Oxazole compound-containing composition

Abstract

To provide a composition containing difamilast, which has excellent skin permeability (and is preferably easy to spread and has low skin irritation). 【Solution】A liquid composition containing (A) difamilast, (B) at least one selected from the group consisting of diethylene glycol monoethyl ether, N-methyl-2-pyrrolidone (NMP), propylene glycol, and 1,3-butylene glycol, (C) liquid hydrocarbon, and (D) fats and oils.

Description

Technical Field

[0001] The present disclosure relates to a composition containing an oxazole compound (especially difamilast), etc. This application claims the priority and benefits of Japanese Patent Application No. 2024-087458 filed on May 9, 2024, and the entire content of that application is incorporated herein by reference.

Background Art

[0002] Patent Documents 1 and 2 report an oxazole compound having a specific inhibitory action on phosphodiesterase 4 (PDE4) and a method for producing the same. PDE4 is a dominant PDE in inflammatory cells, and inhibition of PDE4 increases the intracellular cAMP concentration, and the increase in this concentration down-regulates the inflammatory response through regulation of the expression of TNF-α, IL-23, and other inflammatory cytokines. In addition, the increase in cAMP concentration increases anti-inflammatory cytokines such as IL-10. Therefore, the oxazole compound is considered suitable for use as an anti-inflammatory agent. For example, it is considered useful for suppressing skin eczema and dermatitis, including atopic dermatitis. Patent Document 3 describes an ointment that stably contains an oxazole compound having a specific inhibitory action on PDE4 and can be efficiently absorbed into the skin. Patent Document 4 discloses a novel crystal form of a specific oxazole compound (difamilast), etc. The contents of the following Patent Documents 1 to 4 are incorporated herein by reference.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0004] Difamilast is an example of such an oxazole compound and has the following formula:

[0005]

Chemical Formula

[0006] It is represented by. Its production method is described in, for example, Patent Documents 1 to 4 above. The IUPAC name of difamilast is N-({2-[4-(difluoromethoxy)-3-(propan-2-yloxy)phenyl]-1,3-oxazol-4-yl}methyl)-2-ethoxybenzamide.

[0007] As difamilast preparations for use in the treatment of skin diseases, for example, atopic diseases, creams (o / w, w / o), lotions (o / w, alcohol), etc. can be considered.

[0008] However, since difamilast has very low solubility in water, in order to obtain these dosage forms, it is necessary to dissolve it in alcohol or a fat-soluble solvent and emulsify it with a surfactant. However, due to the use of the surfactant, the resulting creams and lotions have stronger skin irritation than ointments. (Generally, the skin irritation of creams and lotions is higher than that of ointments.) An emulsified lotion (o / w lotion) with suppressed skin irritation was examined, but its skin permeability was lower than that of ointments and was not sufficient to provide effective administration of difamilast.

[0009] Therefore, further studies were conducted with the main purpose of obtaining a composition containing difamilast and having excellent skin permeability.

Means for Solving the Problems

[0010] The present disclosure includes, for example, the subject matter described in the following items. Item 1. (A) difamilast, (B) at least one selected from the group consisting of diethylene glycol monoethyl ether, N-methyl-2-pyrrolidone (NMP), propylene glycol, and 1,3-butylene glycol (preferably, at least one selected from the group consisting of diethylene glycol monoethyl ether and N-methyl-2-pyrrolidone) (C) liquid hydrocarbon, and (D) oil and fat, containing a liquid composition. Item 2. (A) difamilast, (B) at least one selected from the group consisting of diethylene glycol monoethyl ether and N-methyl-2-pyrrolidone (NMP), (C) liquid hydrocarbon, and (D) oil and fat, containing a liquid composition. Item 3. (A) difamilast, (B) diethylene glycol monoethyl ether, (C) liquid hydrocarbon, and (D) oil and fat, containing a liquid composition. Item 4. (C) is at least one selected from the group consisting of liquid paraffin, light liquid paraffin, squalane, and squalene, or (D) is at least one selected from the group consisting of triacetin, fatty acid ester, vegetable fat and oil, and animal fat and oil, The liquid composition according to any one of Items 1 to 3. Item 5. (C) is at least one selected from the group consisting of liquid paraffin, light liquid paraffin, squalane, and squalene, (D) is at least one selected from the group consisting of triacetin, fatty acid ester, vegetable fat and oil, and animal fat and oil, The liquid composition according to any one of items 1 to 3. Item 6. The liquid composition according to any one of items 1 to 5, satisfying at least one condition (preferably two conditions) of the following conditions (I) and (II). (I): Containing 1 to 25 parts by mass of (B) with respect to 1 part by mass of (A) (II): Containing a total of 60 to 400 parts by mass of (C) and (D) with respect to 1 part by mass of (A) Item 7. The liquid composition according to any one of items 1 to 6, satisfying at least one condition (preferably two conditions) of the following conditions (III) and (IV). (III): Containing 50 to 400 parts by mass of (C) with respect to 1 part by mass of (A) (IV): Containing 1 to 80 parts by mass of (D) with respect to 1 part by mass of (A) Item 8. The liquid composition according to any one of items 1 to 7, satisfying at least one condition (preferably two conditions or three conditions) of the following three conditions. Containing 0.1 to 10 parts by mass of (D) with respect to 1 part by mass of (B) Containing 5 to 90 parts by mass of (C) with respect to 1 part by mass of (B) Containing 4 to 50 parts by mass of (C) with respect to 1 part by mass of (D) Item 9. The liquid composition according to any one of items 1 to 8, satisfying at least one condition (preferably two conditions or three conditions) of the following conditions (i), (ii), and (iii). (i): Containing 0.1 to 5% by mass of (A) (ii): Containing 1 to 25% by mass of (B) (iii): Containing a total of 60 to 98% by mass of (C) and (D) Item 10. The liquid composition according to any one of items 1 to 9, satisfying at least one condition (preferably two conditions) of the following conditions (iv) and (v). (iv): containing 8 to 96% by mass of (C) (v): containing 1 to 80% by mass of (D) Item 11. Furthermore (E) cholesterol The liquid composition according to any one of items 1 to 10, containing (preferably 0.2 to 8% by mass). Item 12. The liquid composition according to item 11, containing 0.2 to 25 parts by mass of (E) with respect to 1 part by mass of (A). Item 13. Furthermore (F) at least one selected from the group consisting of dextrin fatty acid ester and beeswax The liquid composition according to any one of items 1 to 12, containing (preferably 0.1 to 20% by mass). Item 14. The liquid composition according to item 13, containing 0.2 to 60 parts by mass of (F) with respect to 1 part by mass of (A). Item 15. Furthermore (E) cholesterol (F) at least one selected from the group consisting of dextrin fatty acid ester and beeswax The liquid composition according to any one of items 1 to 14, containing. Item 16. The liquid composition according to any one of items 1 to 15, and an aerosol preparation in which a propellant is filled in a pressure-resistant container. Item 17. The aerosol preparation according to item 16, wherein the propellant contains dimethyl ether. Item 18. The liquid composition according to any one of items 1 to 15, or the aerosol preparation according to item 16 or 17, which is a pharmaceutical composition. Item 19. The liquid composition according to any one of items 1 to 15, or the aerosol preparation according to item 16 or 17, which is a topical composition. Item 20. The liquid composition or aerosol preparation according to item 18 or 19, which is for treating skin diseases. Item 21. A method for treating skin diseases, which includes administering the liquid composition according to any one of items 1 to 15 or the aerosol preparation according to item 16 or 17 to a subject in need thereof. Item 22. The liquid composition according to any one of items 1 to 15 or the aerosol preparation according to item 16 or 17, for use in the treatment of skin diseases.

Advantages of the Invention

[0011] A composition containing difamilast, and a composition excellent in skin permeability is provided. The composition is preferably easy to spread and has low skin irritation. Further, it is excellent in stability and skin applicability. Therefore, the composition is suitable for applying difamilast to the treatment of skin diseases (for example, dermatitis, particularly atopic dermatitis).

Brief Description of the Drawings

[0012]

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Mode for Carrying Out the Invention

[0013] Hereinafter, each embodiment included in the present disclosure will be described in more detail. The present disclosure preferably includes compositions containing difamilast, methods for producing the same, and the like, but is not limited thereto, and the present disclosure includes all that are disclosed in this specification and can be recognized by those skilled in the art.

[0014] The difamilast-containing composition included in the present disclosure may contain (A) difamilast, (B) at least one selected from the group consisting of diethylene glycol monoethyl ether, N-methyl-2-pyrrolidone (NMP), propylene glycol, and 1,3-butylene glycol, (C) liquid hydrocarbon, and (D) oil and fat. Hereinafter, these components may be referred to as components (A) to (D), respectively. Further, the composition according to the present disclosure containing components (A) to (D) may be referred to as the composition of the present disclosure.

[0015] As described above, difamilast (component (A)) is an oxazole compound represented by the following formula:

[0016]

Chemical formula

[0017] and its production method is described, for example, in Patent Documents 1 to 4 above. All of Patent Documents 1 to 4 are incorporated herein by reference in their entirety, particularly with respect to the production method of difamilast.

[0018] (B) component is, as described above, at least one selected from the group consisting of diethylene glycol monoethyl ether, N-methyl-2-pyrrolidone (NMP), propylene glycol (PG), and 1,3-butylene glycol (1,3-BG). Among these four components, diethylene glycol monoethyl ether and N-methyl-2-pyrrolidone are particularly preferred, and diethylene glycol monoethyl ether is more preferred. These four types can be used alone or in combination of two or more. Diethylene glycol monoethyl ether is a compound represented by CH3-CH2-O-CH2-CH2-O-CH2-CH2-OH and may be abbreviated as DEGEE. This compound is commercially available. For example, Super Refined TM DEGEE (Croda), Transcutol® (Gattefosse), Carbitol TM (Dow), ethoxydiglycol (NOF Corporation), etc. can be purchased and used.

[0019] Examples of the liquid hydrocarbon ((C) component) include hydrocarbons that are liquid at room temperature and normal pressure. Specifically, hydrocarbons that are liquid at 1°C and normal pressure are preferably cited. More specifically, examples include liquid paraffin, light liquid paraffin, squalane, squalene, etc. Among them, liquid paraffin and / or light liquid paraffin are preferred. The liquid hydrocarbon can be used alone or in combination of two or more.

[0020] As the oil or fat ((D) component), oils or fats that are liquid at normal temperature and normal pressure are preferably cited. Specifically, for example, oils or fats that are liquid at 15°C and normal pressure are preferably cited. More specifically, examples include triacetin, fatty acid esters (esters of fatty acids and alcohols), vegetable fats and oils, animal fats and oils, etc.

[0021] Examples of the fatty acids constituting the fatty acid ester include saturated or unsaturated fatty acids having 6 to 20 carbon atoms (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 20). More specifically, examples include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, and the like. Examples of the alcohol constituting the fatty acid ester include linear or branched-chain alkyl alcohols having 1 to 20 carbon atoms (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 20). The alkyl alcohol can be a monohydric or polyhydric (e.g., dihydric, trihydric, or tetrahydric) alcohol. In particular, when the alcohol constituting the fatty acid ester is glycerin (i.e., glycerin fatty acid ester), it is preferable. In this case, the fatty acid ester can be a monoglyceride (monoacylglycerol), a diglyceride (diacylglycerol), or a triglyceride (triacylglycerol). Among them, triglyceride is preferable, and medium-chain fatty acid triglyceride (MCT) is more preferable. The "medium-chain fatty acid" of the medium-chain fatty acid triglyceride is a saturated fatty acid having 4 to 10 carbon atoms, more preferably a saturated fatty acid having 8 or 10 carbon atoms (caprylic acid, capric acid).

[0022] Examples of vegetable fats and oils include olive oil, corn oil, palm oil, sunflower oil, soybean oil, castor oil, almond oil, rapeseed oil, cottonseed oil, sesame oil, and the like. Examples of animal fats and oils include shark oil, liver oil, sardine oil, cod liver oil, salmon oil, and the like.

[0023] Among the fats and oils, medium-chain fatty acid triglyceride, olive oil, almond oil, and soybean oil are preferable, and medium-chain fatty acid triglyceride and olive oil are more preferable.

[0024] The fats and oils can be used alone or in combination of two or more.

[0025] Component (A) is preferably contained in the composition of the present disclosure at, for example, 0.1 to 5% by mass. The upper or lower limit of the range may be, for example, 0.2, 0.3, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, or 4.5% by mass. For example, the range is more preferably 0.2 to 4% by mass, and even more preferably 0.2 to 3% by mass.

[0026] Also, component (B) is preferably contained in the composition of the present disclosure at, for example, 1 to 25% by mass. The upper or lower limit of the range may be, for example, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24% by mass. For example, the range is more preferably 0.5 to 20% by mass, and even more preferably 2 to 10% by mass.

[0027] Also, components (C) and (D) are preferably contained in the composition of the present disclosure in a total amount of, for example, 60 to 98% by mass. The upper or lower limit of the range may be, for example, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, or 98% by mass. For example, the range is more preferably 70 to 98% by mass, and even more preferably 75 to 95% by mass.

[0028] In addition, in the composition of the present disclosure, the content of component (C) is preferably 8 to 96% by mass. The upper or lower limit of the range may be, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% by mass. For example, the range is more preferably 10 to 95% by mass, and even more preferably 15 to 92% by mass. Note that the content of component (C) preferably satisfies the range of the total content of the above components (C) and (D). Further, the content of component (D) is preferably 1 to 80% by mass. The upper or lower limit of the range may be, for example, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or 75% by mass. For example, the range is more preferably 1.5 to 75% by mass, and even more preferably 2 to 60% by mass. Note that the content of component (D) preferably satisfies the range of the total content of the above components (C) and (D).

[0029] Although not particularly limited, in the composition of the present disclosure, within the range of the total content of components (C) and (D), the content of component (C) is preferably not less than the content of component (D). For example, in the composition of the present disclosure, it is particularly preferable that the content of component (C) is 60 to 90% by mass and the content of component (D) is 2 to 30% by mass. Further, the component (D) is preferably contained in the composition of the present disclosure in an amount of, for example, 0.1 to 10 parts by mass with respect to 1 part by mass of the component (B). The upper or lower limit of the range is, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, or 9.9 parts by mass. The range may be, for example, 0.2 to 8 parts by mass, 0.3 to 5 parts by mass, etc. Further, the component (C) is preferably contained in the composition of the present disclosure in an amount of, for example, 5 to 90 parts by mass with respect to 1 part by mass of the component (B). The upper or lower limit of the range is, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or 89 parts by mass. The range may be, for example, 6 to 85 parts by mass, or 10 to 80 parts by mass. Further, the component (B) is preferably contained in the composition of the present disclosure in an amount of, for example, 1 to 25 parts by mass with respect to 1 part by mass of the component (A). The upper or lower limit of the range may be, for example, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 parts by mass. For example, the range is more preferably 0.5 to 20 parts by mass, and even more preferably 2 to 15 parts by mass. Further, the component (C) is preferably contained in the composition of the present disclosure in an amount of, for example, 4 to 50 parts by mass with respect to 1 part by mass of the component (D). The upper or lower limit of the range may be, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49 parts by mass. For example, the range may be 5 to 45 parts by mass. Further, the components (C) and (D) are preferably contained in the composition of the present disclosure in a total amount of, for example, 60 to 400 parts by mass with respect to 1 part by mass of the component (A). The upper or lower limit of the range may be, for example, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, or 395 parts by mass. For example, the range may be 70 to 390 parts by mass. In addition, in the composition of the present disclosure, the component (C) is preferably contained in an amount of 50 to 400 parts by mass with respect to 1 part by mass of the component (A). The upper or lower limit of the range may be, for example, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, or 395 parts by mass. For example, the range may be 55 to 390 parts by mass. In addition, the parts by mass of the component (C) preferably satisfy the range of the total parts by mass of the above components (C) and (D). Further, the component (D) is preferably contained in an amount of 1 to 80 parts by mass with respect to 1 part by mass of the component (A). The upper or lower limit of the range may be, for example, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 parts by mass. For example, the range may be 1.5 to 75 parts by mass, or may be 2 to 60 parts by mass. In addition, the parts by mass of the component (D) preferably satisfy the range of the total parts by mass of the above components (C) and (D).

[0030] The composition of the present disclosure may contain components other than the components (A) to (D). Such components are not particularly limited. In some embodiments, the effects of the composition of the present disclosure are not inhibited by the inclusion of other components. In addition, (especially when the composition of the present disclosure is a liquid composition) since the component (C) and the component (D) are oil components, it may be necessary to use a surfactant (emulsifier) to stably contain a relatively large amount of an aqueous component. Since the surfactant may increase skin irritation, it is preferable to pay attention (especially to the amount of water and surfactant used) when using it.

[0031] From this perspective, although not necessarily limited thereto, components other than the components (A) to (D) are preferably components (preferably oil components) that dissolve in the component (C) or the component (D) without using a surfactant. For example, the composition of the present disclosure may further contain cholesterol. Cholesterol may be referred to as component (E). By further containing cholesterol, the composition of the present disclosure tends to have enhanced compatibility of each component (for example, measured by separation of the solution at about 60°C), which is preferable.

[0032] When the component (E) is contained in the composition of the present disclosure, it is preferably contained in an amount of, for example, 0.2 to 8% by mass. The upper or lower limit of the range may be, for example, 0.5, 0.8, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, or 7% by mass. For example, the range is more preferably 0.2 to 6% by mass, and even more preferably 0.5 to 5% by mass. Also, when the component (E) is contained in the composition of the present disclosure, it is preferably contained in an amount of, for example, 0.2 to 25 parts by mass with respect to 1 part by mass of the component (A). The upper or lower limit of the range may be, for example, 0.5, 0.8, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 parts by mass. For example, the range may be 0.5 to 24 parts by mass.

[0033] The composition of the present disclosure may further contain a thickening agent. The thickening agent may be referred to as the component (F). Examples of the thickening agent include dextrin fatty acid ester, inulin fatty acid ester, hydrogenated castor oil, wax, higher alcohol, higher fatty acid, etc. Examples of the wax include beeswax (preferably bleached beeswax), carnauba wax, microcrystalline wax, paraffin. The higher alcohol is an aliphatic alcohol having 15 or more carbons (C15) in the carbon chain. Examples thereof include C15 - 50 aliphatic alcohols, more preferably C15 - 30 aliphatic alcohols. More specifically, examples include cetyl alcohol, stearyl alcohol (or a mixture thereof), arachidyl alcohol (C20), behenyl alcohol (C22), 1 - triacontanol (C30), etc. The higher fatty acid is a fatty acid having 16 or more carbons (C16) in the carbon chain. Examples thereof include C16 - 50 fatty acids, more preferably C16 - 30 fatty acids. More specifically, examples include hexadecanoic acid (C16), stearic acid (C18), arachidonic acid (C20), behenic acid (C22), octacosanoic acid (C28), etc.

[0034] The thickening agent may be a dextrin fatty acid ester. As the fatty acid in the dextrin fatty acid ester, saturated or unsaturated fatty acids having 14 - 18 carbons are preferred, and among them, myristic acid, palmitic acid, and stearic acid are preferred. As the dextrin fatty acid ester, for example, dextrin myristate and dextrin palmitate are particularly preferably mentioned, and dextrin palmitate is most preferred. The thickening agent can be used alone or in combination of two or more.

[0035] When the component (F) is contained in the composition of the present disclosure, it is preferably contained in an amount of, for example, 0.1 to 20% by mass. The upper or lower limit of the range may be, for example, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19% by mass. For example, the range is more preferably 0.2 to 15% by mass, and even more preferably 0.5 to 10% by mass. Also, when the component (F) is contained in the composition of the present disclosure, it is preferably contained in an amount of, for example, 0.2 to 60 parts by mass with respect to 1 part by mass of the component (A). The upper or lower limit of the range may be, for example, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, or 59 parts by mass. For example, the range may be 0.5 to 55 parts by mass.

[0036] In addition, the descriptions of the preferred contents of the above components (A) to (F) may be arbitrarily combined, and any of the compositions of the present disclosure in which the contents of the respective components are defined in this way are preferred. That is, at least one range, or two ranges, three ranges, four ranges, five ranges, or six ranges, selected from the group consisting of the range of the preferred content of the above component (A), the range of the preferred content of the above component (B), the range of the preferred content of the above component (C), the range of the preferred content of the above component (D), the range of the preferred content of the above component (E), and the range of the preferred content of the above component (F), are combined and defined. Any of the compositions of the present disclosure is preferred. Further, the descriptions of the preferred content parts by mass of the above components (A) to (F) may be arbitrarily combined, and any of the compositions of the present disclosure in which the content parts by mass of each component are defined in this way are preferred. That is, at least one range selected from the group consisting of the range of the preferred content part by mass of the above component (B), the range of the preferred content part by mass of the above component (C), the range of the preferred content part by mass of the above component (D), the range of the preferred content part by mass of the above component (E), and the range of the preferred content part by mass of the above component (F) with respect to 1 part by mass of the above component (A), or two ranges, three ranges, four ranges, or five ranges, are preferably combined and defined for any of the compositions of the present disclosure.

[0037] In addition, it may contain known components used in ordinary external liquid compositions (particularly cosmetic compositions and external pharmaceutical compositions). In some embodiments, the effects of the compositions of the present disclosure are not inhibited by the inclusion of other components. Such components include, for example, humectants (such as hyaluronic acid, collagen, ceramide, glycerin, etc.), fragrances, preservatives, antioxidants, water, alcohol, etc., but are not particularly limited.

[0038] The compositions of the present disclosure can be prepared by using known techniques used in the manufacture of pharmaceutical preparations in light of the disclosure content of the present disclosure. For example, it can be prepared by appropriately mixing each component while heating (for example, to about 60 to 90 °C) using a thermostatic bath or the like.

[0039] The compositions of the present disclosure can be used, in the case of liquid compositions, for example, as lotions (especially oil lotions), liniments, and gels. They can also be used to prepare other topical preparations such as creams, sprays (e.g., pump sprays, aerosol preparations), and ointments. In addition, preparations that form a foam during use are sometimes referred to as foam agents. Sprays (e.g., pump sprays, aerosol preparations) are typical examples of foam agents. In a pump spray, a solution of the active ingredient (the content liquid) is discharged by the pressure of pressing the pump head, and when discharged, the solution passes through a mesh or the like in the pump to form a foam (bubble). In an aerosol preparation, a foam (bubble) is formed by ejecting a solution of the active ingredient (stock solution) together with a gas (e.g., liquefied gas or compressed gas) filled in the container.

[0040] For example, an aerosol preparation can be preferably prepared by combining the composition of the present disclosure with a propellant and filling it into a suitable pressure-resistant container (e.g., a spray can).

[0041] As the propellant, for example, known propellants can be used. Among them, dimethyl ether, butane, propane, LPG, etc. are preferable, and dimethyl ether is particularly preferable. For example, as shown in this specification, dimethyl ether has the ability to stably dissolve difamilast, and provides advantages to compositions containing difamilast, especially aerosolized preparations. The propellant can be used alone or in combination of two or more.

[0042] The combination ratio of the composition of the present disclosure and the propellant is preferably 50:50 to 90:10, more preferably 55:45 to 85:15 or 60:40 to 80:20, by mass ratio (composition of the present disclosure: propellant).

[0043] The composition ejected from the aerosol preparation thus obtained has low skin irritation and excellent skin permeability, as disclosed in this specification, which is preferable. Note that the composition ejected from the aerosol preparation can be in the form of a foam (bubble).

[0044] Further, although not particularly limited, the composition of the present disclosure used in the aerosol preparation preferably contains a thickener ((F) component). By including the thickener, the stability of the foam formed by spraying can be excellent, and the coatability can also be excellent (easy to spread and less likely to drip).

[0045] In addition, in this specification, "comprising" includes "consisting essentially of" and "consisting of" (The term "comprising" includes "consisting essentially of” and "consisting of."). Further, the present disclosure includes all arbitrary combinations of the constituent elements described in this specification. The expression "consisting essentially of" may specify, for example, 95% or more or 99% or more of the total weight of all components in the formulation. For example, it should be understood that, unless otherwise specified, the composition of the present disclosure may contain additional components such as impurities related to production and stability even if it is expressed as "consisting of".

[0046] Moreover, the various characteristics (properties, structures, functions, etc.) described for each embodiment of the present disclosure above may be combined in any manner in identifying the subject matter encompassed by the present disclosure. That is, the present disclosure includes all subject matters consisting of all possible combinations of each combinable characteristic described in this specification.

Examples

[0047] Hereinafter, the embodiments of the present disclosure will be described more specifically with examples, but the embodiments of the present disclosure are not limited to the following examples.

[0048] The compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (International Publication No. 2007 / 058338) and used as difamilast.

[0049] In addition, 0.3% and 1% of commercially available Moiselt (registered trademark) ointment (an ointment containing difamilast as an active ingredient: Otsuka Pharmaceutical Co., Ltd.) were used as 0.3% ointment and 1% ointment, respectively, in the following studies.

[0050] In addition, the following human skin and pig skin were used. Human skin: Human back or abdominal excised skin purchased from C.A.C. Co., Ltd. Pig skin: Yucatan micropig skin purchased from Jackson Laboratory Japan Co., Ltd.

[0051] Examination of the combination of each component 1 According to the formulation described in the following table, a liquid composition (oil lotion) containing 0.3% by mass or 1% by mass of difamilast was prepared.

[0052]

Table 1A

[0053] More specifically, it was prepared as follows. An oil bath was placed on a magnetic stirrer and heated to 70 °C or higher. Each raw material component was weighed into a glass vial, stirred using a magnetic stirrer, and heated to dissolve. After confirming that each raw material was completely dissolved, it was returned to room temperature.

[0054] For the obtained 0.3% formulation composition (Example 1-1) and 1% formulation composition (Example 1-2), the skin permeability of difamilast was evaluated by an in vitro skin permeability test (IVPT test) (n = 6) using human skin. In calculating the cumulative permeation amount in the skin permeability evaluation, it was calculated as the average value of the values obtained from each study. Also, unless otherwise specified, the skin permeability test was conducted with n = 6.

[0055] The human skin used was dermatomed to a thickness of about 500 μm, the thickness (μm) at the center of the skin section was measured, and the skin sections were assigned so that the skin thickness was the same among the test substance groups for each donor. In this test, a Franz cell (aperture diameter 11.28 mm) was used, a 40% aqueous PEG400 solution was used as the receptor solution, and the circulating water temperature was 33°C. Before the start of the test, the TEWL of human skin was measured, and it was confirmed that the trans-epidermal water loss (TEWL) was less than 15 g / m 2 / h.

[0056] In the Franz cell, the test composition (0.3% formulation composition (Example 1-1) and 0.3% ointment) was applied onto human skin at about 10 mg / cm 2 so that a state was established in which human skin was set between the test composition and the receptor solution. After dropping, it was gently spread, and the test was started. The receptor solution was collected in 200 μL aliquots at predetermined time intervals. Also, for each sampling, the same volume (200 μL) of the receptor solution as the sampled sample solution was replenished. The difamilast concentration in the sampling solution was measured using HPLC. From the obtained results, the cumulative permeation amount per unit area (1 cm 2 ) was calculated. The cumulative permeation amount is shown in Fig. 1a. The same test was also conducted for the 1% formulation composition (Example 1-2) and 1% ointment, and the results are shown in Fig. 1b. It was found that all compositions exhibited skin permeability equal to or better than that of the ointment.

[0057] Also, a liquid composition (emulsion lotion: Comparative Example 1) containing 1% by mass of difamilast was prepared according to the formulation described in the following table using polyoxyethylene (196) polyoxypropylene (67) glycol (a block copolymer of polyoxypropylene and polyoxyethylene) as a surfactant.

[0058]

Table 1B

[0059] For the liquid composition (Comparative Example 1) as well, an in vitro permeation test (IVPT) using human skin (n = 8) was conducted together with the 1% ointment. The obtained results are shown in Fig. 1c together with the results for the 1% ointment, as the cumulative permeation amount. It was found that the liquid composition (Comparative Example 1) had poor skin permeability.

[0060] Also, in the above-mentioned examination for evaluating the skin permeability of difamilast for the 1% formulation composition (Examples 1-2), the 24-hour cumulative permeation amount of the 1% formulation composition (Examples 1-2) was compared with the 24-hour cumulative permeation amount of the 1% ointment, and the relative permeation rate (%) with respect to the 1% ointment was calculated. Further, in the above-mentioned examination for evaluating the skin permeability of difamilast for the liquid composition (emulsion lotion: Comparative Example 1) containing 1% by mass of difamilast, the 24-hour cumulative permeation amount of the liquid composition (emulsion lotion: Comparative Example 1) containing 1% by mass of difamilast was compared with the 24-hour cumulative permeation amount of the 1% ointment, and the relative permeation rate (%) with respect to the 1% ointment was calculated. These results are shown in the table below. Also, the 24-hour cumulative permeation amounts of Examples 1-2 and Comparative Example 1 are graphed and shown in Fig. 1d.

[0061]

Table 1C

[0062] Examination of the combination of each component 2 According to the formulation described in the table below (the component amount values indicate mass %), a liquid composition (oil lotion) containing 1% by mass of difamilast was prepared in the same manner as above.

[0063]

Table 2

[0064] For each of the liquid compositions, an in vitro percutaneous absorption test (IVPT) (n = 3) using porcine skin (Yucatan micropig skin) was conducted in the same procedure as when using human skin. The obtained results are shown in the table above as the 24-hour cumulative permeation amount, and are also graphed and shown in Figure 2.

[0065] The composition containing difamilast, liquid hydrocarbon, and fats and oils does not have very good skin permeability. On the other hand, it was found that the composition containing diethylene glycol monoethyl ether (Example 2-1) has significantly excellent skin permeability.

[0066] Examination of the combination of each component 3 According to the formulation described in the table below (the component amount values indicate mass %), a liquid composition (oil lotion) containing 1% by mass of difamilast was prepared in the same manner as above.

[0067] [Table 3]

[0068] For each of the liquid compositions, an in vitro percutaneous absorption test (IVPT) (n = 3) using porcine skin (Yucatan micropig skin) was conducted in the same procedure as when using human skin. The obtained results are shown in the table above as the 24-hour cumulative permeation amount, and are also graphed and shown in Figure 3.

[0069] It was found that the composition containing difamilast, diethylene glycol monoethyl ether, and fats and oils does not have very good skin permeability.

[0070] Examination of the combination of each component 4 According to the formulation described in the table below (the component amount values indicate mass %), a liquid composition (oil lotion) containing 1% by mass of difamilast was prepared in the same manner as above.

[0071] [Table 4]

[0072]

Table 5A

Table 5B

[0073]

Table 6

[0074] For each of these liquid compositions, an in vitro percutaneous absorption test (IVPT) using pig skin (Yucatan micropig skin) (n = 3) was conducted in the same procedure as when using human skin. The results obtained are shown in the table above as the 24-hour cumulative permeation amount, and are also graphed and shown in FIGS. 4, 5a, 5b, and 6.

[0075] Compositions containing difamilast, liquid hydrocarbons, fats and oils, and diethylene glycol monoethyl ether were found to have excellent skin permeability, and furthermore, it was considered that the skin permeability was even better when the content ratio of the liquid hydrocarbon was relatively high. This unexpected effect was observed despite the fact that the liquid hydrocarbon and difamilast did not mix with each other. Also, compared with Examples 5-6 using diethylene glycol monoethyl ether, Examples 5-10 (with addition of N-methyl-2-pyrrolidone (NMP)) showed comparable skin permeability. In Reference Example 5-6 (with addition of isopropyl myristate (IPM)), a slight improvement in skin permeability was observed compared with other comparative examples, but the permeability improvement effect was not as high as that of Example 5-6 (with addition of diethylene glycol monoethyl ether) and Example 5-10 (with addition of N-methyl-2-pyrrolidone (NMP)). From these results, it was considered that compositions containing difamilast, liquid hydrocarbons, fats and oils, and in particular, compositions containing diethylene glycol monoethyl ether or NMP, were excellent in skin permeability. On the other hand, other additives generally said to have an effect of improving skin permeability were considered to have a low effect of improving skin permeability with respect to difamilast.

[0076] Examination of the combination of each component 5 A liquid composition (oil lotion) containing 0.3% by mass of difamilast was prepared in the same manner as above according to the formulation described in the following table (the component amount values indicate mass %).

[0077] [Table 7]

[0078] For each of the liquid compositions, an IVPT test (n = 3) using porcine skin (Yucatan micropig skin) was conducted in the same procedure as when using human skin. The results obtained were shown in the above table as the 24-hour cumulative permeation amount and were also graphed and shown in Figure 7.

[0079] Examination of the foam agent The case where the composition containing difamilast is applied to the skin as a foam was also assumed, and the skin permeability of the composition when it was made into a foam agent (specifically, an aerosol preparation) was also examined.

[0080] A liquid composition (oil lotion) containing 1% by mass of difamilast was prepared in the same manner as above. A predetermined amount of this was placed in an aerosol can, a valve was installed and vacuum crimped, and further a propellant was filled to prepare an aerosol preparation. The following table shows the formulation of the prepared preparation (the component amount values indicate mass %). Example 8a is the oil lotion, and Example 8b is the aerosol preparation prepared using the oil lotion as the formulation stock solution. Also, the liquid composition obtained by spraying the aerosol preparation was in the form of a foam.

[0081] [Table 8A]

[0082] For each of the liquid compositions and aerosol preparations, an in vitro percutaneous absorption test (IVPT test, n = 3) using porcine skin (Yucatan micropig skin) was conducted in the same procedure as when using human skin. The obtained results are shown in the table above as the 24-hour cumulative permeation amount, and are also graphed and shown in Figure 8a. In the IVPT test of the aerosol preparation, an aerosol preparation containing the same amount of difamilast as that contained in the liquid composition of Example 8a was spray-discharged into a weighing dish, an appropriate amount was weighed with a spatula, and then applied onto the porcine skin set in a Franz cell.

[0083] Regarding the difamilast-containing composition, it was confirmed that even when the liquid composition was made into a foam agent, it exhibited skin permeability equivalent to that of the liquid composition. Furthermore, a liquid composition (oil lotion) containing 1% by mass of difamilast was prepared in the same manner as above, a predetermined amount of this was placed in an aerosol can, a valve was installed and vacuum-crimped, and then a propellant was filled to prepare an aerosol preparation. The formulation of the prepared preparation (the component amount values indicate mass%) is shown in the table below.

Table 8B

[0084] Examination of skin irritation Formulation compositions obtained by removing difamilast and beeswax from the 0.3% formulation composition of Example 1-1 and the 1% formulation composition of Example 1-2 were prepared. For these, a skin irritation test was conducted using rabbit skin. As a result, all the compositions were classified as "weak irritants", indicating low skin irritation and being preferable.

[0085] Examination of the properties of the foam agent after spraying In the same manner as above, a liquid composition (oil lotion) containing 1% by mass of difamilast was prepared. A predetermined amount of this was collected in an aerosol can, a valve was installed and vacuum crimped, and further a propellant was filled to prepare an aerosol preparation. The formulation of the aerosol preparation (component amount values indicate mass %) is shown in the table below.

[0086]

Table 9

[0087] The liquid composition (formulation stock solution) was sprayed from the obtained aerosol formulation, and an appropriate amount was applied as a foam onto a slide glass. This was left standing and stored on a hot plate at 32.5 °C (skin surface temperature) for about 1 hour. When the foam was no longer visually observable, the formulation application area was sandwiched between cover glasses, the formulation was spread to an appropriate thickness, and then placed on the hot plate again. One day, four days, and one week after standing, the properties of the formulation were confirmed using a polarized light microscope. The foam immediately after spraying was also confirmed in the same manner. For Example 9b, although it was after one day after spraying, some crystals of difamilast were observed. On the other hand, for Examples 9a, 9c, and 9d, no crystals of difamilast were observed at any time point.

[0088] Since no difamilast crystals precipitated, in Examples 9a, 9c, and 9d, the liquid compositions (formulation stock solutions) containing no propellant were all in a supersaturated state with respect to difamilast, and it was considered that supersaturation was maintained even after the propellant volatilized after spraying. Also, from these results, it was considered that the thickening agent contributed to the maintenance of the supersaturated state. Also, for this reason, it was considered that some crystal precipitation was observed for Example 9b which did not contain a thickening agent.

[0089] Examination of the compatibility of the components contained in the preparation Diethylene glycol monoethyl ether, a polar solvent, and hydrocarbons (especially liquid hydrocarbons), a nonpolar solvent, do not mix. However, from the viewpoint of the stability of the formulation, it is preferable to make a composition in which these components are compatible. Therefore, the compatibility of the components in the formulation was examined.

[0090] Specifically, diethylene glycol monoethyl ether (DEGEE), medium-chain fatty acid triglyceride (MCT), olive oil, squalane, light liquid paraffin, and liquid paraffin were mixed according to the formulation described in the following table (the numerical values indicate mass %), and a mixed composition was prepared. Further, cholesterol (Chol) was added to the mixed composition to a predetermined concentration to prepare a test composition, and the compatibility of each component was examined.

[0091] Specifically, it was carried out as follows. Each component was weighed in a predetermined amount into a glass vial and mixed well. It was left standing at 60°C, room temperature, or in a cold place for a certain period of time, and the compatibility (separation of the solution) was visually confirmed. A score was given according to the following compatibility score from the compatibility results at each temperature. (The lower the compatibility score, the higher the compatibility.) Compatibility score 0: No separation in a cold place 1: No separation at room temperature (separation in a cold place) 2: Separation at room temperature (no separation upon heating (near 60°C)) 3: Separation upon heating (near 60°C)

[0092]

Table 10A

[0093]

Table 10B

[0094]

Table 10C

[0095]

Table 10D

[0096] Based on the results of the blending ratios of each component (compatibility score), a ternary phase diagram was created using the statistical analysis software JMP16 (SAS Institute). Figure 9a shows the ternary phase diagram for medium-chain triglyceride (MCT), olive oil, and squalane based on the compatibility scores described in Table 10A (diethylene glycol monoethyl ether is 15% by mass in all cases). In this ternary phase diagram, the boundary of the portion where the compositions with each compatibility score are plotted is indicated by a line (contour line). Also, in the ternary phase diagram for 0% by mass of cholesterol, as an example, the point where the compatibility score of the composition of 10A-3 was plotted is highlighted. Figure 9b collectively shows the ternary phase diagrams created based on the compatibility scores of each component described in Tables 10B to 10D.

[0097] From these results, it was found that the addition of cholesterol tended to enhance the compatibility of each component.

[0098] Furthermore, with the formulations described in the following table (the numerical values indicate % by mass), medium-chain triglyceride (MCT) and light liquid paraffin were further mixed with diethylene glycol monoethyl ether (DEGEE), polyethylene glycol (PEG400), propylene carbonate, or propylene glycol to prepare a mixed composition, and the compatibility of each component was examined in the same manner as above. The compatibility scores of each mixed composition are also shown in the following table.

[0099]

Table 10E

[0100] From the above results, it was considered that MCT and olive oil are miscible with both diethylene glycol monoethyl ether and hydrocarbons, and have the effect of making diethylene glycol monoethyl ether and hydrocarbons, which are immiscible with each other, miscible. From this, it was considered that this effect is preferably obtained particularly when diethylene glycol monoethyl ether is used.

[0101] Examination of the propellant used in the aerosol preparation The components used as propellants for aerosol formulations were examined.

[0102] The solubility of difamilast and the liquid composition (oil lotion) in dimethyl ether (DME) and butane used as propellants was examined.

[0103] A predetermined amount of difamilast was weighed into a compatibility bottle and a valve was attached. This was filled with a predetermined amount of propellant (see the following table for the composition ratio), and the solubility of difamilast at 5°C and 25°C was evaluated. The results are shown in accordance with the following table.

[0104]

Table 11

[0105] Also, in the same manner as in Example 9b, a liquid composition (oil lotion) was prepared, and an aerosol formulation was prepared using this and a propellant. The propellant used in Example 9b was dimethyl ether, and it was prepared by combining 70% by mass of the liquid composition (formulation stock solution) and 30% by mass of the propellant. However, in this study, the propellants and combination ratios shown in the following table were used.

[0106] After thoroughly shaking the prepared aerosol formulation, it was allowed to stand at 5°C or 25°C for 3 days, and the dissolved state was visually confirmed. Those in which the difamilast-containing liquid composition remained dissolved were evaluated as +, and those in which precipitation or deposition occurred in the difamilast-containing liquid composition were evaluated as -. This evaluation is also shown in accordance with the following table (NA indicates not implemented).

[0107]

Table 12

[0108] When only butane is used as the propellant, the solubility of difamilast and the difamilast-containing liquid composition is low. As the component used as the propellant, dimethyl ether (DME) or a mixture of dimethyl ether and butane is considered to be more preferable from the viewpoints of the solubility of difamilast and the solubility of the difamilast-containing liquid composition.

[0109] Examination of the stability of the high-concentration difamilast preparation According to the formulation described in the following table (the component amount values indicate mass %), a liquid composition (oil lotion) containing 1 mass % or 2 mass % of difamilast was prepared in the same manner as above.

[0110]

Table 13A

[0111] The composition of Example 13-1 was used as a 1% formulation stock solution, and the composition of Example 13-2 was used as a 2% formulation stock solution. If necessary, difamilast raw powder was further added thereto to adjust the difamilast content of the formulation stock solution (see the following table).

[0112]

Table 13B

[0113] Then, the stock solution and the propellant (dimethyl ether: DME) were combined and used at the ratios described in the following table in the same manner as above to prepare an aerosol formulation. The dissolution state of the aerosol formulation was visually confirmed at 25°C. After standing at 5°C for about 3 months, the dissolution state was visually confirmed again. Those that maintained the dissolution state were evaluated as +, those in which precipitation or deposition occurred were evaluated as -, and those in which phase separation occurred were evaluated as ±. When visually observing, those in which the whole formulation appeared to reflect blue, purple, yellow, etc. due to dispersion were evaluated as "phase separation". The results are shown in the following table.

[0114]

Table 13C

[0115] Examination of the foaming property of the foam agent A liquid composition (oil lotion) containing 1% by mass of difamilast was prepared in the same manner as above according to the formulation described in the following table (the component amount values indicate mass%). Then, a predetermined amount of this was collected into an aerosol can, a valve was installed and vacuum crimped, and further a propellant was filled to prepare an aerosol preparation. Dimethyl ether was used as the propellant, and those having a mass ratio of dimethyl ether:liquid composition (formulation stock solution) of 20:80, 30:70, or 40:60 were prepared respectively.

[0116] [Table 14]

[0117] For any of the aerosol preparations prepared from the liquid compositions, the foaming (foamability) of the foam obtained immediately after spraying was good, and there were no problems with the cooling sensation or dripping. Regarding the stability of the foam (foam retention time), among the thickeners, the one using dextrin palmitate was particularly preferred.

[0118] Photographs of the foams formed by spraying each of the aerosol preparations prepared using the liquid compositions of Examples 14-5, 14-6, 14-7, and 14-11 are shown in FIG. 10 immediately after spraying at room temperature.

[0119] It was found that the foamability of the foaming agent can be enhanced by using a thickener (especially dextrin palmitate).

[0120] Examination of each composition According to the composition of the following table (the component amount values indicate mass%), a liquid composition (Example D) and a foaming agent (specifically, an aerosol preparation) (Examples A to C) were prepared in the same manner as above. Further, the skin permeability of difamilast was evaluated by an IVPT test using human skin in the same manner as above, and the cumulative permeation amount over 24 hours was measured. The results are shown together with the following table and FIG. 11a.

[0121]

Table 15A

Table 15B

Claims

1. (A) difamilast, (B) at least one selected from the group consisting of diethylene glycol monoethyl ether, N-methyl-2-pyrrolidone (N-methyl-2-pyrrolidone; NMP), propylene glycol, and 1,3-butylene glycol, (C) liquid hydrocarbon, and (D) oil and fat, containing A liquid composition for applying to the skin.

2. (A) difamilast, (B) at least one selected from the group consisting of diethylene glycol monoethyl ether and N-methyl-2-pyrrolidone (N-methyl-2-pyrrolidone; NMP), (C) liquid hydrocarbon, and (D) oil and fat, containing A liquid composition for applying to the skin.

3. (A) difamilast, (B) diethylene glycol monoethyl ether, (C) liquid hydrocarbon, and (D) oil and fat, containing A liquid composition for applying to the skin.

4. (C) is at least one selected from the group consisting of liquid paraffin, light liquid paraffin, squalane, and squalene, or (D) is at least one selected from the group consisting of triacetin, fatty acid ester, vegetable fat oil, and animal fat oil, The liquid composition according to any one of Claims 1 to 3.

5. (C) is at least one selected from the group consisting of liquid paraffin, light liquid paraffin, squalane, and squalene, and (D) is at least one selected from the group consisting of triacetin, fatty acid ester, vegetable fat oil, and animal fat oil, The liquid composition according to any one of Claims 1 to 3.

6. The liquid composition according to any one of Claims 1 to 3, satisfying at least one of the following conditions (I) and (II). (I): Containing 1 to 25 parts by mass of (B) with respect to 1 part by mass of (A) (II): Containing a total of 60 to 400 parts by mass of (C) and (D) with respect to 1 part by mass of (A)

7. The liquid composition according to any one of Claims 1 to 3, satisfying at least one of the following conditions (i), (ii), and (iii). (i): Containing 0.1 to 5% by mass of (A) (ii): Containing 1 to 25% by mass of (B) (iii): Containing a total of 60 to 98% by mass of (C) and (D) Item 8: (D) is at least one selected from the group consisting of triacetin, an ester of a fatty acid and a linear or branched alkyl alcohol having 1 to 20 carbon atoms, a vegetable fat and oil that is liquid at 15°C and normal pressure, and an animal fat and oil that is liquid at 15°C and normal pressure. The liquid composition according to any one of Items 1 to 3. Item 9 Furthermore (E) cholesterol The liquid composition according to Item 8, further containing the same. Item 10 Furthermore (F) at least one selected from the group consisting of dextrin fatty acid ester and beeswax The liquid composition according to Item 8, further containing the same. Item 11 Furthermore (E) cholesterol, (F) at least one selected from the group consisting of dextrin fatty acid ester and beeswax The liquid composition according to Item 8, further containing the same. Item 12 The liquid composition according to any one of Items 1 to 3, and an aerosol preparation for skin application, wherein a propellant is filled in a pressure-resistant container. Item 13 The aerosol preparation according to Item 12, wherein the propellant contains dimethyl ether. Item 14 The liquid composition according to any one of Items 1 to 3, which is a pharmaceutical composition.

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