkali metals or alkaline earth metals such as sodium, potassium, magnesium, calcium and the like, and organic base addition salts such as methylamine, ethylamine, ethanolamine, pyridine, lysine, arginine, ornithine and the like.

[0235] These salts can be obtained by conventional procedures, for example, by mixing an equivalent amount of a compound of the present disclosure with a solution containing the desired acid or base, then filtering out the desired salt, or collecting the desired salt by distilling off the solvent. The compounds of the present disclosure or their salts can also form solvates with water or solvents such as ethanol.

[0236] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide has an excellent antagonistic effect on transient receptor potential vanilloid 1 (hereinafter described as "TRPV1". TRPV1 is also called "capsaicin receptor 1 (VR1)").

[0237] (E) -2- (7-trifluoromethylchroman-4-ylidene) -N- (7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl) acetamide R isomer (compound (1)), S isomer or racemate is described in PCT International Publication No. WO2007 / 010383, Japanese Patent No. 4754566, Japanese Patent No. 6230743, PCT International Publication No. WO2018 / 221543, Japanese Patent No. 6830569, PCT International Publication No. WO2021 / 038889 and PCT International Publication No. WO2021 / 039023. R isomer (compound (1)), S isomer or racemate can be produced by the production method described in the above patent document. The contents of the above patent document are incorporated herein by reference in their entirety.

[0238] TRPV1 is a TRP channel cloned from dorsal root ganglion (DRG) as a cation channel in response to capsaicin, is sensitive to heat and protons above 43°C, and has been studied as a key nociceptive molecule (SEIKAGAKU Vol.85, No.7:561-565). TRPV1 is known to increase its activity and cause hyperalgesia during inflammation and tissue damage. Therefore, TRPV1 has attracted attention as a candidate drug target for the treatment of pain.

[0239] TRPV1 antagonists have been previously reported to be effective in various pain models, including inflammatory pain, neuropathic pain, and osteoarthritis (SEIKAGAKU Vol. 85, No. 7: 561-565).

[0240] 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 heat-treated, and then the thus heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is mixed with a solvent to form an aqueous suspension formulation. Therefore, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof may have improved redispersibility.

[0241] In another embodiment of the present disclosure, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is sterilized with gamma rays, and then the thus sterilized (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is mixed with a solvent to form an aqueous suspension formulation. Therefore, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof may have improved redispersibility.

[0242] 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 may be present in the aqueous suspension of the present disclosure at a concentration of generally 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 further preferably about 0.3 w / v% to about 1.0 w / v%.

[0243] 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 may be present in the aqueous suspension preparation of the present disclosure at a concentration of generally 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 further preferably about 0.3 w / v% to about 1.0 w / v%.

[0244] 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 may be heat-treated as a treatment in the sterilization step 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, typically at a temperature below about 180°C, preferably below about 175°C, more preferably about 100 to about 175°C, particularly about 100 to about 170°C, further preferably about 120 to about 170°C, even more preferably about 145 to about 175°C, and most preferably about 150 to about 170°C.

[0245] 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 generally heat-treated for about 10 minutes to about 24 hours, more preferably about 30 minutes to about 12 hours, particularly preferably about 30 minutes to about 8 hours, and further preferably about 30 minutes to about 5 hours.

[0246] 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 sterilized with gamma rays as a treatment in the sterilization step 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, typically at a dose of about 10 to 50 kGy, more preferably about 25 kGy.

[0247] In one embodiment of the present disclosure, there is no particular limitation on nonionic surfactants as long as they are pharmaceutically acceptable. Examples thereof include tyloxapol, polyethylene glycol stearate (polyethylene glycol monostearate, polyethylene glycol monostearate 40 (MYS-40), polyethylene glycol monostearate 400, 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 oil (polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 (HCO-60), etc.). Nonionic surfactants can be used alone, or two or more thereof can be used in combination. From the viewpoint of redispersibility or stability of aqueous suspension preparations, the nonionic surfactant is preferably tyloxapol, polysorbate, polyethylene glycol monostearate or polyoxyethylene hydrogenated castor oil, more preferably tyloxapol, polysorbate or polyethylene glycol monostearate, further preferably tyloxapol.

[0248] In one embodiment of the present disclosure, the nonionic surfactant may be present in the aqueous suspension formulation of the present disclosure in a concentration of about 0.0001 w / v% to about 1 w / v%, preferably about 0.0005 w / v% to about 0.5 w / v%, more preferably about 0.001 w / v% to about 0.5 w / v%, particularly preferably about 0.005 w / v% to about 0.1 w / v%, and further preferably about 0.01 w / v% to about 0.05 w / v%.

[0249] (Redispersibility)

[0250] 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 is relatively insoluble in water, in the absence of a dispersant such as a nonionic surfactant, an ionic surfactant or a water-soluble polymer, its particles float on the water surface, so that an aqueous suspension cannot be prepared. In addition, if a dispersant other than a nonionic surfactant is used, the dispersant needs to be included in a concentration significantly higher than a pharmaceutically acceptable concentration, so a nonionic surfactant must be included in the aqueous suspension formulation. The present disclosure can provide an aqueous suspension formulation with improved redispersibility by heat treating (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 presence of a nonionic surfactant as a dispersant.

[0251] In another aspect of the present disclosure, an aqueous suspension formulation with improved redispersibility can be provided by sterilizing (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 γ rays.

[0252] In one embodiment, when the number of oscillations required for the above redispersion is generally less than about 35 times, preferably about 30 times or less, more preferably about 25 times or less, and particularly preferably about 20 times or less, it can be determined that the redispersion property is improved.

[0253] Measurement using the inversion operation can be said to reproduce the evaluation when the handgrip is used by a patient whose grip is weak due to certain disabilities or symptoms and who has difficulty in redistributing the handgrip by oscillation, and can therefore also be said to evaluate the redistributability when used by patients or elderly people.

[0254] In one embodiment, the redispersibility is determined to be improved when the number of inversion operations required for the above redispersibility is generally less than about 50 times, preferably about 45 times or less.

[0255] In one embodiment, redispersibility can also be assessed by any means, for example, by filling an aqueous suspension of the present disclosure into a container and shaking the container at any rate and / or any oscillation amplitude, or inverting the container, thereby measuring the number of times required for the suspended particles to redisperse.

[0256] In one embodiment, the average particle size (D 50) is not particularly limited, and is generally about 1 μm to about 10 μm, preferably about 0.5 μm to about 5 μm, particularly preferably about 2 μm to about 4 μm, further preferably about 2.3 μm to about 3.3 μm, and most preferably about 2.1 μm to about 3.3 μm. The average particle size within such a range can improve redispersibility.

[0257] In one embodiment, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or its pharmaceutically acceptable salt or solvate in the aqueous suspension of the present disclosure can be used in a crystalline form, without particular limitation, as long as redispersibility is not affected. For example, in the present disclosure, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide disclosed in PCT International Publication No. WO 2018 / 221543 and Japanese Patent No. 6230743 can be used. Type I crystals, type II crystals, type III crystals or mixtures thereof. Preferably, type I crystals are used.

[0258] (Dosage Form)

[0259] In one embodiment of the present disclosure, the aqueous suspension formulation is an ophthalmic suspension formulation and can be provided as an ocular injection, eye drops or ocular perfusion. For example, an ophthalmic suspension formulation can be provided in the form of a suspension of the active ingredient in an aqueous solvent (e.g., phosphate buffered saline) or in the form of a solution of the active ingredient in an aqueous solvent.

[0260] In one embodiment of the present disclosure, the aqueous suspension formulation may be an eye drop for treating dry eye. Dry eye is a disease accompanied by subjective symptoms such as eye discomfort and requires long-term and regular treatment. In addition, since therapeutic drugs for dry eye are generally designed for frequent administration, formulations with good patient compliance and convenience are highly desirable. In addition, 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 therefore 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 formulation of the present disclosure with excellent redispersibility is very valuable.

[0261] The aqueous suspension formulations of the present disclosure can be administered by any suitable route determined by a person skilled in the art, and can be formulated to be suitable for administration by an administration route selected from, but not limited to, ocular injection, topical application (including application to the eye), instillation, intravenous injection, infusion, oral, parenteral, transdermal, and the like.

[0262] (Additives and / or excipients)

[0263] The aqueous suspension formulations of the present disclosure may include any pharmaceutically acceptable additives and / or excipients known in the art. Examples of additives include, but are not limited to, thickeners, stabilizers, pH adjusters, buffers, and preservatives (preservatives).

[0264] There is no particular limitation on the thickener, as long as it is pharmaceutically acceptable. Examples thereof include water-soluble polymers such as carboxyvinyl polymers, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, etc.; and cellulose polymers such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc. The thickener can be used alone, or two or more thereof can be used in combination. From the perspective of redispersibility, cellulose polymers are preferred, and methyl cellulose is particularly preferred.

[0265] There is no particular limitation on the stabilizer as long as it is pharmaceutically acceptable. Examples thereof include polyvinylpyrrolidone, monoethanolamine, cyclodextrin, dextran, ascorbic acid, tocopherol, butylated hydroxytoluene, sulfite and sodium edetate. Its content is preferably about 0.001 w / v% to about 1 w / v% relative to the total amount of the aqueous suspension preparation.

[0266] There is no particular limitation on the pH adjuster as long as it is pharmaceutically acceptable. Examples thereof include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, ε-aminocaproic acid, etc.; bases such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, sodium carbonate, etc. Its content is, for example, 0 to about 20 w / v% relative to the total amount of the aqueous suspension preparation.

[0267] In one embodiment of the present disclosure, the aqueous suspension of the present disclosure may be mixed with the above-mentioned pH adjuster, if necessary, to achieve a pH of 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, further preferably about 7.2 to about 7.8.

[0268] There is no particular limitation on the buffer used in the aqueous suspension formulation of the present disclosure, as long as it is pharmaceutically acceptable. Examples thereof include borate buffers, phosphate buffers, Tris buffers, citrate buffers, tartrate buffers, acetate buffers, amino acid buffers, and the like, among which borate buffers or phosphate buffers are preferred from the perspective of redispersibility or stability of the aqueous suspension formulation, and borate buffers are particularly preferred.

[0269] From the viewpoint of improving redispersibility or stability, the concentration of the buffer 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%, preferably about 1 w / v% to about 5 w / v%, more preferably about 1 w / v% to about 3 w / v%.

[0270] There is no particular limitation on the borate buffer as long as it is pharmaceutically acceptable. For example, boric acid and / or its salts can be used. There is no particular limitation on boric acid as long as it is pharmaceutically acceptable. Examples thereof include orthoboric acid, metaboric acid and tetraboric acid, etc. There is no particular limitation on the salt of boric acid as long as it is pharmaceutically acceptable. Examples thereof include metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, etc.; and organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, etc. Boric acid or its salts can be used alone, or two or more thereof can be used in combination. One suitable aspect of the borate buffer is a combination of boric acid and borax.

[0271] When boric acid and borax are used in combination, the ratio of boric acid to borax is not particularly limited and may be, for example, 10 to 300 parts by mass, preferably 10 to 250 parts by mass, more preferably 30 to 100 parts by mass, particularly preferably 40 to 60 parts by mass of borax per 100 parts by mass of boric acid.

[0272] Specifically, the phosphate buffer may be phosphoric acid and / or a salt thereof. There is no particular limitation on the salt of phosphoric acid as long as it is pharmaceutically acceptable. Examples thereof include dialkali metal hydrogen phosphates, such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.; alkali metal dihydrogen phosphates, such as sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.; and trialkali metal phosphates, such as trisodium phosphate, tripotassium phosphate, etc. The salt of phosphoric acid may also be in the form of a solvate such as a hydrate, for example, disodium hydrogen phosphate may be in the form of a dodecahydrate, or sodium dihydrogen phosphate may be in the form of a dihydrate. As a phosphate buffer, one selected from phosphoric acid and its salts may be used alone, or two or more thereof may be used in combination. Among phosphoric acid and its salts, phosphates are preferred, at least one of dialkali metal hydrogen phosphates and alkali metal dihydrogen phosphates is more preferred, and at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate is particularly preferred.

[0273] The Tris buffer can be Tris (also known as trishydroxymethylaminomethane) and / or its salt. There is no particular restriction on the salt of Tris, as long as it is pharmaceutically acceptable. For example, salts such as acetate, hydrochloride, maleate or sulfonate can be used. As a Tris buffer, one selected from Tris and its salt can be used alone, or two or more thereof can be used in combination. In another embodiment, the Tris buffer can be specifically tromethamine and / or its salt. There is no particular restriction on the salt of tromethamine, as long as it is pharmaceutically acceptable. For example, organic acid salts such as acetate can be used; inorganic acid salts such as hydrochloride and sulfonate can be used. As a Tris buffer, one selected from tromethamine and its salt can be used alone, or two or more thereof can be used in combination. Among tromethamine and its salt, tromethamine is preferred.

[0274] Specifically, the citrate buffer may be citric acid and / or a salt thereof. There is no particular limitation on the salt of citric acid as long as it is pharmaceutically acceptable. Examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts, etc. The salt of citric acid may also be in the form of a solvate such as a hydrate. As the citrate buffer, one selected from citric acid and a salt thereof may be used alone, or two or more thereof may be used in combination. Among citric acid and a salt thereof, a salt of citric acid is preferred, an alkali metal salt of citric acid is more preferred, and sodium citrate is particularly preferred.

[0275] Specifically, the tartrate buffer may be tartaric acid and / or a salt thereof. There is no particular limitation on the salt of tartaric acid as long as it is pharmaceutically acceptable. Examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts, etc. The salt of tartaric acid may also be in the form of a solvate such as a hydrate. As the tartrate buffer, one selected from tartaric acid and its salts may be used alone, or two or more thereof may be used in combination.

[0276] Specifically, the acetate buffer may be acetic acid and / or a salt thereof. There is no particular limitation on the salt of acetic acid as long as it is pharmaceutically acceptable. Examples thereof 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, etc. The salt of acetic acid may also be in the form of a solvate such as a hydrate. As the acetate buffer, one selected from acetic acid and a salt thereof may be used alone, or two or more thereof may be used in combination.

[0277] Specifically, the amino acid buffer can be an acidic amino acid and / or a salt thereof. Specific examples of the acidic amino acid include aspartic acid and glutamic acid. There is no particular limitation on the salt of the acidic amino acid as long as it is pharmaceutically acceptable. For example, alkali metal salts such as sodium salts and potassium salts can be used. As the amino acid buffer, one selected from the acidic amino acid and its salt can be used alone, or two or more thereof can be used in combination.

[0278] There is no particular limitation on the preservative as long as it is pharmaceutically acceptable. Examples thereof include sorbic acid, potassium sorbate, parabens such as methyl paraben, ethyl paraben, propyl paraben, butyl paraben, etc., quaternary ammonium salts such as chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, etc., alkyl polyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine, etc. Its content can be appropriately changed according to the type, and can be, for example, about 0.0001 w / v% to about 0.2 w / v% relative to the total amount of the aqueous suspension preparation.

[0279] Eye drops can be prepared, for example, by dissolving or suspending the desired components as described above in an aqueous solvent such as sterile purified water, a saline solution, a buffer (e.g., a phosphate buffer, a citrate buffer or an acetate buffer, etc.) or a non-aqueous solvent such as a vegetable oil, for example, cottonseed oil, soybean oil, sesame oil, peanut oil, etc.; adjusting the resulting solution or suspension to a predetermined osmotic pressure; and subjecting the resultant to a sterilization treatment such as filtration sterilization.

[0280] (container)

[0281] The container for holding the aqueous suspension formulation of the present disclosure is not particularly limited, and includes, for example, a glass container or a plastic container. The plastic container can be formed by any material, such as polyester (polyethylene terephthalate, polyarylate), polycarbonate, polyethylene or polypropylene, their mixture or a mixture with another material. The container used in the present disclosure may or may not be those used in the medical field. In one embodiment, it can be formed by any material that can meet the "eye drop plastic container standard" or other equivalent standards of Japan.

[0282] The container used may have any shape, and generally any shape can be used as long as it is used for eye drops.

[0283] In a specific embodiment, the aqueous suspension formulation of the present disclosure can be filled into any eye drop container commonly used in the medical field, such as a polyethylene (preferably low-density polyethylene) container or a polypropylene container, preferably a colorless polypropylene container.

[0284] (General Technology)

[0285] The molecular biology, biochemistry and microbiology procedures used herein are well known and common 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 edition (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). from Current Protocols in Molecular Biology, Wiley and Annual Update; Sninsky, JJ et 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). 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,AcademicPress,and Bessatsu Jikken Igaku "Experimental Methods for Gene Transfer & Expression Analysis", Yodosha, 1997, etc. The relevant parts (which may be the entire text) of these are incorporated herein by reference. .

[0286] References cited herein, such as scientific literature, patents, and patent applications are hereby incorporated by reference in their entirety as if expressly set forth herein.

[0287] For ease of understanding, the present disclosure has been described with reference to preferred embodiments. The present disclosure will be described below with reference to examples, but the above description and the examples below are provided only for illustrative purposes 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 only limited by the claims.

[0288] [Example]

[0289] (Test Example 1: Effect of Heat Treatment Temperature on Drug Redispersibility)

[0290] Preparation of suspension

[0291] Base solutions were prepared according to the compositions shown in Tables 1 and 2, and compound (1) was added to each base solution and dispersed therein under stirring. A suspension was thus obtained. Tyloxapol manufactured by AMRI Rensselaer (Curia Global, Inc.) was used. Compound (1) was in the form of the above-mentioned type I crystal.

[0292] Container storage

[0293] Each of the suspensions thus prepared was collected in 5 mL portions under stirring by a stirrer and filled into eye drop containers. Each eye drop container was a colorless container made of polyethylene (container for GATIFRO eye drops 0.3% (manufactured and sold by Senju Pharmaceutical Co., Ltd.)).

[0294] Evaluation of redispersibility

[0295] Method for evaluation by flipping operation: Confirm that the suspended particles in the suspension contained in the eye drop container have completely settled. Repeat the flipping operation (i.e., hold the container in your hand and turn it upside down) until the sediment disappears from the bottom and wall of the eye drop container and is redispersed. Note that turning the container vertically 180° and then turning it 180° again to stand upright at a rate of 1 second / flip is defined as one flip. Count the number of flips required for redispersion. The test is performed with 3 samples of each preparation, and the average number of flips is calculated.

[0296] Evaluation method by oscillation operation: Confirm that the suspended particles in the suspension contained in the eye drop container have completely settled. 5 oscillations are defined as one group, and the oscillation is repeated until the sediment disappears from the bottom and wall of the eye drop container and is redispersed. Note that one oscillation is defined as: oscillating the container vertically downward by 10 to 5 cm and then oscillating upward to its original position. This action is performed at a rate of 1.1 seconds / group. Count the number of groups required for redispersion and calculate the number of oscillations.

[0297] Particle size measurement

[0298] After shaking the sample until the precipitate is redispersed, about 1 mL of the sample is added dropwise into the dispersion tank of a laser diffraction particle size analyzer (SALD-2300). After 2 minutes of ultrasonic treatment, the particle size distribution is measured, and the D10, D50 and D90 values ​​are determined as the particle size.

[0299] result

[0300] The results are shown in Tables 1 and 2. The aqueous suspension preparation in which the compound (1) heat-treated at 150 to 170° C. was dispersed showed good redispersibility.

[0301] [Table 1]

[0302]

[0303] *1 Treat at the specified temperature for 2 hours

[0304] *2 This is the rate of change in the number of flip operations relative to Reference Example 1

[0305] *3 Oscillation frequency is 16.7

[0306] [Table 2]

[0307]

[0308] *4 Treat at the specified temperature for 2 hours

[0309] *5 The number of flip operations is 45.7

[0310] (Test Example 2: Heat Treatment Time)

[0311] Preparation of suspension

[0312] A base solution was prepared according to the composition shown in Table 3, and compound (1) was added thereto and stirred to be dispersed therein. Thus, a suspension was obtained.

[0313] Container storage

[0314] The suspension was filled into a container in the same manner as in Test Example 1.

[0315] Evaluation of redispersibility

[0316] The suspension was evaluated in the same manner as in Test Example 1 for redispersibility.

[0317] result

[0318] The results are shown in Table 3. The aqueous suspension preparation in which the compound (1) heat-treated for 30 minutes to 5 hours was dispersed showed good redispersibility.

[0319] [Table 3]

[0320]

[0321] (Test Example 3: Changes in redispersibility caused by different surfactants)

[0322] Preparation of suspension

[0323] A matrix solution was prepared according to the composition shown in Table 4, and compound (1) was added thereto and stirred to be dispersed therein. A suspension was thus obtained. Tyloxapol from AMRI Rensselaer (Curia Global, Inc.) was used. Polysorbate 80 manufactured by NOF CORPORATION, polyethylene glycol monostearate 40 (MYS-40) manufactured by NIPPON SURFACTANT INDUSTRIES CO., LTD., and polyoxyethylene hydrogenated castor oil 60 manufactured by NIPPON SURFACTANT INDUSTRIES CO., LTD. were used. Compound (1) was in the form of the above-mentioned type I crystal.

[0324] Container storage

[0325] The suspension was filled into a container in the same manner as in Test Example 1.

[0326] Evaluation of redispersibility

[0327] The suspension was evaluated in the same manner as in Test Example 1 for redispersibility.

[0328] result

[0329] The results are shown in Table 4. The aqueous suspension preparation in which the compound (1) heat-treated at 160°C was dispersed showed good redispersibility in the presence of any nonionic surfactant.

[0330] [Table 4]

[0331]

[0332] *6 Treat at the specified temperature for 2 hours

[0333] (Test Example 4: Concentration of surfactant)

[0334] Preparation of suspension

[0335] A matrix solution was prepared according to the composition shown in Table 5, and compound (1) was added thereto and stirred to be dispersed therein. A suspension was thus obtained. Tyloxapol from AMRI Rensselaer (Curia Global, Inc.) was used. Compound (1) was in the form of the above-mentioned type I crystal.

[0336] Container storage

[0337] The suspension was filled into a container in the same manner as in Test Example 1.

[0338] Evaluation of redispersibility

[0339] The suspension was evaluated in the same manner as in Test Example 1 for redispersibility.

[0340] result

[0341] The results are shown in Table 5. Aqueous suspension formulations containing tyloxapol at concentrations ranging from 0.01% to 0.04% showed good redispersibility.

[0342] [Table 5]

[0343]

[0344] *7 Treat at the specified temperature for 2 hours

[0345] (Test Example 5: Changes in redispersibility caused by different sterilization methods)

[0346] Preparation of suspension

[0347] A matrix solution was prepared according to the composition shown in Table 6, and compound (1) was added thereto and stirred to be dispersed therein. A suspension was thus obtained. Tyloxapol from AMRI Rensselaer (Curia Global, Inc.) was used. Compound (1) was in the form of the above-mentioned type I crystal. Compound (1) irradiated with electron rays of about 25 kGy was used in Comparative Example 7, and compound (1) irradiated with gamma rays of about 25 kGy was used in Example 13. Compound (1) sterilized by dry heat treatment at 160°C for 2 hours was used in Example 14.

[0348] Container storage

[0349] The suspension was filled into a container in the same manner as in Test Example 1.

[0350] Evaluation of redispersibility

[0351] The suspension was evaluated in the same manner as in Test Example 1 for redispersibility.

[0352] result

[0353] The results are shown in Table 6. The aqueous suspension preparation in which the γ-ray-treated compound (1) was dispersed showed good redispersibility.

[0354] [Table 6]

[0355]

[0356] (Test Example: Stability of Preparations Using Dry Heat Drugs)

[0357] Preparation of Suspension A base solution was prepared according to the composition shown in Table 7. Tyloxapol from AMRI Rensselaer (Curia Global, Inc.) was used. Compound (1) was in the form of the above-mentioned Type I crystal.

[0358] [Table 7]

[0359]

[0360] Container storage

[0361] Each suspension was filled into a container in the same manner as in Test Example 1.

[0362] store

[0363] Each suspension was stored under the following conditions.

[0364] Storage conditions: 60±2℃ (average: 60.1℃), humidity not controlled manually

[0365] Storage period: Initially, 2 weeks, 4 weeks

[0366] pH Measurement

[0367] The pH value was measured according to the pH value measurement method in the Japanese Pharmacopoeia General Test Methods, that is, using a pH meter with a glass electrode.

[0368] Osmotic pressure measurement

[0369] The osmotic pressure was measured according to the osmotic pressure measurement method (osmotic pressure molar concentration measurement method) in the Japanese Pharmacopoeia General Test Methods.

[0370] Measurement of content and impurities

[0371] In Example 15, the sample solution was prepared by diluting the suspension 2 times with acetonitrile. In Example 16, 2 mL of the suspension was accurately weighed, and mobile phase B was added thereto so that the volume was exactly 20 mL and dissolved, and used as the sample solution. In addition, about 20 mg of compound (1) was accurately weighed, and mobile phase B was added thereto so that the volume was exactly 20 mL and dissolved, and used as standard solution A. 2 mL of this solution was accurately weighed, and mobile phase B was added thereto so that the volume was exactly 20 mL and dissolved, and used as standard solution B. Standard solution B was used in Example 15, and standard solution A was used in Example 16. Accurately sample 10 μL of the sample and the standard solution, and test by liquid chromatography under the following conditions.

[0372] Test conditions

[0373] Detector: UV absorption spectrophotometer (measurement wavelength: 250nm)

[0374] Column: A commercially available column made of a stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm filled with 5 μm octadecylsilanized silica gel was used for liquid chromatography.

[0375] Column temperature: Constant temperature about 40℃

[0376] Mobile phase A: 1.79 g of disodium hydrogen phosphate dodecahydrate was dissolved in 1000 mL of water. Phosphoric acid was added to the resulting solution to adjust the pH to 6.5. Then, 350 mL of acetonitrile was added to the 650 mL solution and mixed together.

[0377] Mobile phase B: acetonitrile / water mixed solution (80:20)

[0378] Delivery of mobile phase: The mixing ratio of mobile phase A and B was controlled according to the linear concentration gradient shown in the table below.

[0379] Particle size measurement

[0380] The particle size of the suspension was measured in the same manner as in Test Example 1.

[0381] result

[0382] The results (n=3) are shown in Table 8. Storage stability for 4 weeks was shown in each case.

[0383] [Table 8]

[0384]

[0385] (Notes)

[0386] Although the present disclosure has been illustrated with reference to the preferred embodiments of the present disclosure, it is to be understood that the scope of the present disclosure should be interpreted solely by the claims. It is to be understood that the patents, patent applications, and other references cited herein should be incorporated herein by reference in their entirety, just as their contents themselves are expressly set forth herein. This application claims priority to Japanese Patent Application No. 2022-156060 filed with the Japan Patent Office on September 29, 2022, the contents of which are incorporated herein by reference in their entirety.

[0387] [Industrial Applicability]

[0388] The present disclosure can be used in the fields of medicine, pharmacy, health care, biology, biochemistry, etc.

Claims

1. An aqueous suspension formulation comprising: Heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

2. The aqueous suspension formulation according to claim 1, wherein the heat treatment is a treatment in a sterilization step.

3. The aqueous suspension formulation according to any one of claims 1 or 2, further comprising a nonionic surfactant.

4. The aqueous suspension formulation according to any one of claims 1 to 3, wherein the heat treatment comprises a heat treatment performed at a temperature below about 180°C.

5. The aqueous suspension formulation according to any one of claims 1 to 4, wherein the heat treatment comprises a heat treatment performed at about 100°C to about 175°C.

6. The aqueous suspension formulation according to any one of claims 1 to 5, wherein the heat treatment comprises a heat treatment performed at about 150°C to about 170°C.

7. The aqueous suspension formulation according to any one of claims 1 to 6, wherein the heat treatment is performed for about 30 minutes to about 5 hours.

8. The aqueous suspension formulation according to any one of claims 3 to 7, wherein the nonionic surfactant has a concentration of about 0.0001 w / v% to about 1 w / v% in the aqueous suspension formulation.

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

10. The aqueous suspension preparation according to any one of claims 1 to 9, wherein (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 a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension preparation.

11. The aqueous suspension formulation according to any one of claims 1 to 10, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.

12. An aqueous suspension formulation comprising: The heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, and 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 in the aqueous suspension preparation is improved.

13. The aqueous suspension formulation of claim 12, wherein the improved redispersibility is the property of redispersing suspended particles in less than about 35 shakes as assessed by a shaking operation.

14. The aqueous suspension formulation according to claim 12 or 13, wherein the improved redispersibility is the property of redispersing suspended particles in less than about 50 inversions as assessed by an inversion operation.

15. An aqueous suspension formulation comprising: The heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, (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 an average particle size (D50) of about 1 μm to about 10 μm in the aqueous suspension formulation.

16. A method for producing an aqueous suspension formulation, the method comprising: thermally treating (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof; and The thus heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof is mixed with a solvent.

17. A heat-treated (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

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