Combination formulations containing 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 a first component and a second component wherein the first component is (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, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof. And the second component comprises at least one component selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharmaceutically acceptable salts or solvates thereof.

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 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] [Technical issues]

[0010] The present disclosure provides an aqueous suspension formulation with excellent redispersibility, the formulation comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (which is one of the heterocyclic acetamide derivatives) or a pharmaceutically acceptable salt or solvate thereof as a first component; and at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and a pharmaceutically acceptable salt or solvate thereof as a second component.

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

[0012] (Item 1)

[0013] An aqueous suspension formulation comprising:

[0014] A first component; and

[0015] The second component,

[0016] The first component is (E)-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

[0017] The second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharmaceutically acceptable salts or solvates thereof.

[0018] (Item 2)

[0019] The aqueous suspension preparation according to the above item, further comprising a nonionic surfactant.

[0020] (Item 3)

[0021] 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.

[0022] (Item 4)

[0023] 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 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60.

[0024] (Item 5)

[0025] The aqueous suspension formulation according to any one of the above items, wherein the nonionic surfactant is tyloxapol.

[0026] (Item 6)

[0027] 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.

[0028] (Item 7)

[0029] The aqueous suspension formulation according to any one of the above items, wherein the first component has a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension formulation.

[0030] (Item 8)

[0031] The aqueous suspension formulation according to any one of the above items, wherein the first component has a concentration of about 0.3 w / v% to about 1 w / v% in the aqueous suspension formulation.

[0032] (Item 9)

[0033] The aqueous suspension formulation according to any one of the above items, wherein the second component has a concentration of about 0.005 w / v% to about 10 w / v% in the aqueous suspension formulation.

[0034] (Item 10)

[0035] The aqueous suspension formulation according to any one of the above items, wherein diquafosol or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.3 w / v% to about 10 w / v% in the aqueous suspension formulation,

[0036] Cyclosporine or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.005 w / v% to about 0.5 w / v% in the aqueous suspension formulation,

[0037] Hyaluronic acid or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.01 w / v% to about 1 w / v% in the aqueous suspension formulation,

[0038] Loteprednol etabonate or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.025 w / v% to about 2.5 w / v% in the aqueous suspension formulation,

[0039] bromfenac or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.01 w / v% to about 1 w / v% in the aqueous suspension formulation, and

[0040] Fluorometholone or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.01 w / v% to about 1 w / v% in the aqueous suspension preparation.

[0041] (Item 11)

[0042] The aqueous suspension formulation according to any one of the above items, wherein the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

[0043] (Item 12)

[0044] The aqueous suspension formulation according to any one of the above items, further comprising boric acid.

[0045] (Item 13)

[0046] 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.

[0047] (Item 14)

[0048] The aqueous suspension preparation according to any one of the above items, wherein 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.

[0049] (Item 15)

[0050] 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 30 inversions or less as evaluated by an inversion operation.

[0051] (Project A1)

[0052] An aqueous suspension formulation comprising:

[0053] The first component;

[0054] The second component; and

[0055] Nonionic surfactants,

[0056] The first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof,

[0057] The second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and

[0058] The nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate and polyoxyethylene hydrogenated castor oil.

[0059] (Project A2)

[0060] An aqueous suspension formulation comprising:

[0061] The first component;

[0062] The second component; and

[0063] Nonionic surfactants,

[0064] The first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof,

[0065] The second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and

[0066] The nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40, and polyoxyethylene hydrogenated castor oil 60.

[0067] (Item A3)

[0068] An aqueous suspension formulation comprising:

[0069] The first component;

[0070] The second component; and

[0071] Nonionic surfactants,

[0072] The first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof,

[0073] The second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof,

[0074] The nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60,

[0075] The first component has a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension formulation,

[0076] The second component has a concentration of about 0.005 w / v% to about 10 w / v% in the aqueous suspension formulation, and

[0077] The nonionic surfactant has a concentration of about 0.0001 w / v% to about 1 w / v% in the aqueous suspension formulation.

[0078] (Item A4)

[0079] An aqueous suspension formulation comprising:

[0080] The first component;

[0081] The second component; and

[0082] Nonionic surfactants,

[0083] The first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof,

[0084] The second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof,

[0085] The nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60,

[0086] The first component has a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension formulation,

[0087] Diquafosol or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.3 w / v% to about 10 w / v% in the aqueous suspension formulation,

[0088] Cyclosporine or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.005 w / v% to about 0.5 w / v% in the aqueous suspension formulation,

[0089] Hyaluronic acid or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.01 w / v% to about 1 w / v% in the aqueous suspension formulation,

[0090] Loteprednol etabonate or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.025 w / v% to about 2.5 w / v% in the aqueous suspension formulation,

[0091] Bromfenac or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.01 w / v% to about 1 w / v% in the aqueous suspension formulation,

[0092] Fluorometholone or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.01 w / v% to about 1 w / v% in the aqueous suspension formulation, and

[0093] The nonionic surfactant has a concentration of about 0.0001 w / v% to about 1 w / v% in the aqueous suspension formulation.

[0094] (Item A5)

[0095] An aqueous suspension formulation comprising:

[0096] The first component;

[0097] The second component; and

[0098] Nonionic surfactants,

[0099] The first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof,

[0100] The second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof,

[0101] The nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60,

[0102] The first component has a concentration of about 0.3 w / v% to about 1 w / v% in the aqueous suspension formulation,

[0103] Diquafosol or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 3 w / v% in the aqueous suspension formulation,

[0104] Cyclosporine or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.05 w / v% in the aqueous suspension formulation,

[0105] Hyaluronic acid or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.1 w / v% in the aqueous suspension formulation,

[0106] Loteprednol etabonate or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.25 w / v% in the aqueous suspension formulation, and

[0107] The nonionic surfactant has a concentration of about 0.01 w / v % to about 0.05 w / v % in the aqueous suspension formulation.

[0108] (Item A6)

[0109] An aqueous suspension formulation comprising:

[0110] The first component;

[0111] The second component;

[0112] nonionic surfactants; and

[0113] Boric acid,

[0114] The first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof,

[0115] The second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof,

[0116] The nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60,

[0117] The first component has a concentration of about 0.3 w / v% in the aqueous suspension formulation,

[0118] Diquafosol or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 3 w / v% in the aqueous suspension formulation,

[0119] Cyclosporine or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.05 w / v% in the aqueous suspension formulation,

[0120] Hyaluronic acid or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.1 w / v% in the aqueous suspension formulation,

[0121] Loteprednol etabonate or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.25 w / v% in the aqueous suspension formulation,

[0122] Bromfenac or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.1 w / v% in the aqueous suspension formulation,

[0123] Fluorometholone or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.1 w / v% in the aqueous suspension formulation,

[0124] The nonionic surfactant has a concentration of about 0.01 w / v% to about 0.05 w / v% in the aqueous suspension formulation,

[0125] The aqueous suspension formulation has a pH of about 4 to about 8, and

[0126] The redispersibility of the aqueous suspension formulation was evaluated by an inversion operation, and the aqueous suspension formulation included suspended particles that were redispersed in about 30 inversions or less.

[0127] (Item B1)

[0128] A method for producing an aqueous suspension formulation, the method comprising:

[0129] Mixing the first component, the second component and the nonionic surfactant to prepare the aqueous suspension formulation,

[0130] The first component is (E)-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] The second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and

[0132] The nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate and polyoxyethylene hydrogenated castor oil.

[0133] (Project C1)

[0134] A method for improving the redispersibility of an aqueous suspension formulation, the method comprising:

[0135] mixing the first component, the second component and the nonionic surfactant to prepare the aqueous suspension formulation,

[0136] The first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof,

[0137] The second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and

[0138] The nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate and polyoxyethylene hydrogenated castor oil.

[0139] [Advantageous Effects of the Invention]

[0140] The present disclosure can provide an aqueous suspension formulation having excellent redispersibility.

[0141] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0142] [ Figure 1 ] Figure 1 The transmittance of the bottle body of each container used in the examples at various wavelengths is shown. DETAILED DESCRIPTION

[0143] 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.

[0144] (definition)

[0145] As used herein, unless otherwise indicated, the term "about" means ±10% of the numerical value that follows it.

[0146] 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.

[0147] As used herein, the phrase "aqueous suspension formulation" is used in the same sense as the term is commonly used in the art, and refers to a liquid formulation 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-tetrahydronaphthalene-1-yl)acetamide or its pharmaceutically acceptable salt or solvate serving as the first component is extremely insoluble in water, (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)acetamide or its pharmaceutically acceptable salt or solvate becomes suspended particles in the aqueous suspension formulation of the present disclosure, but partially dissolves. In addition to the first component, the second component may also be suspended particles.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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 to 6 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.

[0152] 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 to 6 samples for 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.

[0153] 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.

[0154] 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.

[0155] 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.).

[0156] (Preferred Implementation)

[0157] 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.

[0158] (Aqueous suspension preparation)

[0159] The present disclosure may provide an aqueous suspension formulation comprising a first component and a second component, wherein the first component is (E)-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 second component is at least one selected from the group consisting of other active components and pharmaceutically acceptable salts or solvates thereof.

[0160] The present disclosure may provide an aqueous suspension formulation comprising a first component and a second component, wherein the first component is (E)-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 second component is at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and a pharmaceutically acceptable salt or solvate thereof.

[0161] The present disclosure may provide an aqueous suspension preparation, which comprises a first component, a second component and a non-ionic surfactant, wherein the first component is (E)-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 second component is at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and the non-ionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate and polyoxyethylene hydrogenated castor oil.

[0162] The present disclosure may provide an aqueous suspension preparation, which comprises a first component, a second component and a non-ionic surfactant, wherein the first component is (E)-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 second component is at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and the non-ionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60.

[0163] The present disclosure may provide an aqueous suspension preparation, which comprises a first component, a second component, a nonionic surfactant and boric acid, wherein the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, the second component is at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60.

[0164] Another aspect of the present disclosure may provide an aqueous suspension formulation comprising a first component and a second component, wherein the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, and the second component is at least one selected from the group consisting of rebamipide, olodaterol, digaotinib and pharmaceutically acceptable salts or solvates thereof; or, an aqueous suspension formulation comprising a first component, a second component, a nonionic surfactant, Surfactant and boric acid, the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, the second component is at least one selected from the group consisting of rebamipide, olodaterol, digaotinib and pharmaceutically acceptable salts or solvates thereof; the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60.

[0165] One aspect of the present disclosure may provide a method for producing an aqueous suspension formulation, the method comprising mixing a first component and a second component to prepare an aqueous suspension formulation, wherein the first component is (E)-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 second component is at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof.

[0166] Another aspect can also provide a method for producing an aqueous suspension preparation, the method comprising mixing a first component, a second component and a non-ionic surfactant to prepare an aqueous suspension preparation, the first component being (E)-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 second component being at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and the non-ionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate and polyoxyethylene hydrogenated castor oil.

[0167] Another aspect can also provide a method for producing an aqueous suspension preparation, the method comprising mixing a first component, a second component and a non-ionic surfactant to prepare an aqueous suspension preparation, the first component being (E)-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 second component being at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and the non-ionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60.

[0168] Another aspect can also provide a method for producing an aqueous suspension preparation, the method comprising mixing a first component, a second component, a nonionic surfactant and boric acid to prepare an aqueous suspension preparation, the first component being (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, the second component being at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and the nonionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60.

[0169] Another aspect of the present disclosure may provide a method for improving the redispersibility of an aqueous suspension formulation, the method comprising mixing a first component and a second component to prepare an aqueous suspension formulation, the first component being (E)-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 second component being at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof.

[0170] Another aspect can also provide a method for improving the redispersibility of an aqueous suspension preparation, the method comprising mixing a first component, a second component and a non-ionic surfactant to prepare an aqueous suspension preparation, the first component being (E)-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 second component being at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and the non-ionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate, polyethylene glycol monostearate and polyoxyethylene hydrogenated castor oil.

[0171] Another aspect can also provide a method for improving the redispersibility of an aqueous suspension preparation, the method comprising mixing a first component, a second component and a non-ionic surfactant to prepare an aqueous suspension preparation, the first component being (E)-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 second component being at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and the non-ionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60.

[0172] Another aspect can also provide a method for improving the redispersibility of an aqueous suspension preparation, the method comprising mixing a first component, a second component, a nonionic surfactant and boric acid to prepare an aqueous suspension preparation, the first component being (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, the second component being at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof, and the nonionic surfactant being at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60.

[0173] In the present disclosure, (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 its R isomer ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide Amine (also referred to herein as compound (1)). Compound (1) that can be used in the present disclosure can be provided in any form, for example, it can be a sterilized compound (1) or a non-sterilized compound (1). Examples of sterilization methods include dry heat sterilization, high pressure steam sterilization, filtration sterilization, electron beam sterilization, gamma ray, ethylene oxide gas sterilization or hydrogen peroxide gas sterilization, among which dry heat sterilization is suitably used. The temperature for dry heat sterilization is not particularly limited, and is generally about 100 to about 175°C, preferably about 100 to about 170°C, and more preferably about 150 to about 170°C.

[0174] In the present disclosure, diquafosol is a compound (IUPAC: P 1 ,P 4 -tetrasodium bis(5'-uridine)tetraphosphate / CAS.No.211427-08-6). As diquafosol or its pharmaceutically acceptable salt or solvate, a commercially available compound, a compound prepared by a method described in a public document, or a pharmaceutically acceptable salt or solvate thereof can be used.

[0175] In the present disclosure, cyclosporin is a compound incorporated as an active ingredient in RESTASIS eye drops (IUPAC: cyclo{-[(2S,3R,4R,6E)-3-hydroxy-4-methyl-2-methylaminooct-6-enoyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-} / CAS.No.59865-13-3). As cyclosporin or its pharmaceutically acceptable salt or solvate, a commercially available compound, a compound prepared by a method described in a public document, or a pharmaceutically acceptable salt or solvate thereof can be used.

[0176] In the present disclosure, hyaluronic acid is a compound incorporated as an active ingredient in HYALEIN eye drops in the form of its salt (IUPAC: [→3)-2-acetylamino-2-deoxy-β-D-pyranoglucopyranosyl-(1→4)-β-D-pyranoglucuronic acid-(1→] n / CAS.9067-32-7). The weight average molecular weight of hyaluronic acid or its pharmaceutically acceptable salt or solvate is generally 500,000 to 1,200,000, preferably 600,000 to 1,200,000. As hyaluronic acid or its pharmaceutically acceptable salt or solvate, a commercially available compound, a compound prepared by a method described in a public document, or its pharmaceutically acceptable salt or solvate can be used.

[0177] In the present disclosure, loteprednol etabonate is a compound incorporated as an active ingredient in EYSUVIS eye drops (IUPAC: 17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17-carboxylic acid chloromethyl ester / CAS No.82034-46-6). As loteprednol etabonate or a pharmaceutically acceptable salt or solvate thereof, a commercially available compound, a compound prepared by a method described in a public document, or a pharmaceutically acceptable salt or solvate thereof can be used.

[0178] In the present disclosure, bromfenac is a compound (2-[2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium sesquihydrate / CAS.No.120638-55-3) incorporated as an active ingredient in BRONUCK eye drops in the form of its salt. As bromfenac or its pharmaceutically acceptable salt or solvate, a commercially available compound, a compound prepared by a method described in a public document, or a pharmaceutically acceptable salt or solvate thereof can be used.

[0179] In the present disclosure, fluorometholone is a compound incorporated as an active ingredient in FLUMETHOLON eye drops (IUPAC: 9-fluoro-11β, 17-dihydroxy-6α-methylpregna-1,4-diene-3,20-dione / CAS.No.426-13-1). As fluorometholone or its pharmaceutically acceptable salt or solvate, a commercially available compound, a compound prepared by a method described in a public document, or a pharmaceutically acceptable salt or solvate thereof can be used.

[0180] In the present disclosure, rebamipide is a compound incorporated as an active ingredient in MUCOSTA eye drops (IUPAC: (2RS)-2-(4-chlorobenzamido)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionic acid / CAS.No.90098-04-7). As rebamipide or its pharmaceutically acceptable salt or solvate, a commercially available compound, a compound prepared by a method described in a public document, or a pharmaceutically acceptable salt or solvate thereof can be used.

[0181] In the present disclosure, olodaterol is a compound (6-hydroxy-8-((1R)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino}ethyl)-2H-1,4-benzoxazin-3(4H)-one hydrochloride / CAS.No.869477-96-3) incorporated as an active ingredient in SPIOLTO RESPIMAT 28 inhaler in its salt form. As olodaterol or its pharmaceutically acceptable salt or solvate, a commercially available compound, a compound prepared by a method described in a public document, or a pharmaceutically acceptable salt or solvate thereof can be used.

[0182] In the present disclosure, dercositinib is a compound known as a Janus kinase (JAK) inhibitor (IUPAC: 3-[(3S, 4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl]-3-oxopropionitrile / CAS No. 869477-96-3). As dercositinib or a pharmaceutically acceptable salt or solvate thereof, a commercially available compound, a compound prepared by a method described in a public document, or a pharmaceutically acceptable salt or solvate thereof can be used.

[0183] The pharmaceutically acceptable salts of the first component and the second component of the present disclosure are each independently not particularly limited as long as they are pharmaceutically acceptable salts. 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.

[0184] 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.

[0185] (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)").

[0186] (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.

[0187] 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.

[0188] 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).

[0189] 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 at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and a pharmaceutically acceptable salt or solvate thereof 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.

[0190] Another aspect of the present disclosure may provide a composition for improving the redispersibility of an aqueous suspension formulation 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 composition comprising at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and a pharmaceutically acceptable salt or solvate thereof.

[0191] Another aspect of the present disclosure may provide a composition for improving the redispersibility of an aqueous suspension formulation including (E)-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 at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof; and a nonionic surfactant.

[0192] Another aspect of the present disclosure may provide a composition for improving the redispersibility of an aqueous suspension formulation including (E)-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 at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof; a nonionic surfactant; and boric acid.

[0193] 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%.

[0194] 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%.

[0195] 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 the aqueous suspension preparation, 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, further preferably tyloxapol.

[0196] 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%.

[0197] In one embodiment of the present disclosure, when tyloxapol is used as the nonionic surfactant, it 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%.

[0198] In one embodiment of the present disclosure, the second component may be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.005 w / v% to about 12 w / v%, preferably about 0.005 w / v% to about 10 w / v%.

[0199] In one embodiment of the present disclosure, diquafosol or a pharmaceutically acceptable salt or solvate thereof may be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.3 w / v% to about 12 w / v%, preferably about 0.3 w / v% to about 10 w / v%, and more preferably about 3 w / v% to about 5 w / v%. Without wishing to be bound by any theory, diquafosol may be mixed with (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, thereby improving its redispersibility in the aqueous suspension formulation. In the present specification, unless otherwise specified, the concentration of diquafosol or a pharmaceutically acceptable salt or solvate thereof is the concentration calculated as diquafosol sodium.

[0200] In one embodiment of the present disclosure, cyclosporin or a pharmaceutically acceptable salt or solvate thereof may be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.005 w / v% to about 1 w / v%, preferably about 0.005 w / v% to about 0.5 w / v%, more preferably about 0.05 w / v% to about 0.1 w / v%. In the present specification, unless otherwise specified, the concentration of cyclosporin or a pharmaceutically acceptable salt or solvate thereof is the concentration calculated as cyclosporin (free form).

[0201] In one embodiment of the present disclosure, hyaluronic acid or a pharmaceutically acceptable salt or solvate thereof may be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.01 w / v% to about 2 w / v%, preferably about 0.01 w / v% to about 1 w / v%, more preferably about 0.1 w / v% to about 0.5 w / v%. In the present specification, unless otherwise specified, the concentration of hyaluronic acid or a pharmaceutically acceptable salt or solvate thereof is the concentration calculated as sodium hyaluronate.

[0202] In one embodiment of the present disclosure, loteprednol etabonate or a pharmaceutically acceptable salt or solvate thereof may be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.025 w / v% to about 3 w / v%, preferably about 0.025 w / v% to about 2.5 w / v%, more preferably about 0.25 w / v% to about 1 w / v%. In the present specification, unless otherwise specified, the concentration of loteprednol etabonate or a pharmaceutically acceptable salt or solvate thereof is the concentration calculated as loteprednol etabonate (free form).

[0203] In one embodiment of the present disclosure, bromfenac or a pharmaceutically acceptable salt or solvate thereof may be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.01 w / v% to about 2 w / v%, preferably about 0.01 w / v% to about 1 w / v%, more preferably about 0.1 w / v% to about 0.5 w / v%. In the present specification, unless otherwise specified, the concentration of bromfenac or a pharmaceutically acceptable salt or solvate thereof is the concentration calculated as bromfenac sodium 1.5 hydrate.

[0204] In one embodiment of the present disclosure, fluorometholone or a pharmaceutically acceptable salt or solvate thereof may be present in the aqueous suspension formulation of the present disclosure at a concentration of about 0.01 w / v% to about 2 w / v%, preferably about 0.01 w / v% to about 1 w / v%, more preferably about 0.1 w / v% to about 0.5 w / v%. In the present specification, unless otherwise specified, the concentration of fluorometholone or a pharmaceutically acceptable salt or solvate thereof is the concentration calculated as fluorometholone (free form).

[0205] In one embodiment of the present disclosure, the aqueous suspension formulation of the present disclosure may contain any additional active ingredients in addition to the first component and the second component.

[0206] (Redispersibility)

[0207] 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 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 including any amount of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone or a pharmaceutically acceptable salt or solvate thereof in the presence of a nonionic surfactant as a dispersant.

[0208] In one embodiment of the present disclosure, by including at least one selected from the group consisting of diquafosol, cyclosporin, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone and pharmaceutically acceptable salts or solvates thereof in (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof, an aqueous suspension preparation with improved redispersibility can be provided.

[0209] 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.

[0210] In one embodiment, when the number of inversion operations required for the above redispersion is generally about 44 times or less, preferably about 40 times or less, more preferably about 35 times or less, particularly preferably about 30 times or less, further preferably about 25 times or less, and most preferably about 20 times or less, it can be determined that the redispersibility is improved.

[0211] 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.

[0212] In one embodiment, the average particle size (D 50 ) is not particularly limited, and may be generally 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, further preferably about 1 μm to about 5 μm. The average particle size within such a range can improve redispersibility.

[0213] 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.

[0214] (Dosage Form)

[0215] 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.

[0216] 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 that is 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.

[0217] 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.

[0218] (Additives and / or excipients)

[0219] 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).

[0220] 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.

[0221] 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 and sulfite. Its content is preferably about 0.001 w / v% to about 1 w / v% relative to the total amount of the composition.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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%.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] Eye drops can be prepared, for example, by dissolving or suspending the required 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.

[0236] (container)

[0237] 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.

[0238] The container used may have any shape, and generally any shape can be used as long as it is used for eye drops.

[0239] 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.

[0240] (General Technology)

[0241] 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. .

[0242] 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.

[0243] 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.

[0244] [Example]

[0245] (Test Example 1: Evaluation of redispersibility)

[0246] Preparation of suspension

[0247] Base solutions were prepared according to the compositions shown in Tables 1 to 6, 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.), 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. Diquafosol sodium manufactured by KyongBo Pharmaceutical Co., Ltd., cyclosporine manufactured by Tokyo Chemical Industry Co., Ltd., sodium hyaluronate manufactured by SEIKAGAKU CORPORATION, loteprednol etabonate manufactured by Jinan Chenghui Shuangda Chemical Co., Ltd., bromfenac sodium manufactured by Regis, or fluorometholone manufactured by Sicor was used.

[0248] Container storage

[0249] 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.)).

[0250] Evaluation of redispersibility (tumbling operation)

[0251] Confirm that the suspended particles in the suspension of 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. Count the number of flips required for redispersion. The container is vertically rotated 180 ° and then rotated 180 ° again to stand upright at a rate of 1 second / flip, which is defined as a flip. The test is carried out with 3 to 6 samples of each preparation, and the average flipping number is calculated.

[0252] result

[0253] The results are shown in Tables 1 to 7. The aqueous suspension preparations each comprising Compound (1) exhibited good redispersibility with a reduced number of inversion operations because they were formulated with diquafosol sodium, cyclosporin, sodium hyaluronate, loteprednol etabonate, bromfenac sodium or fluorometholone, respectively. When Example 1 was evaluated by a shaking operation, the number of shaking was 10.0.

[0254] [Table 1]

[0255]

[0256] [Table 2]

[0257]

[0258] [Table 3]

[0259]

[0260] [Table 4]

[0261]

[0262] [Table 5]

[0263]

[0264] [Table 6]

[0265]

[0266] [Table 7]

[0267]

[0268] (Production Example)

[0269] Eye drops can be produced by preparing aqueous suspension formulations having the compositions shown in Tables 8 to 9. Note that the formulation amounts of compound (1) and additives are expressed in "g / 100 mL".

[0270] Table 8

[0271]

[0272] [Table 9]

[0273]

[0274] Tyloxapol (cloud point: 90 to 100° C.) manufactured by AMRI Rensselaer (Curia Global, Inc.), METOLOSE SM-15 manufactured by Shin-Etsu Chemical Co., Ltd. as methylcellulose, 60SH-4000 manufactured by Shin-Etsu Chemical Co., Ltd. as hydroxypropylmethylcellulose (HPMC), CELLOGEN PR-S manufactured by DKS Co. Ltd. as carboxymethylcellulose (CMC), and lifalast manufactured by Shanghai Sumway Pharmaceutical Technology were used. Compound (1) was in the form of type I crystals.

[0275] Container specifications

[0276] The container consists of a bottle (colorless PE, colorless PP or brown PP), a nozzle (PE) and a cap (PP). The appearance, brightness, chromaticity, saturation and transmittance at various wavelengths of each container are calculated according to Table 10 and Figure 1 The containers are also shrink-wrapped for product labeling.

[0277] [Table 10]

[0278]

[0279] The shape of the bottle

[0280] Each bottle has a size of about 23 mm x about 17 mm x about 50 mm and a resin weight of about 3 g. Its shape is similar to that of SOFTEAR (registered trademark) eye drops 0.02% (manufactured and distributed by Senju Pharmaceutical CO., LTD.).

[0281] Bottle material

[0282] Polyethylene refers to low-density polyethylene. Polypropylene refers to a propylene-ethylene copolymer composed of propylene component / ethylene component=50 / 50 to 99.9 / 0.1, and is the same material as the bottle of SOFTEAR (registered trademark) eye drops 0.02% (manufactured and distributed by Senju Pharmaceutical CO., LTD.).

[0283] Method for measuring the brightness, saturation and transmittance of bottles

[0284] The lightness (L) of the side portion (wider side portion, 1.0 cm x 2.0 cm to 3.0 cm) cut from the bottle body was measured using a spectrophotometer (CM-5, manufactured by KONICA MINOLTA, INC.). * value) and chromaticity (a * Value, b * Saturation (c * Value): ((a * value) 2 +(b * value) 2 ) 1 / 2 The transmittance (%) of the side surface portion to light in the range of 200 to 800 nm was measured using an ultraviolet-visible spectrophotometer ("Model UV-2450", manufactured by SHIMADZU CORPORATION).

[0285] Bottle sterilization method

[0286] EB (Electron Beam Sterilization): Eye drop bottles are sterilized by irradiation with electron beams of 10 to 60 kGy.

[0287] EOG (ethylene oxide gas sterilization): Eye drop bottles are sterilized under the following conditions: ethylene oxide concentration of 400 to 700 mg / L, temperature of 40 to 50° C., relative humidity of 45 to 85%, and treatment time of more than 3 hours.

[0288] VHP (Vapor Hydrogen Peroxide Sterilization): Eye drop bottles were sterilized under the following conditions: 3% VHP spray, temperature of 20 to 50°C, relative humidity of 30 to 90%, and treatment time of approximately 1 hour.

[0289] Gamma irradiation (gamma ray sterilization): Eye drop bottles are sterilized by irradiation with 20 to 60 kGy of gamma rays.

[0290] Method for producing eye drops on a 50L scale

[0291] Purified water and a predetermined amount of boric acid, borax, sodium chloride and zinc chloride are added to a 30L stainless steel container and stirred. A predetermined amount of tyloxapol aqueous solution is prepared in a 1L stainless steel container and added to the 30L stainless steel container. In another 1L stainless steel container, a predetermined amount of methylcellulose is dispersed in hot water (50 to 90°C), cooled, and the resulting methylcellulose aqueous solution is added to the 30L stainless steel container. Once all additives are confirmed to be dissolved in the 30L stainless steel container, purified water is added thereto to dilute by weight to a 1.5X matrix solution. The matrix solution is sterilized by filtration and diluted by weight with purified water (including for washing insoluble residues) to prepare a predetermined amount of matrix solution. Compound (1) serving as the first component and a second component (diquafosol sodium, cyclosporin, sodium hyaluronate, loteprednol etabonate, bromfenac sodium, fluorometholone, rebamipide, olodaterol hydrochloride or dercositinib) are added to the matrix solution and dispersed under stirring to prepare a suspension. After confirming that compound (1) is dispersed in the liquid, the suspension is gently stirred to eliminate foam. The suspension is then coarsely filtered through a filter having a pore size of 75 μm, the thus filtered suspension is added to a bottle under stirring, and then a nozzle and a cap are mounted on the bottle.

[0292] (Notes)

[0293] 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 clearly set forth herein. This application claims priority to Japanese Patent Application No. 2022-156062 filed with the Japan Patent Office, the contents of which are incorporated herein by reference in their entirety.

[0294] [Industrial Applicability]

[0295] The present disclosure can be used in the fields of medicine, pharmacy, health care, biology, biochemistry, etc.

Claims

1. An aqueous suspension formulation comprising: A first component; and The second component, The first component is (E)-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 second component is at least one selected from the group consisting of diquafosol, cyclosporine, hyaluronic acid, loteprednol etabonate, bromfenac, fluorometholone, and pharmaceutically acceptable salts or solvates thereof.

2. The aqueous suspension formulation according to claim 1, further comprising a nonionic surfactant.

3. The aqueous suspension preparation according to claim 2, wherein the nonionic surfactant is at least one selected from the group consisting of tyloxapol, polysorbate 80, polyethylene glycol monostearate 40 and polyoxyethylene hydrogenated castor oil 60.

4. The aqueous suspension formulation according to claim 2, wherein the nonionic surfactant is tyloxapol.

5. The aqueous suspension formulation according to claim 2, wherein the nonionic surfactant has a concentration of about 0.0001 w / v% to about 1 w / v% in the aqueous suspension formulation.

6. The aqueous suspension formulation of claim 1, wherein the first component has a concentration of about 0.01 w / v% to about 5 w / v% in the aqueous suspension formulation.

7. The aqueous suspension formulation of claim 1, wherein diquafosol or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.3 w / v% to about 10 w / v% in the aqueous suspension formulation; Cyclosporine or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.005 w / v% to about 0.5 w / v% in the aqueous suspension formulation; Hyaluronic acid or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.01 w / v% to about 1 w / v% in the aqueous suspension formulation; Loteprednol etabonate or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.025 w / v% to about 2.5 w / v% in the aqueous suspension formulation; Bromfenac or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.01 w / v% to about 1 w / v% in the aqueous suspension formulation; and Fluorometholone or a pharmaceutically acceptable salt or solvate thereof has a concentration of about 0.01 w / v% to about 1 w / v% in the aqueous suspension preparation.

8. The aqueous suspension formulation according to any one of claims 1 to 7, wherein the first component is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

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