Difamilast-containing composition

Abstract

Provided is a difamilast-containing composition that has excellent skin permeability (and preferably is easy to spread and has low skin irritation). Specifically, provided is a liquid composition comprising (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) fat and oil.

Description

DIFAMILAST-CONTAINING COMPOSITION

[0001] The present disclosure relates to, for example, a composition containing an oxazole compound (particularly difamilast). The present application claims priority to and the benefit of Japanese Patent Application No. 2024-087458 filed on May 29, 2024, which is hereby incorporated by reference in its entirety.

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

[0003] WO2007 / 058338 (JP2009-515872A)WO2014 / 034958 (JP2015-528433A)WO2017 / 115780 (JP2019-503989A)WO2019 / 194211 (JP2021-517111A)

[0004] Difamilast is an example of such oxazole compounds represented by the following formula:

[0005]

[0006] and the production methods thereof are disclosed, for example, in PTL 1 to PTL 4. The IUPAC name of difamilast is (N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxybenzamide).

[0007] Examples of difamilast preparations for use in the treatment of skin diseases, such as atopic diseases, include creams (o / w, w / o), lotions (o / w, alcohol), and the like.

[0008] However, since difamilast has very low solubility in water, in order to make these dosage forms, it is necessary to dissolve difamilast in alcohol or a Lipophilic solvent, followed by emulsification with a surfactant. However, due to the use of a surfactant, the resulting creams and lotions have stronger skin irritation than ointments. (In general, creams and lotions cause more skin irritation than ointments.) An emulsion lotion (o / w lotion) with reduced skin irritation was examined; however, its skin permeability was lower than that of an ointment and was not sufficient to provide efficacious delivery of difamilast.

[0009] Accordingly, further examination was carried out with the primary object of obtaining a difamilast-containing composition that has excellent skin permeability.

[0010] The present disclosure includes, for example, the subject matter described in the following items. Item 1. A liquid composition comprising: (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) fat and oil. Item 2. A liquid composition comprising: (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) fat and oil. Item 3. A liquid composition comprising: (A) difamilast; (B) diethylene glycol monoethyl ether; (C) liquid hydrocarbon; and (D) fat and oil. Item 4. The liquid composition according to any one of Items 1 to 3, wherein (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, a fatty acid ester, vegetable oil, and animal oil. Item 5. The liquid composition according to any one of Items 1 to 3, wherein (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, a fatty acid ester, vegetable oil, and animal oil. Item 6. The liquid composition according to any one of Items 1 to 5, which satisfies at least one (preferably two) of the following conditions (I) and (II): (I): containing 1 to 25 parts by mass of (B) per part by mass of (A); and (II): containing 60 to 400 parts by mass of (C) and (D) in total per part by mass of (A). Item 7. The liquid composition according to any one of Items 1 to 6, which satisfies at least one (preferably two) of the following conditions (III) and (IV): (III): containing 50 to 400 parts by mass of (C) per part by mass of (A); and (IV): containing 1 to 80 parts by mass of (D) per part by mass of (A). Item 8. The liquid composition according to any one of Items 1 to 7, which satisfies at least one (preferably two or three) of the following three conditions: containing 0.1 to 10 parts by mass of (D) per part by mass of (B); containing 5 to 90 parts by mass of (C) per part by mass of (B); and containing 4 to 50 parts by mass of (C) per part by mass of (D). Item 9. The liquid composition according to any one of Items 1 to 8, which satisfies at least one (preferably two or three) of the following conditions (i), (ii), and (iii): (i): containing 0.1 to 5 mass% of (A); (ii): containing 1 to 25 mass% of (B); and (iii): containing 60 to 98 mass% of (C) and (D) in total. Item 10. The liquid composition according to any one of Items 1 to 9, which satisfies at least one (preferably two) of the following conditions (iv) and (V): (iv): containing 8 to 96 mass% of (C); and (v): containing 1 to 80 mass% of (D). Item 11. The liquid composition according to any one of Items 1 to 10, further comprising: (E) cholesterol (preferably in an amount of 0.2 to 8 mass%). Item 12. The liquid composition according to Item 11, wherein (E) is contained in an amount of 0.2 to 25 parts by mass per part by mass of (A). Item 13. The liquid composition according to any one of Items 1 to 12, further comprising: (F) at least one selected from the group consisting of a dextrin fatty acid ester and beeswax (preferably in an amount of 0.1 to 20 mass%). Item 14. The liquid composition according to Item 13, wherein (F) is contained in an amount of 0.2 to 60 parts by mass per part by mass of (A). Item 15. The liquid composition according to any one of Items 1 to 14, further comprising: (E) cholesterol, and (F) at least one selected from the group consisting of a dextrin fatty acid ester and beeswax. Item 16. An aerosol preparation comprising the liquid composition according to any one of Items 1 to 15 and a propellant, both of which are placed in a pressure-resistant container. Item 17. The aerosol preparation according to Item 16, wherein the propellant comprises 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 an external composition. Item 20. The liquid composition or aerosol preparation according to Item 18 or 19, which is for use in the treatment of skin diseases. Item 21. A method for treatment of skin diseases, comprising: 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.

[0011] Provided is a difamilast-containing composition that has excellent skin permeability. The composition is preferably easy to spread and has low skin irritation. Further, the composition has excellent stability and skin applicability. Therefore, the composition is suitable for applying difamilast to the treatment of skin diseases (e.g., dermatitis, particularly atopic dermatitis).

[0012] Fig. 1a shows the results of an in vitro permeation test (IVPT) using human skin for a 0.3 mass% difamilast-containing composition (Example 1-1), which are shown as the cumulative amounts of difamilast permeated. The results of a similar examination on a 0.3% ointment are also shown.Fig. 1b shows the results of IVPT using human skin for a 1 mass% difamilast-containing composition (Example 1-2), which are shown as the cumulative amounts of difamilast permeated. The results of a similar examination on a 1% ointment are also shown.Fig. 1c shows the results of IVPT using human skin for a 1 mass% difamilast-containing emulsion lotion (o / w) composition (Comparative Example 1), which are shown as the cumulative amounts of difamilast permeated. The results of a similar examination on a 1% ointment are also shown.Fig. 1d shows the cumulative amounts of difamilast permeated over 24 hours when evaluating its skin permeability for Examples 1-2 and Comparative Example 1 (IVPT).Fig. 2 shows the skin permeability of liquid compositions containing 1 mass% difamilast (oil lotions) examined by IVPT using pig skin, and the results are shown as the cumulative amounts of difamilast permeated.Fig. 3 shows the skin permeability of liquid compositions containing 1 mass% difamilast (oil lotions) examined by IVPT using pig skin, and the results are shown as the cumulative amounts of difamilast permeated.Fig. 4 shows the skin permeability of liquid compositions containing 1 mass% difamilast (oil lotions) examined by IVPT using pig skin, and the results are shown as the cumulative amounts of difamilast permeated.Fig. 5a shows the skin permeability of liquid compositions containing 1 mass% difamilast (oil lotions) examined by IVPT using pig skin, and the results are shown as the cumulative amounts of difamilast permeated.Fig. 5b shows the skin permeability of liquid compositions containing 1 mass% difamilast (oil lotions) examined by IVPT using pig skin, and the results are shown as the cumulative amounts of difamilast permeated.Fig. 6 shows the skin permeability of liquid compositions containing 1 mass% difamilast (oil lotions) examined by IVPT using pig skin, and the results are shown as the cumulative amounts of difamilast permeated.Fig. 7 shows the skin permeability of liquid compositions containing 0.3 mass% difamilast (oil lotions) examined by IVPT using pig skin, and the results are shown as the cumulative amounts of difamilast permeated.Fig. 8a shows the skin permeability of a liquid composition containing 1 mass% difamilast (oil lotion) and a foam agent prepared from the liquid composition examined by IVPT using pig skin, and the results are shown as the cumulative amounts of difamilast permeated.Fig. 8b shows the skin permeability of foam agents prepared from a liquid composition containing 1 mass% difamilast (oil lotion) examined by IVPT using pig skin, and the results are shown as the cumulative amounts of difamilast permeated.Fig. 9a shows the results of examining the compatibility of components using a test composition prepared by mixing diethylene glycol monoethyl ether (DEGEE), medium-chain fatty acid triglyceride (MCT), olive oil, and squalane in the formulation shown in Table 11A (the numerical values indicate mass%) to prepare a mixed composition, and further adding cholesterol to the mixed composition to a predetermined concentration. The results are shown as three-phase diagrams.Fig. 9b shows the results of examining the compatibility of components using a test composition prepared by mixing diethylene glycol monoethyl ether (DEGEE), medium-chain fatty acid triglyceride (MCT), squalane, light liquid paraffin, and liquid paraffin in the formulations shown in Tables 10B to 10D (the numerical values indicate mass%) to prepare a mixed composition, and further adding cholesterol to the mixed composition to a predetermined concentration. The results are shown as three-phase diagrams.Fig. 10 shows photographs of foams formed by spraying aerosol preparations prepared using the liquid compositions of Examples 14-5, 14-6, 14-7, and 14-11 at room temperature immediately after spraying.Fig. 11a shows the skin permeability of foam agents prepared from a liquid composition containing 1 mass% difamilast (oil lotion) examined by IVPT using human skin, and the results are shown as the cumulative amounts of difamilast permeated.Fig. 11b shows the skin permeability of foam agents prepared from a liquid composition containing 1 mass% difamilast (oil lotion) examined by IVPT using human skin, and the results are shown as the cumulative amounts of difamilast permeated.

[0013] Embodiments included in the present disclosure will be described in more detail below. The present disclosure preferably includes a difamilast-containing composition and a method for producing the same, but is not limited thereto. The present disclosure includes everything disclosed in the present specification and recognizable to a person skilled in the art.

[0014] The difamilast-containing composition included in the present disclosure may comprise (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) fat and oil. Hereinafter, these components may be referred to as “component (A)” to “component (D),” respectively. In addition, the composition comprising the components (A) to (D) according to the present disclosure 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]

[0017] and the production methods thereof are disclosed, for example, in PTL 1 to PTL 4, listed above, which are hereby incorporated by reference in their entirety and particularly in relation to production methods of difamilast.

[0018] The component (B) is 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), as described above. Among these four components, diethylene glycol monoethyl ether and N-methyl-2-pyrrolidone are particularly preferred, with diethylene glycol monoethyl ether being more preferred. These four types can be used singly or in combination of two or more. The 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 RefinedTMDEGEE (Croda), TranscutolTM(Gattefosse), CarbitolTM(Dow), and Ethoxydiglycol (NOF Corporation) can be purchased and used.

[0019] Examples of the liquid hydrocarbon (component (C)) include hydrocarbons that are liquid at room temperature and normal pressure, and specific preferred examples include hydrocarbons that are liquid at 1°C and normal pressure. More specific examples include liquid paraffin, light liquid paraffin, squalane, squalene, and the like. Preferred among these are liquid paraffin and / or light liquid paraffin. The liquid hydrocarbons can be used singly or in combination of two or more.

[0020] The fat and oil (component (D)) are preferably fat and oil that are liquid at room temperature and normal pressure. Specific preferred examples include fats and oils that are liquid at 15°C and normal pressure. More specific examples include triacetin, fatty acid esters (esters of fatty acids and alcohols), vegetable oils, animal oils, and the like.

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

[0022] Examples of vegetable 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 oils include shark oil, liver oil, herring oil, cod liver oil, salmon oil, and the like.

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

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

[0025] The component (A) is preferably contained in an amount of, for example, 0.1 to 5 mass% in the composition of the present disclosure. 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 mass%. For example, the range is more preferably 0.2 to 4 mass%, and even more preferably 0.2 to 3 mass%.

[0026] The component (B) is preferably contained in an amount of, for example, 1 to 25 mass% in the composition of the present disclosure. 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 mass%. For example, the range is more preferably 0.5 to 20 mass%, and even more preferably 2 to 10 mass%.

[0027] The components (C) and (D) are preferably contained in a total amount of, for example, 60 to 98 mass% in the composition of the present disclosure. 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 mass%. For example, the range is more preferably 70 to 98 mass%, and even more preferably 75 to 95 mass%.

[0028] The component (C) is preferably contained in an amount of 8 to 96 mass% in the composition of the present disclosure. 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 mass%. For example, the range is more preferably 10 to 95 mass%, and even more preferably 15 to 92 mass%. The content of the component (C) preferably satisfies the range of the total content of the components (C) and (D) described above. The component (D) is preferably contained in an amount of 1 to 80 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 mass%. For example, the range is more preferably 1.5 to 75 mass%, and even more preferably 2 to 60 mass%. The content of the component (D) preferably satisfies the range of the total content of the components (C) and (D) described above.

[0029] Although it is not particularly limited, it is preferable for the components (C) and (D) in the composition of the present disclosure that the content of the component (C) is equal to or greater than the content of the component (D) in the range of the total content of the components (C) and (D). For example, it is particularly preferable that in the composition of the present disclosure, the content of the component (C) is 60 to 90 mass%, whereas the content of the component (D) is 2 to 30 mass%. 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 per part by mass of the component (B). The upper or lower limit of the range may be, 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 or 0.3 to 5 parts by mass. 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 per part by mass of the component (B). The upper or lower limit of the range may be, 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. It may be 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. 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 per 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. 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 per 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. 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 per 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. The component (C) is preferably contained in the composition of the present disclosure in an amount of 50 to 400 parts by mass per 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, It may be 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. The parts by mass of the component (C) preferably also satisfy the range of the total parts by mass of the components (C) and (D) described above. The component (D) is preferably contained in an amount of 1 to 80 parts by mass per 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 2 to 60 parts by mass. The parts by mass of the component (D) preferably also satisfy the range of the total parts by mass of the components (C) and (D) described above.

[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 disclosure are not impaired by incorporation of other components. Since the components (C) and (D) are oily components (particularly when the composition of the present disclosure is a liquid composition), it may be necessary to use a surfactant (emulsifier) to stably contain a relatively large amount of aqueous components. Since surfactants may increase skin irritation, it is preferable to be careful when using them (particularly with the amounts of water and surfactant used).

[0031] From this viewpoint, the components other than the components (A) to (D) are preferably components (preferably oily components) that dissolve in the components (C) and (D) without the use of a surfactant, although they are not limited thereto. For example, the composition of the present disclosure may further contain cholesterol. Cholesterol is also referred to as the component (E). The composition of the present disclosure preferably further contains cholesterol because the compatibility (e.g., as measured by solution separation at around 60°C) of each component tends to increase.

[0032] When contained in the composition of the present disclosure, the component (E) is preferably contained in an amount of, for example, 0.2 to 8 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 mass%. For example, the range is more preferably 0.2 to 6 mass%, and even more preferably 0.5 to 5 mass%. Further, when contained in the composition of the present disclosure, the component (E) is preferably contained in an amount of, for example, 0.2 to 25 parts by mass per 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 thickener. The thickener is also referred to as the “component (F).” Examples of the thickener include dextrin fatty acid esters, inulin fatty acid esters, Hydrogenated Castor Oils, waxes, Fatty alcohols, higher fatty acids, and the like. Examples of waxes include beeswax (preferably white beeswax), carnauba wax, microcrystalline wax, and paraffin wax. Fatty alcohols are aliphatic alcohols having 15 or more carbon atoms in the carbon chain (C15), and examples include C15-50aliphatic alcohols, and more preferably C15-30aliphatic alcohols. More specific examples include cetyl alcohol, stearyl alcohol (or a mixture thereof), arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), and the like. Higher fatty acids are fatty acids having 16 or more carbon atoms in the carbon chain (C16), and examples include C16-50fatty acids, and more preferably C16-30fatty acids. More specific examples include hexadecanoic acid (C16), stearic acid (C18), arachidonic acid (C20), behenic acid (C22), octacosanoic acid (C28), and the like.

[0034] The thickener is may be a dextrin fatty acid ester. The fatty acid of the dextrin fatty acid ester is preferably a C14-18saturated or unsaturated fatty acid. Preferred among these are myristic acid, palmitic acid, and stearic acid. As the dextrin fatty acid ester, dextrin myristate and dextrin palmitate are particularly preferred, with dextrin palmitate being the most preferred. The thickeners can be used singly or in combination of two or more.

[0035] When contained in the composition of the present disclosure, the component (F) is preferably contained in an amount of, for example, 0.1 to 20 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, or 19 mass%. For example, the range is more preferably 0.2 to 15 mass%, and even more preferably 0.5 to 10 mass%. Further, when contained in the composition of the present disclosure, the component (F) is preferably contained in an amount of, for example, 0.2 to 60 parts by mass per 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] The descriptions of the preferred contents of the components (A) to (F) may be combined in any way, and any of the compositions of the present disclosure in which the content of each component is thus specified is preferred. That is, preferred is any of the compositions of the present disclosure defined by at least one range, or by combining two, three, four, five, or six ranges, selected from the group consisting of the preferred content range of the component (A), the preferred content range of the component (B), the preferred content range of the component (C), the preferred content range of the component (D), the preferred content range of the component (E), and the preferred content range of the component (F). The descriptions of the preferred parts by mass of the components (A) to (F) may be combined in any way, and any of the compositions of the present disclosure in which the parts by mass of each component are thus specified is preferred. That is, preferred is any of the compositions of the present disclosure defined by at least one range, or by combining two, three, four, or five ranges, selected from the group consisting of the preferred range of parts by mass of the component (B), the preferred range of parts by mass of the component (C), the preferred range of parts by mass of the component (D), the preferred range of parts by mass of the component (E), and the preferred range of parts by mass of the component (F), per part by mass of the component (A).

[0037] In addition, known components used for general external liquid compositions (particularly cosmetic compositions and topical pharmaceutical compositions) may also be contained. In some embodiments, the effects of the composition of the disclosure are not impaired by incorporation of other components. Examples of such components include, but are not particularly limited to, moisturizing components (e.g., hyaluronic acid, collagen, ceramide, and glycerin), fragrances, preservatives, antioxidants, water, alcohol, and the like.

[0038] The composition of the present disclosure can be prepared by using techniques known for the preparation of formulations in light of the present disclosure. For example, the composition of the present disclosure can be prepared by mixing each component appropriately while heating (e.g., at about 60 to 90°C) using, for example, a thermostatic chamber or the like.

[0039] In the case of a liquid composition, the composition of the present disclosure can be used, for example, as a lotion (particularly an oil lotion), a liniment, or a gel. The composition of the present disclosure can also be used, for example, to prepare creams, sprays (e.g., pump sprays and aerosol preparations), ointments, and other external preparations. Preparations that form foam when used are also referred to as “foam agents.” Sprays (e.g., pump sprays and aerosol preparations) are typical examples of foam agents. In a pump spray, a solution of the active ingredient (content liquid) is discharged by pressure to push a pump head, and as the solution is discharged, foam is formed as it passes through a mesh or the like inside the pump. In an aerosol preparation, foam is formed by spraying a solution of the active ingredient (stock solution) together with a gas (e.g., liquefied gas or compressed gas) contained in a container.

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

[0041] As the propellant, for example, known propellants can be used, among which dimethyl ether, butane, propane, LPG, etc. are preferred, with dimethyl ether being particularly preferred. For example, dimethyl ether, which, as shown herein is able to stably dissolve difamilast, provides other benefit to compositions comprising difamilast and, specifically, aerosolized formulations. The propellants can be used singly or in combination of two or more.

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

[0043] The composition sprayed from the thus-obtained aerosol preparation is preferred because it has low skin irritation and excellent skin permeability as disclosed in the present application. The composition sprayed from the aerosol preparation may be in the form of foam.

[0044] Although it is not particularly limited, the composition of the present disclosure used for aerosol preparations preferably contains a thickener (component (F)). By containing a thickener, the foam formed by spraying may have excellent stability and excellent spreadability (easy to spread and does not easily drip).

[0045] In the present specification, the term “comprising” includes “consisting essentially of” and “consisting of.” Further, the present disclosure includes all of any combinations of the constituent requirements described in the present specification. “Consisting essentially of” may identify, for example, more than 95% or more than 99% by weight of all the components in a formulation. For example, it will be understood that the compositions of the present disclosure, even in “consisting of” constructions, may include some additional components such as impurities associated with manufacturing and stability unless indicated otherwise.

[0046] In addition, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure described above may be combined in any way in specifying the subject matters included in the present invention. In other words, the present disclosure includes all the subject matters comprising all combinations of the combinable characteristics described in the present specification.

[0047] An embodiment of the present disclosure will be described in more detail below by showing examples; however, the embodiment of the present disclosure is not limited to the following examples.

[0048] Using the method described in Example 352 of PTL 1 (WO2007 / 058338), Compound (5) (white powder) was prepared and used as difamilast.

[0049] Commercially available Moizerto (trademark) ointments (ointments containing difamilast as an active ingredient: Otsuka Pharmaceutical Co., Ltd.) 0.3% and 1% were used as a 0.3% ointment and a 1% ointment, respectively, in the following examinations.

[0050] The following human skin and pig skin were used. Human skin: human back or abdominal skin purchased from KAC Co., Ltd. Pig skin: Yucatan micropig skin purchased from Jackson Laboratory Japan, Inc.

[0051] Examination of Combinations of Each Component 1 Liquid compositions (oil lotions) containing 0.3 mass% or 1 mass% difamilast were prepared according to the formulations shown in the table below.

[0052]

[0053] More specifically, the liquid compositions were 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 the magnetic stirrer, and dissolved by heating. After confirming that each raw material was completely dissolved, the mixture 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 permeation test (IVPT) using human skin (n = 6). When calculating the cumulative permeation amount in the skin permeability evaluation, the average of the values obtained from the examinations was calculated. Unless otherwise specified, the skin permeability test was carried out with n = 6.

[0055] The human skin used was dermatomed to a thickness of approximately 500 μm, and the thickness (μm) of the center of each skin section was measured. The skin sections were assigned to each donor so that the skin thickness was similar among the test substance groups. In this test, a Franz cell (opening diameter: 11.28 mm) was used, a 40% aqueous solution of PEG 400 was used as a receptor liquid, and the circulating water temperature was set at 33°C. Before the start of the test, the Transepidermal Water Loss (TEWL) of the human skin was measured and confirmed to be less than 15 g / m2 / h.

[0056] In the Franz cell, the test compositions (0.3% formulation composition (Example 1-1) and 0.3% ointment) were each dropped on the human skin at about 10 mg / cm2so that the human skin was set between the test composition and the receptor liquid. Then, the test composition was lightly spread, and the test was started. 200 μL of the receptor liquid was collected at predetermined time intervals. At each time of sampling, the same amount (200 μL) of the receptor liquid as the amount of the sampled solution was replenished. The difamilast concentration in the sampled solution was measured by HPLC. From the results obtained, the cumulative amount permeated per unit area (1 cm2) was calculated. The cumulative permeation amount is shown in Fig. 1a. The 1% formulation composition (Example 1-2) and the 1% ointment were also tested in the same manner, and the results are shown in Fig. 1b. It was found that both compositions had skin permeability equal to or greater than that of ointments.

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

[0058]

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

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

[0061]

[0062] Examination of Combinations of Each Component 2 Liquid compositions containing 1 mass% difamilast (oil lotions) were prepared in the same manner as described above according to the formulations shown in the table below (the component amounts are expressed in mass%).

[0063]

[0064] The liquid compositions were each subjected to IVPT (n = 3) using pig skin (Yucatan micropig skin) in the same manner as when using human skin. The results obtained are shown as 24-hour cumulative permeation amounts in the table above, and are shown graphically in Fig. 2.

[0065] It was found that the compositions containing difamilast, liquid hydrocarbon, and fat and oil did not have very good skin permeability, whereas the composition further containing diethylene glycol monoethyl ether (Example 2-1) had significantly excellent skin permeability.

[0066] Examination of Combinations of Each Component 3 Liquid compositions containing 1 mass% difamilast (oil lotions) were prepared in the same manner as described above according to the formulations shown in the table below (the component amounts are expressed in mass%).

[0067]

[0068] The liquid compositions were each subjected to IVPT (n = 3) using pig skin (Yucatan micropig skin) in the same manner as when using human skin. The results obtained are shown as 24-hour cumulative permeation amounts in the table above, and are shown graphically in Fig. 3.

[0069] It was found that the compositions containing difamilast, diethylene glycol monoethyl ether, and fat and oil did not have very good skin permeability.

[0070] Examination of Combinations of Each Component 4 Liquid compositions containing 1 mass% difamilast (oil lotions) were prepared in the same manner as described above according to the formulations shown in the tables below (the component amounts are expressed in mass%).

[0071]

[0072]

[0073]

[0074] The liquid compositions were each subjected to IVPT (n = 3) using pig skin (Yucatan micropig skin) in the same manner as when using human skin. The results obtained are shown as 24-hour cumulative permeation amounts in the table above, and are shown graphically in Figs. 4, 5a, 5b, and 6.

[0075] The compositions containing difamilast, liquid hydrocarbon, fat and oil, and diethylene glycol monoethyl ether had excellent skin permeability. Further, a relatively higher content of liquid hydrocarbon as compared to those described in Table 3 was considered to result in more excellent skin permeability. This unexpected effect was seen despite liquid hydrocarbons and difamilast being immiscible. Compared with Example 5-6, which used diethylene glycol monoethyl ether, Example 5-10 (N-methyl-2-pyrrolidone (NMP) added) showed the same degree of skin permeability. Reference Example 5-6 (isopropyl myristate (IPM) added) showed a slight improvement in skin permeability compared with other Comparative Examples, but did not show the same degree of improvement in permeability as Example 5-6 (diethylene glycol monoethyl ether added) and Example 5-10 (N-methyl-2-pyrrolidone (NMP) added). From these results, the compositions containing particularly diethylene glycol monoethyl ether or NMP in addition to difamilast, liquid hydrocarbon, and fat and oil were considered to have excellent skin permeability. On the other hand, other additives that are generally said to have a skin permeability-enhancing effect were considered to have a low skin permeability-enhancing effect on difamilast.

[0076] Examination of Combinations of Each Component 5 Liquid compositions containing 0.3 mass% difamilast (oil lotions) were prepared in the same manner as described above according to the formulations shown in the table below (the component amounts are expressed in mass%).

[0077]

[0078] The liquid compositions were each subjected to IVPT (n = 3) using pig skin (Yucatan micropig skin) in the same manner as when using human skin. The results obtained are shown as 24-hour cumulative permeation amounts in the table above, and are shown graphically in Fig. 7.

[0079] Examination of Foam Agents Considering the case in which a composition containing difamilast is applied to the skin as foam, the skin permeability when the composition was used as a foam agent (specifically an aerosol preparation) was also examined.

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

[0081]

[0082] The liquid composition and aerosol preparation were each subjected to IVPT (n = 3) using pig skin (Yucatan micropig skin) in the same manner as when using human skin. The results obtained are shown as 24-hour cumulative permeation amounts in the table above, and are shown graphically in Fig. 8a. In the IVPT of the aerosol preparation, the aerosol preparation containing the same amount of difamilast as the amount of difamilast contained in the liquid composition of Example 8a was sprayed into a weighing dish, and an appropriate amount was weighed using a spatula and applied to the pig skin set in the Franz cell.

[0083] It was confirmed that even when the liquid composition was formed into a foam agent, the difamilast-containing composition exhibited skin permeability equivalent to that of the liquid composition. Further, liquid compositions containing 1 mass% difamilast (oil lotions) were prepared in the same manner as described above, a predetermined amount of each composition was placed in an aerosol can, a valve was installed and vacuum-clinched, and further a propellant was placed therein to prepare aerosol preparations. The table below shows the formulations of the prepared preparations (the component amounts are expressed in mass%). The aerosol compositions were each subjected to IVPT (n = 3) using pig skin (Yucatan micropig skin) in the same manner as when using human skin. The results obtained are shown as 24-hour cumulative permeation amounts in the table above, and are shown graphically in Fig. 8b. Example 8-3 (propylene glycol added) and Example 8-4 (1,3-BG added) showed a slight increase in the cumulative permeation amount. Examples 8-1 and 8-2, in which diethylene glycol monoethyl ether was used, showed even higher effects than Examples 8-3 and 8-4. No improvement in permeability was confirmed in Comparative Example 8-2 (PEG 400 added), Comparative Example 8-3 (propylene carbonate added), Comparative Example 8-4 (dimethyl isosorbide added), or Comparative Example 8-5 (glycerin added). The cumulative permeation amount of Comparative Example 8-1 (diethylene glycol monoethyl ether-free formulation) was clearly lower than that of Examples 8-1 and 8-2, and the permeability-promoting effect of diethylene glycol monoethyl ether was also confirmed in the foaming agent.

[0084] Examination of Skin Irritation A formulation composition was prepared in which difamilast and white beeswax were removed from the 0.3% formulation composition of Example 1-1, and a formulation composition was prepared in which difamilast and white beeswax were removed from the 1% formulation composition of Example 1-2. When a skin irritation test using rabbit skin was carried out on these compositions, both of them were classified as “slight irritants,” indicating that they caused low skin irritation and were therefore preferable.

[0085] Examination of Properties of Foam Agent after Spraying Liquid compositions containing 1 mass% difamilast (oil lotions) were prepared in the same manner as described above, a predetermined amount of each composition was placed in an aerosol can, a valve was installed and vacuum-clinched, and further a propellant was placed therein to prepare aerosol preparations. The table below shows the formulations of the aerosol preparations (the component amounts are expressed in mass%).

[0086]

[0087] The liquid composition (preparation stock solution) was sprayed from each of the resulting aerosol preparations, and an appropriate amount was applied as foam to a glass slide. This was allowed to stand on a hot plate at 32.5°C (skin surface temperature) for about 1 hour. When the foam was no longer visible to the naked eye, the area coated with the preparation was sandwiched between the glass slide and cover glass to spread the preparation to an appropriate thickness, and then the glass slide was placed back on the hot plate. After one day, four days, and one week of standing, the properties of the preparations were observed using a polarizing microscope. The foam immediately after spraying was also observed in the same manner. Regarding Example 9b, some difamilast crystals were observed one day after spraying. On the other hand, regarding Examples 9a, 9c, and 9d, no difamilast crystals were observed at any time point.

[0088] Since no difamilast crystals precipitated, it was considered that in all of the propellant-free liquid compositions (preparation stock solutions) of Examples 9a, 9c, and 9d, difamilast was in a supersaturated state, and that the supersaturated state was maintained even after evaporation of the propellant after spraying. The results also suggested that the thickener contributed to maintaining the supersaturated state. This was also considered to be the reason why some crystal precipitation was observed in Example 9b, which did not contain any thickener.

[0089] Examination of Compatibility of Components Contained in Preparations Diethylene glycol monoethyl ether as a polar solvent and hydrocarbon (particularly liquid hydrocarbon) as a non-polar solvent are immiscible. However, from the viewpoint of preparation stability, compositions in which these components are compatible with each other are preferred. Therefore, the compatibility of components in preparations was examined.

[0090] Specifically, diethylene glycol monoethyl ether (DEGEE), medium-chain fatty acid triglyceride (MCT), olive oil (Olive), squalane, light liquid paraffin, and liquid paraffin were mixed according to the formulations shown in the tables below (the numerical values indicate mass%) to prepare mixed compositions, and cholesterol (Chol) was further added to each of the mixed compositions at a predetermined concentration to prepare test compositions. Then, the compatibility of each component was examined.

[0091] Specifically, the procedure was as follows. A predetermined amount of each component was weighed into a glass vial and mixed thoroughly. The resulting mixture was allowed to stand at 60°C, room temperature, or in a cool place for a certain period of time, and compatibility (solution separation) was visually confirmed. Based on the compatibility results for each temperature, scores were assigned according to the compatibility scores below. (A lower compatibility score indicates higher compatibility.) Compatibility Score 0: Not separated in cool place 1: Not separated at room temperature (separated in cool place) 2: Separated at room temperature (not separated when heated (at around 60°C)) 3: Separated when heated (at around 60°C)

[0092]

[0093]

[0094]

[0095]

[0096] Based on the results of the mixing ratio of each component (compatibility scores), three-phase diagrams were created using the statistical analysis software JMP16 (SAS Institute). Fig. 9a shows three-phase diagrams created for medium-chain fatty acid triglyceride (MCT), olive oil, and squalane based on the compatibility scores listed in Table 10A (diethylene glycol monoethyl ether: 15 mass% in all diagrams). In the three-phase diagrams, the boundaries of the plots of the compositions that obtained each compatibility score are shown with lines (contour lines). In the three-phase diagram with 0 mass% cholesterol, the point where the compatibility score of the composition 10A-3 is plotted is highlighted as an example. Fig. 9b shows three-phase diagrams created based on the compatibility scores of each component listed in Tables 10B to 10D.

[0097] These results revealed that the addition of cholesterol tends to increase the compatibility of each component.

[0098] Further, medium-chain fatty acid triglyceride (MCT) and light liquid paraffin, and further diethylene glycol monoethyl ether (DEGEE), polyethylene glycol (PEG 400), propylene carbonate, or propylene glycol were mixed according to the formulations shown in the table below (the numerical values indicate mass%) to prepare mixed compositions, and the compatibility of each component was examined in the same manner as described above. The compatibility scores of the mixed compositions are also shown in the table below.

[0099]

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

[0101] Examination of Propellants Used for Aerosol Preparations Components used as propellants for aerosol preparations were examined.

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

[0103] A predetermined amount of difamilast was weighed into a compatibility bottle, and a valve was attached. A predetermined amount of propellant (see the table below for the composition ratios) was placed therein, and the solubility of difamilast at 5°C and 25°C was evaluated. The results are also shown in the table below.

[0104]

[0105] A liquid composition (oil lotion) was prepared in the same manner as in Example 9b, and the liquid composition and a propellant were used to prepare aerosol preparations. The propellant used in Example 9b was dimethyl ether, and 70 mass% of the liquid composition (preparation stock solution) and 30 mass% of the propellant were combined for preparation. In this examination, the propellants and combination ratios shown in the table below were used.

[0106] The prepared aerosol preparations were each thoroughly shaken and then allowed to stand at 5°C or 25°C for 3 days, after which the dissolved state was visually confirmed. Those in which the difamilast-containing liquid composition remained dissolved were rated as +, and those in which precipitation or deposition of the difamilast-containing liquid composition occurred were rated as -. The evaluation is also shown in the table below (NA means not available).

[0107]

[0108] When butane alone is used as a propellant, the solubility of difamilast and the difamilast-containing liquid composition is low. The component to be used as a propellant was considered to be more preferably dimethyl ether (DME) or a mixture of dimethyl ether and butane, from the viewpoint of the solubility of difamilast and the solubility of the difamilast-containing liquid composition.

[0109] Examination of Stability of High-Concentration Difamilast Preparation Liquid compositions containing 1 mass% or 2 mass% difamilast (oil lotions) were prepared in the same manner as described above according to the formulations shown in the table below (the component amounts are expressed in mass%).

[0110]

[0111] The composition of Example 13-1 was used as a 1% preparation stock solution, and the composition of Example 13-2 was used as a 2% preparation stock solution. Optionally, difamilast bulk powder was further added to these stock solutions to adjust the difamilast content of each preparation stock solution (see the table below).

[0112]

[0113] Then, in the same manner as described above, the stock solutions were each combined with a propellant (dimethyl ether: DME) in the ratios shown in the table below to prepare aerosol preparations. The dissolved state of the aerosol preparations was visually checked at 25°C. After leaving them at 5°C for about 3 months, the dissolved state was visually checked again. Those that maintained the dissolved state were rated as +, those in which precipitation or deposition occurred were rated as -, and those that underwent phase separation were rated as ±. When visually checked, the entire preparations that appeared to reflect blue, purple, yellow, etc. as a result of dispersion were rated as “phase separation.” The results are also shown in the table below.

[0114]

[0115] Examination of Foaming Ability of Foam Agents Liquid compositions containing 1 mass% difamilast (oil lotions) were prepared in the same manner as described above according to the formulations shown in the table below (the component amounts are expressed in mass%). Then, a predetermined amount of each composition was placed in an aerosol can, a valve was installed and vacuum-clinched, and further a propellant was placed therein to prepare aerosol preparations. Dimethyl ether was used as a propellant, and aerosol preparations were prepared such that the mass ratio of dimethyl ether to the liquid composition (preparation stock solution) was 20:80, 30:70, or 40:60.

[0116]

[0117] The aerosol preparations prepared from all liquid compositions produced good foam (foaming ability) immediately after spraying, and there were no problems with cooling sensation or dripping. Regarding foam stability (foam retention time), those using dextrin palmitate among thickeners were particularly preferred.

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

[0119] It was found that the foaming ability of foam agents can be increased by using a thickener (particularly dextrin palmitate).

[0120] Examination of Each Composition A liquid composition (Example D) and foam agents (specifically aerosol preparations) (Examples A to C) were prepared in the same manner as described above according to the formulations shown in the table below (the component amounts are expressed in mass%). Further, in the same manner as described above, the skin permeability of difamilast was evaluated by IVPT using human skin, and the 24-hour cumulative permeation amounts were measured. The results are also shown in the table below and Fig. 11a.

[0121] In addition, foaming agents (specifically aerosol preparations) (Examples E to H and Comparative Example A) were prepared in the same manner as described above according to the formulations shown in the table below (the component amounts are expressed in mass%). Further, in the same manner as described above, the skin permeability of difamilast was evaluated by IVPT using human skin, and the 24-hour cumulative permeation amounts were measured. The results are also shown in the table below and Fig. 11b. A foam agent (specifically an aerosol preparation) was prepared as an Example in the same manner as described above, except that the amount of diethylene glycol monoethyl ether was 2.5 mass% and the amount of liquid paraffin was 58.74 mass% in Example E. Further, when the skin permeability of difamilast was evaluated by IVPT using human skin in the same manner as described above, the cumulative amount permeated over 24 hours was 0.32 μg / cm2. Compared to Comparative Example A (diethylene glycol monoethyl ether-free formulation), each Example in which diethylene glycol monoethyl ether was added showed higher skin permeability. These results suggest that the addition of diethylene glycol monoethyl ether also improves skin permeability in human skin.

Claims

1. A liquid composition comprising: (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) fat and oil.

2. A liquid composition comprising: (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) fat and oil.

3. A liquid composition comprising: (A) difamilast; (B) diethylene glycol monoethyl ether; (C) liquid hydrocarbon; and (D) fat and oil.

4. The liquid composition according to any one of claims 1 to 3, wherein (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, a fatty acid ester, vegetable fatty oil, and animal fatty oil.

5. The liquid composition according to any one of claims 1 to 4, wherein (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, a fatty acid ester, vegetable fatty oil, and animal fatty oil.

6. The liquid composition according to any one of claims 1 to 5, which satisfies at least one of the following conditions (I) and (II): (I): containing 1 to 25 parts by mass of (B) per part by mass of (A); and (II): containing 60 to 400 parts by mass of (C) and (D) in total per part by mass of (A).

7. The liquid composition according to any one of claims 1 to 6, which satisfies at least one of the following conditions (i), (ii), and (iii): (i): containing 0.1 to 5 mass% of (A); (ii): containing 1 to 25 mass% of (B); and (iii): containing 60 to 98 mass% of (C) and (D) in total.

8. The liquid composition according to any one of claims 1 to 7, further comprising: (E) cholesterol.

9. The liquid composition according to any one of claims 1 to 8, further comprising: (F) at least one selected from the group consisting of a dextrin fatty acid ester and beeswax.

10. The liquid composition according to any one of claims 1 to 7, further comprising: (E) cholesterol, and (F) at least one selected from the group consisting of a dextrin fatty acid ester and beeswax.

11. An aerosol preparation comprising the liquid composition according to any one of claims 1 to 10 and a propellant, both of which are placed in a pressure-resistant container.

12. The aerosol preparation according to claim 11, wherein the propellant comprises dimethyl ether.

13. The liquid composition according to any one of claims 1 to 10, which is a pharmaceutical composition.

14. The liquid composition according to any one of claims 1 to 10, which is an external composition.

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