Oxazole compound-containing composition

Abstract

To provide a difamilast-containing composition that has excellent skin permeability (and preferably is easy to spread and has low skin irritation).SOLUTION: A liquid composition comprises (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.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to compositions containing oxazole compounds (particularly difamilast), etc. This application claims priority to and the benefit of Japanese Patent Application No. 2024-087458, filed May 9, 2024, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Patent Documents 1 and 2 report oxazole compounds with specific inhibitory activity against phosphodiesterase 4 (PDE4) and methods for producing the same. PDE4 is the predominant PDE in inflammatory cells. Inhibition of PDE4 increases intracellular cAMP levels, which downregulates inflammatory responses by regulating the expression of TNF-α, IL-23, and other inflammatory cytokines. Increased cAMP levels also increase anti-inflammatory cytokines such as IL-10. Therefore, these oxazole compounds are considered suitable for use as anti-inflammatory agents. For example, they are considered useful for suppressing skin eczema and dermatitis, including atopic dermatitis. Patent Document 3 describes an ointment that stably contains an oxazole compound with specific inhibitory activity against PDE4 and can be efficiently absorbed into the skin. Patent Document 4 discloses a novel crystalline form of a specific oxazole compound (difamilast). The contents of Patent Documents 1 to 4 listed below are incorporated herein by reference. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2007 / 058338 (Patent Publication No. 2009-515872) [Patent Document 2] International Publication No. 2014 / 034958 (Patent Publication No. 2015-528433) [Patent Document 3] International Publication No. 2017 / 115780 (Patent Publication No. 2019-503989) [Patent Document 4] International Publication No. 2019 / 194211 (Patent Publication No. 2021-517111) Summary of the Invention [Problem to be solved by the invention]

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

[0005] [ka]

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

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

[0008] However, because difamilast has very low solubility in water, these dosage forms require dissolving it in alcohol or a fat-soluble solvent and emulsifying it with a surfactant. However, the use of a surfactant results in the resulting creams and lotions being more irritating to the skin than ointments. (In general, creams and lotions are more irritating to the skin than ointments.) Emulsion-type lotions (o / w lotions) with reduced skin irritation were investigated, but their skin permeability was lower than that of ointments, and they were not sufficient to provide effective administration of difamilast.

[0009] Therefore, further investigations were carried out with the main objective of obtaining a composition containing difamilast that has excellent skin permeability. [Means for solving the problem]

[0010] The present disclosure includes, for example, the subject matter described in the following sections: Section 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 hydrocarbons, and (D) Fats and oils; Contains Liquid composition. Section 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 hydrocarbons, and (D) Fats and oils; Contains Liquid composition. Section 3. (A) Difamilast, (B) diethylene glycol monoethyl ether, (C) liquid hydrocarbons, and (D) Fats and oils; Contains Liquid composition. Section 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 esters, vegetable fatty oils, and animal fatty oils; Item 4. The liquid composition according to any one of Items 1 to 3. Section 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 esters, vegetable fatty oils, and animal fatty oils; Item 4. The liquid composition according to any one of Items 1 to 3. Section 6. 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): Contains 1 to 25 parts by mass of (B) per part by mass of (A). (II): Contains 60 to 400 parts by mass of (C) and (D) in total per part by mass of (A). Section 7. 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): Contains 50 to 400 parts by mass of (C) per part by mass of (A). (IV): Contains 1 to 80 parts by mass of (D) per 1 part by mass of (A). Section 8. 8. The liquid composition according to any one of items 1 to 7, which satisfies at least one of the following three conditions (preferably two or three of the following three conditions): (D) is contained in an amount of 0.1 to 10 parts by mass per part by mass of (B). (C) is contained in an amount of 5 to 90 parts by mass per part by mass of (B). (C) is contained in an amount of 4 to 50 parts by mass per part by mass of (D). Section 9. Item 9. The liquid composition according to any one of items 1 to 8, which satisfies at least one of the following conditions (i), (ii), and (iii) (preferably two or three conditions): (i): Contains 0.1 to 5 mass% of (A). (ii): Contains 1 to 25 mass% of (B). (iii): (C) and (D) are contained in a total amount of 60 to 98% by mass. Section 10. 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): Contains 8 to 96 mass% of (C). (v): Contains 1 to 80 mass% of (D). Section 11. moreover (E) Cholesterol 11. The liquid composition according to any one of items 1 to 10, comprising (preferably 0.2 to 8% by mass) Section 12. Item 12. The liquid composition according to Item 11, comprising 0.2 to 25 parts by mass of (E) per 1 part by mass of (A). Section 13. moreover (F) at least one selected from the group consisting of dextrin fatty acid esters and beeswax 13. The liquid composition according to any one of items 1 to 12, comprising (preferably 0.1 to 20% by mass) Section 14. Item 14. The liquid composition according to Item 13, comprising 0.2 to 60 parts by mass of (F) per 1 part by mass of (A). Section 15. moreover (E) cholesterol, (F) at least one selected from the group consisting of dextrin fatty acid esters and beeswax 15. The liquid composition according to any one of items 1 to 14, comprising: Section 16. Item 16. An aerosol preparation comprising the liquid composition according to any one of Items 1 to 15 and a propellant packed in a pressure-resistant container. Section 17. Item 17. The aerosol formulation according to item 16, wherein the propellant comprises dimethyl ether. Section 18. Item 18. The liquid composition according to any one of Items 1 to 15, or the aerosol formulation according to Item 16 or 17, which is a pharmaceutical composition. Section 19. 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 composition for external use. Section 20. Item 20. The liquid composition or aerosol preparation according to Item 18 or 19, which is for treating a skin disease. Section 21. A method for treating a skin disease, comprising administering the liquid composition according to any one of items 1 to 15 or the aerosol formulation according to item 16 or 17 to a subject in need thereof. Section 22. Item 18. 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 treating a skin disease. [Effects of the Invention]

[0011] A composition containing difamilast is provided that has excellent skin permeability. The composition is preferably easy to spread and has low skin irritation. Furthermore, 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). [Brief explanation of the drawings]

[0012] [Figure 1a] The results of an in vitro skin permeation test (IVPT test) using human skin for a composition containing 0.3% by mass of difamilast (Example 1-1) are shown as the cumulative permeation amount of difamilast. The results of a similar test for a 0.3% ointment are also shown. [Figure 1b] The results of an IVPT test using human skin for a composition containing 1% by mass of difamilast (Example 1-2) are shown as cumulative permeation of difamilast. The results of a similar test for a 1% ointment are also shown. [Figure 1c] The results of an IVPT test using human skin for an emulsion-type lotion (o / w) composition containing 1% by mass of difamilast (Comparative Example 1) are shown as cumulative permeation of difamilast. The results of a similar test for a 1% ointment are also shown. [Figure 1d]1 shows the cumulative permeation amount over 24 hours when evaluating the skin permeability of difamilast for Examples 1-2 and Comparative Example 1 (IVPT test). [Figure 2] The skin permeability of a liquid composition (oil lotion) containing 1% by mass of difamilast was investigated by an IVPT test using pig skin, and the results are shown as the cumulative permeation amount of difamilast. [Figure 3] The skin permeability of a liquid composition (oil lotion) containing 1% by mass of difamilast was investigated by an IVPT test using pig skin, and the results are shown as the cumulative permeation amount of difamilast. [Figure 4] The skin permeability of a liquid composition (oil lotion) containing 1% by mass of difamilast was investigated by an IVPT test using pig skin, and the results are shown as the cumulative permeation amount of difamilast. [Figure 5a] The skin permeability of a liquid composition (oil lotion) containing 1% by mass of difamilast was investigated by an IVPT test using pig skin, and the results are shown as the cumulative permeation amount of difamilast. [Figure 5b] The skin permeability of a liquid composition (oil lotion) containing 1% by mass of difamilast was investigated by an IVPT test using pig skin, and the results are shown as the cumulative permeation amount of difamilast. [Figure 6] The skin permeability of a liquid composition (oil lotion) containing 1% by mass of difamilast was investigated by an IVPT test using pig skin, and the results are shown as the cumulative permeation amount of difamilast. [Figure 7] The skin permeability of a liquid composition (oil lotion) containing 0.3% by mass of difamilast was investigated by an IVPT test using pig skin, and the results are shown as the cumulative amount of difamilast permeated. [Figure 8a] The skin permeability of a liquid composition (oil lotion) containing 1% by mass of difamilast and that liquid composition in the form of a foam was investigated by an IVPT test using pig skin, and the results are shown as the cumulative amount of difamilast permeated. [Figure 8b]The skin permeability of a liquid composition (oil lotion) containing 1% by mass of difamilast in the form of a foam was investigated by an IVPT test using pig skin, and the results are shown as the cumulative amount of difamilast permeated. [Figure 9a] A mixed composition was prepared by mixing diethylene glycol monoethyl ether (DEGEE), medium-chain triglyceride (MCT), olive oil, and squalane according to the formulation shown in Table 11A (values ​​indicate mass %). Cholesterol was then added to the mixed composition to a predetermined concentration to prepare a test composition. The compatibility of each component was examined, and the results are shown in a three-phase diagram. [Figure 9b] Mixed compositions were prepared by mixing diethylene glycol monoethyl ether (DEGEE), medium-chain triglyceride (MCT), squalane, light liquid paraffin, and liquid paraffin according to the formulations shown in Tables 10B to 10D (values ​​indicate mass %). Test compositions were then prepared by adding cholesterol to the mixed compositions to achieve a predetermined concentration. The compatibility of each component was examined, and the results are shown in a three-phase diagram. [Figure 10] Photographs of foams formed by spraying each aerosol formulation prepared using the liquid compositions of Examples 14-5, 14-6, 14-7, and 14-11 at room temperature immediately after spraying are shown. [Figure 11a] The skin permeability of a liquid composition (oil lotion) containing 1% by mass of difamilast in the form of a foam was investigated by an IVPT test using human skin, and the results are shown as the cumulative amount of difamilast permeated. [Figure 11b] The skin permeability of a liquid composition (oil lotion) containing 1% by mass of difamilast in the form of a foam was investigated by an IVPT test using human skin, and the results are shown as the cumulative amount of difamilast permeated. DETAILED DESCRIPTION OF THE INVENTION

[0013] Each embodiment of the present disclosure will be described in more detail below. The present disclosure preferably includes, but is not limited to, a composition containing difamilast and a method for producing the same, and the present disclosure includes all that is disclosed herein and that would be recognized by a person skilled in the art.

[0014] The difamilast-containing composition encompassed by 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) a liquid hydrocarbon, and (D) an oil or fat. Hereinafter, these components will be referred to as components (A) to (D), respectively. Furthermore, a 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 a compound represented by the following formula:

[0016] [ka]

[0017] and methods for producing it are described, for example, in the above-mentioned Patent Documents 1 to 4. All of the above-mentioned Patent Documents 1 to 4 are incorporated herein by reference in their entirety, particularly with regard to the method for producing difamilast.

[0018] As described above, 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). 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 components can be used alone or in combination of two or more. Diethylene glycol monoethyl ether (DGE) is a compound represented by the formula CH3-CH2-O-CH2-CH2-O-CH2-CH2-OH, and is sometimes abbreviated as DEGEE. This compound is commercially available, for example, in Super Refined TM DEGEE (Croda), Transcutol (registered) Registered trademark (Gattefosse), Carbitol TM (Dow), ethoxydiglycol (NOF), etc. It is available for use.

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

[0020] Preferred examples of the fats and oils (component (D)) include fats and oils that are liquid at room temperature and normal pressure, and specifically, for example, 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 fatty oils, and animal fatty oils.

[0021] Examples of 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, and oleic acid. Examples of alcohols constituting the fatty acid ester include linear or branched 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 may be a monohydric or polyhydric (e.g., dihydric, trihydric, or tetrahydric) alcohol. In particular, it is preferred that the alcohol constituting the fatty acid ester is glycerin (i.e., glycerin fatty acid ester). In this case, the fatty acid ester may be a monoglyceride (monoacylglycerol), a diglyceride (diacylglycerol), or a triglyceride (triacylglycerol). Among these, triglycerides are preferred, and medium-chain triglycerides (MCT) are more preferred. The "medium-chain fatty acid" in the medium-chain fatty acid triglyceride is preferably 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 fatty oils include olive oil, corn oil, palm oil, sunflower oil, soybean oil, castor oil, almond oil, rapeseed oil, cottonseed oil, sesame oil, etc. Examples of animal fatty oils include shark oil, liver oil, herring oil, cod liver oil, salmon oil, etc.

[0023] Of the fats and oils, medium-chain fatty acid triglycerides, olive oil, almond oil, and soybean oil are preferred, with medium-chain fatty acid triglycerides and olive oil being more preferred.

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

[0025] The component (A) is preferably contained in the composition of the present disclosure in an amount of, for example, 0.1 to 5 mass%. The upper or lower limit of this 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] Furthermore, the (B) component is preferably contained in the composition of the present disclosure in an amount of, for example, 1 to 25 mass%. The upper or lower limit of this 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, this range is more preferably 0.5 to 20 mass%, and even more preferably 2 to 10 mass%.

[0027] The composition of the present disclosure preferably contains, for example, 60 to 98 mass% of the components (C) and (D) in total. The upper or lower limit of this 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, this range is more preferably 70 to 98 mass%, and even more preferably 75 to 95 mass%.

[0028] The composition of the present disclosure preferably contains 8 to 96% by mass of component (C). The upper or lower limit of this 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. The content of component (C) preferably also satisfies the range for the combined content of components (C) and (D) described above. Furthermore, component (D) is preferably contained in an amount of 1 to 80% by mass. The upper or lower limit of this 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 mass%, and even more preferably 2 to 60 mass%. The content of component (D) preferably also satisfies the range of the combined content of components (C) and (D) above.

[0029] Although not particularly limited, in the composition of the present disclosure, the content of component (C) and component (D) is preferably equal to or greater than the content of component (D), within the range of the total content of component (C) and component (D) described above. For example, it is particularly preferable that the content of component (C) in the composition of the present disclosure is 60 to 90 mass % and the content of component (D) is 2 to 30 mass %. The composition of the present disclosure preferably contains, for example, 0.1 to 10 parts by mass of component (D) per part by mass of component (B). The upper and lower limits of this range are, 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. The composition of the present disclosure preferably contains, for example, 5 to 90 parts by mass of component (C) per part by mass of component (B). The upper or lower limit of this 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, The amount 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. Furthermore, 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 this 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 composition of the present disclosure preferably contains, for example, 4 to 50 parts by mass of component (C) per 1 part by mass of component (D). The upper or lower limit of this 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. The composition of the present disclosure preferably contains, for example, 60 to 400 parts by mass of the components (C) and (D) in total per part by mass of the component (A). The upper and lower limits of this range are, 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 the composition of the present disclosure, the component (C) is preferably contained in an amount of 50 to 400 parts by mass per part by mass of the component (A). The upper and lower limits of this range are, for example, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 1 The amount may be 25, 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. It is preferable that the parts by mass of the component (C) also satisfy the range of the total parts by mass of the components (C) and (D) described above. Furthermore, 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 this 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, this range may be 1.5 to 75 parts by mass or 2 to 60 parts by mass. Furthermore, the parts by mass of the component (D) preferably also satisfy the range for the total parts by mass of the components (C) and (D).

[0030] The composition of the present disclosure may contain components other than 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. Note that (particularly when the composition of the present disclosure is a liquid composition), because components (C) and (D) are oily components, it may be necessary to use a surfactant (emulsifier) ​​to stably incorporate a relatively large amount of aqueous components. Because surfactants may increase skin irritation, it is preferable to exercise caution when using them (particularly with regard to the amount of water and surfactant used).

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

[0032] When 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 mass%. The upper or lower limit of this 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%. Furthermore, when 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 per part by mass of component (A). The upper or lower limit of this 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, this range may be 0.5 to 24 parts by mass.

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

[0034] The thickener may be a dextrin fatty acid ester, and the fatty acid in the dextrin fatty acid ester is preferably a saturated or unsaturated fatty acid having 14 to 18 carbon atoms, with myristic acid, palmitic acid, and stearic acid being particularly preferred. Examples of the dextrin fatty acid ester include dextrin myristate and dextrin palmitate, with dextrin palmitate being most preferred. The thickener may be used alone or in combination of two or more.

[0035] When 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 mass%. The upper or lower limit of this 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%. Furthermore, when 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 per part by mass of component (A). The upper or lower limit of this 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 preferred contents of the components (A) to (F) may be combined in any desired manner, and any composition of the present disclosure in which the contents of each component are specified in such a manner is preferred. That is, any composition of the present disclosure in which the content is specified by combining at least one range, or two, three, four, five, or six ranges selected from the group consisting of the preferred range of the content of the component (A), the preferred range of the content of the component (B), the preferred range of the content of the component (C), the preferred range of the content of the component (D), the preferred range of the content of the component (E), and the preferred range of the content of the component (F) is preferred. Furthermore, the preferred part by mass content of the above components (A) to (F) may be arbitrarily combined, and any composition of the present disclosure in which the part by mass content of each component is defined in such a manner is preferred. That is, any composition of the present disclosure in which the range of preferred parts by mass content of the above component (A) per 1 part by mass of the above component (A) is defined by combining at least one range, or two, three, four, or five ranges selected from the group consisting of the preferred range of parts by mass content of the above component (B), the preferred range of parts by mass content of the above component (C), the preferred range of parts by mass content of the above component (D), the preferred range of parts by mass content of the above component (E), and the preferred range of parts by mass content of the above component (F) is preferred.

[0037] In addition, known ingredients used in ordinary liquid compositions for external use (particularly cosmetic compositions and pharmaceutical compositions for external use) may be contained. In some embodiments, the effects of the composition of the present disclosure are not inhibited by the inclusion of other ingredients. Such ingredients include, for example, preservatives. Examples of moisturizing ingredients include, but are not limited to, moisturizing ingredients (for example, hyaluronic acid, collagen, ceramide, glycerin, etc.), fragrances, preservatives, antioxidants, water, alcohol, etc.

[0038] The composition of the present disclosure can be prepared by using known techniques used in the manufacture of pharmaceutical preparations in light of the disclosure of the present disclosure, for example, by appropriately mixing each component while heating (for example, to about 60 to 90°C) using a thermostatic bath 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. It can also be used to prepare other topical preparations, such as creams, sprays (e.g., pump sprays and aerosol preparations), and ointments. Preparations that form a foam upon use are sometimes called foams. Sprays (e.g., pump sprays and aerosol preparations) are considered to be typical examples of foams. In pump sprays, a solution of the active ingredient (content liquid) is expelled by the pressure of the pump head, and as the solution is expelled, a foam (foam) is formed as the solution passes through a mesh or the like within the pump. In aerosol preparations, a solution of the active ingredient (concentrate) is expelled together with a gas (e.g., liquefied gas or compressed gas) filled in a container, forming a foam (foam).

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

[0041] As the propellant, for example, known propellants can be used, among which dimethyl ether, butane, propane, LPG, etc. are preferred, and dimethyl ether is particularly preferred. For example, as shown herein, dimethyl ether has the ability to stably dissolve difamilast, providing advantages to compositions containing difamilast, particularly aerosolized formulations. The propellants can be used alone 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, more preferably 55:45 to 85:15 or 60:40 to 80:20, in mass ratio (composition of the present disclosure:propellant).

[0043] The composition sprayed from the aerosol formulation thus obtained is preferable because it has low skin irritation and excellent skin permeability, as disclosed herein. The composition sprayed from the aerosol formulation may be in the form of a foam.

[0044] Although not particularly limited, the composition of the present disclosure used in an aerosol formulation preferably contains a thickener (component (F)). The inclusion of a thickener can improve the stability of the foam formed by spraying and also improve the applicability (easy to spread and less likely to drip).

[0045] In this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present disclosure encompasses any and all combinations of the constituent elements described herein. The expression "consisting essentially of" may specify, for example, 95% or more or 99% or more by weight of all components in the formulation. For example, unless otherwise specified, the compositions of the present disclosure, even when expressed as "consisting of," may contain components related to manufacturing or stability. It should be understood that the composition may contain additional components such as impurities.

[0046] Furthermore, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure above may be combined in any way to specify the subject matter encompassed by the present disclosure. That is, the present disclosure includes all subject matter consisting of any and all combinations of each combinable feature described herein. [Example]

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

[0048] Compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (WO 2007 / 058338) and used as difamilast.

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

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

[0051] Consideration of the combination of each ingredient 1 According to the formulation shown in the table below, liquid compositions (oil lotions) containing 0.3% by mass or 1% by mass of difamilast were prepared.

[0052] [Table 1A]

[0053] More specifically, the preparation was carried out 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] The obtained 0.3% formulation (Example 1-1) and 1% formulation (Example 1-2) were subjected to an in vitro skin permeation test (IVPT test) (n=6) using human skin. The skin permeability of difamilast was evaluated. When calculating the cumulative permeation amount in the skin permeability evaluation, the average value obtained from each study was used. 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 of the center of the skin section (μ The skin thickness was measured (11.28 mm) and skin sections were allocated for each donor so that the skin thickness would be comparable among the test substance groups. A Franz cell (opening diameter 11.28 mm) was used for this test, with a 40% PEG400 aqueous solution as the receptor fluid and the circulating water temperature set at 33°C. Before the start of the test, the TEWL of human skin was measured, and transepidermal water loss (TEWL) was 15 g / m². 2 / h I confirmed that.

[0056] In the Franz cell, the test compositions (0.3% formulation (Example 1-1) and 0.3% ointment) were applied to human skin at a concentration of approximately 10 mg / cm 2 so that the human skin was set between the test compositions and the receptor fluid. 2 After dripping, the test was started by gently spreading the drops. 200 μL of the sample solution was collected. The receptor solution (200 μL) was replenished. The difamilast concentration in the sampling solution was measured using the HP The results were measured using LC. 2 The cumulative permeation amount per 1000 mg / mL was calculated. The cumulative permeation amount is shown in Figure 1a. The same test was also conducted for the 1% formulation composition (Example 1-2) and the 1% ointment, and the results are shown in Figure 1b. It was found that both compositions exhibited skin permeability equal to or greater than that of the ointment.

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

[0058] [Table 1B]

[0059] The liquid composition (Comparative Example 1) was also subjected to an in vitro permeation test (IVPT) using human skin (n=8) together with the 1% ointment. The results, expressed as cumulative permeation amounts, are shown in Figure 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 addition, in the above study evaluating the skin permeability of difamilast for the 1% formulation composition (Example 1-2), the cumulative permeation amount for 24 hours for the 1% formulation composition (Example 1-2) was compared with the cumulative permeation amount for 24 hours for the 1% ointment, and the relative permeability (%) to the 1% ointment was calculated. In addition, in the above study evaluating the skin permeability of difamilast for a liquid composition containing 1% by mass of difamilast (emulsion lotion: Comparative Example 1), The cumulative permeation rate over 24 hours for a liquid composition containing 1% by mass (emulsion lotion: Comparative Example 1) was compared with the cumulative permeation rate over 24 hours for a 1% ointment, and the relative permeation rate (%) to the 1% ointment was calculated. The results are shown in the table below. The cumulative permeation rates over 24 hours for Examples 1-2 and Comparative Example 1 are also plotted in a graph in Figure 1d.

[0061] [Table 1C]

[0062] Consideration of the combination of each ingredient 2 According to the formulation shown in the table below (component amounts are in mass %), a liquid composition (oil lotion) containing 1 mass % of difamilast was prepared in the same manner as above.

[0063] [Table 2]

[0064] For each liquid composition, an IVPT test (n=3) using pig skin (Yucatan micropig skin) was performed in the same manner as when using human skin. The results obtained are shown in the table above as 24-hour cumulative permeation amounts, and are also shown graphically in Figure 2.

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

[0066] Consideration of the combination of each ingredient 3 According to the formulation shown in the table below (component amounts are in mass %), a liquid composition (oil lotion) containing 1 mass % of difamilast was prepared in the same manner as above.

[0067] [Table 3]

[0068] For each liquid composition, an IVPT test (n=3) using pig skin (Yucatan micropig skin) was carried out in the same manner as when using human skin. The results obtained are summarized in Table 2. The 4-hour cumulative permeation amount is shown in the table above and also graphed in Figure 3.

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

[0070] Consideration of the combination of each ingredient 4 According to the formulation shown in the table below (component amounts are in mass %), a liquid composition (oil lotion) containing 1 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 liquid composition, an IVPT test (n=3) using pig skin (Yucatan micropig skin) was performed in the same manner as for human skin. The results obtained are shown in the table above as 24-hour cumulative permeation amounts, and are also shown graphically in Figures 4, 5a, 5b, and 6.

[0075] It was thought that a composition containing difamilast, a liquid hydrocarbon, an oil, and diethylene glycol monoethyl ether exhibited excellent skin permeability, and that a relatively high content of liquid hydrocarbons would result in even better skin permeability. This unexpected effect was observed even though the liquid hydrocarbons and difamilast were not miscible with each other. Furthermore, compared with Example 5-6, which used diethylene glycol monoethyl ether, Example 5-10 (addition of N-methyl-2-pyrrolidone (NMP)) showed comparable skin permeability. Reference Example 5-6 (addition of isopropyl myristate (IPM)) showed a slight improvement in skin permeability compared to other comparative examples, but did not exhibit the same permeability improvement effect as Example 5-6 (addition of diethylene glycol monoethyl ether) and Example 5-10 (addition of N-methyl-2-pyrrolidone (NMP)). From these results, it was considered that compositions containing difamilast, liquid hydrocarbons, oils, and especially diethylene glycol monoethyl ether or NMP have excellent skin permeability. On the other hand, other additives generally believed to have a skin permeability-improving effect on difamilast were considered to have a low skin permeability-improving effect.

[0076] Consideration of the combination of each ingredient5 According to the formulation shown in the table below (component amounts are in mass %), a liquid composition (oil lotion) containing 0.3 mass % of difamilast was prepared in the same manner as above.

[0077] [Table 7]

[0078] For each liquid composition, an IVPT test (n=3) using pig skin (Yucatan micropig skin) was performed in the same manner as when using human skin. The results obtained are shown in the above table as 24-hour cumulative permeation amounts, and are also shown graphically in Figure 7.

[0079] Considering foam formulations Considering the case where a composition containing difamilast is applied to the skin as a foam, The skin permeability of the composition in the form of a foam (specifically, an aerosol formulation) was also investigated.

[0080] A liquid composition (oil lotion) containing 1% by mass of difamilast was prepared in the same manner as above, and a predetermined amount of this was placed in an aerosol can, a valve was attached, vacuum clinched, and a propellant was then added to prepare an aerosol formulation. The formulations of the prepared formulations (component amounts are shown in mass%) are shown in the table below. Example 8a is an oil lotion, and Example 8b is an aerosol formulation prepared using the oil lotion as the formulation concentrate. The liquid composition obtained by spraying the aerosol formulation was in the form of a foam.

[0081] [Table 8A]

[0082] For each of the liquid compositions and aerosol formulations, an IVPT test (n=3) using pig skin (Yucatan micropig skin) was conducted in the same manner as when using human skin. The results obtained are shown in the above table as a 24-hour cumulative permeation amount, and are also shown graphically in Figure 8a. In the IVPT test of the aerosol formulations, the liquid composition of Example 8a An aerosol preparation containing the same amount of difamilast as that contained in the sample was sprayed onto a weighing dish, and an appropriate amount was weighed out onto a spatula and applied to pig skin placed in a Franz cell.

[0083] It was confirmed that the difamilast-containing composition exhibited skin permeability equivalent to that of the liquid composition even when the liquid composition was made into a foam. Furthermore, a liquid composition (oil lotion) containing 1% by mass of difamilast was prepared in the same manner as above, and a predetermined amount of this was placed in an aerosol can, a valve was attached, and the can was vacuum-clinched, and a propellant was then filled to prepare an aerosol formulation. The formula of the prepared formulation (component amounts are shown in mass%) is shown in the table below. [Table 8B] An IVPT test (n=3) using pig skin (Yucatan micropig skin) was conducted using the same procedure as for human skin. The results are shown in the table above as cumulative permeation over 24 hours, and are also shown graphically in Figure 8b. A slight increase in cumulative permeation was observed in Example 8-3 (propylene glycol added) and Example 8-4 (1,3-BG added). Furthermore, Examples 8-1 and 8-2, which used diethylene glycol monoethyl ether, showed even greater effects than Examples 8-3 and 8-4. Furthermore, no improvement in permeability was observed in Comparative Example 8-2 (PEG400 added), Comparative Example 8-3 (propylene carbonate added), Comparative Example 8-4 (dimethyl isosorbide added), and Comparative Example 8-5 (glycerin added). Furthermore, Comparative Example 8-1 (formulation without diethylene glycol monoethyl ether added) showed a significantly lower cumulative permeation than Examples 8-1 and 8-2, confirming the permeation-promoting effect of diethylene glycol monoethyl ether even in the foam agent.

[0084] Skin irritation study A formulation was prepared by omitting difamilast and white beeswax from the 0.3% formulation of Example 1-1, and a formulation was prepared by omitting difamilast and white beeswax from the 1% formulation of Example 1-2. When these compositions were subjected to a skin irritation test using rabbit skin, both compositions were classified as "weak irritants," indicating that they were preferable in terms of low skin irritation.

[0085] Examination of the properties of foam after spraying In the same manner as above, a liquid composition (oil lotion) containing 1% by mass of difamilast was prepared, and a predetermined amount of this was placed in an aerosol can, a valve was attached, vacuum clinched, and a propellant was then filled to prepare an aerosol formulation. The formulation of the aerosol formulation (component amounts are shown in mass%) is shown in the table below.

[0086] [Table 9]

[0087] The liquid composition (formulation concentrate) was sprayed from the resulting aerosol formulation and an appropriate amount was applied to a glass slide as a foam. This was left standing on a hot plate at 32.5°C (skin surface temperature) for approximately 1 hour. When the foam was no longer visible, the applied portion of the formulation was sandwiched between cover glasses, the formulation was spread to an appropriate thickness, and then placed back on the hot plate. After 1 day, 4 days, and 1 week of standing, the properties of the formulation were confirmed using a polarizing microscope. The foam immediately after spraying was also similarly confirmed. For Example 9b, slight crystallization of difamilast was observed, although only 1 day after spraying. On the other hand, for Examples 9a, 9c, and 9d, no crystallization of difamilast was observed at any time point.

[0088] Since difamilast crystals did not precipitate, it was confirmed that the propellant In all liquid compositions (undiluted formulations) that do not contain difamilast, difamilast is in a supersaturated state. Therefore, it was thought that supersaturation was maintained even after the propellant evaporated after spraying. Furthermore, from these results, it was thought that the thickener contributed to maintaining the supersaturated state. This was also thought to be the reason why some crystal precipitation was observed in Example 9b, which did not contain a thickener.

[0089] Examination of compatibility of ingredients contained in the formulation The polar solvent diethylene glycol monoethyl ether and the nonpolar solvent hydrocarbons (especially liquid hydrocarbons) are immiscible. However, from the viewpoint of formulation stability, it is preferable to have a composition in which these components are compatible. Therefore, we investigated the compatibility of the components in the formulation.

[0090] Specifically, a mixed composition was prepared by mixing diethylene glycol monoethyl ether (DEGEE), medium-chain triglyceride (MCT), olive oil, squalane, light liquid paraffin, and liquid paraffin according to the formulation shown in the table below (values ​​indicate mass %), and then 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, the test was carried out as follows: A predetermined amount of each component was weighed into a glass vial and mixed thoroughly. The mixture was left to stand for a certain period of time at 60°C, room temperature, or in a cool place, and compatibility (solution separation) was visually confirmed. The compatibility results at each temperature were scored according to the compatibility score below. (The lower the compatibility score, the higher the compatibility.) Compatibility Score 0: No separation in a cool place 1: No separation at room temperature (separates in a cold place) 2: Separation at room temperature (no separation when heated (around 60°C)) 3: Separation by heating (around 60°C)

[0092] [Table 10A]

[0093] [Table 10B]

[0094] [Table 10C]

[0095] [Table 10D]

[0096] In addition, based on the results of the blending ratios of each component (compatibility scores), a three-phase diagram was created using the statistical analysis software JMP16 (SAS Institute). Figure 9a shows the phase diagram for medium-chain triglycerides (MCT), olive oil, and squalane, created based on the compatibility scores listed in Table 10A. The phase diagram for each of the compositions (diethylene glycol monoethyl ether was 15% by mass) is shown (in each case, diethylene glycol monoethyl ether was 15% by mass). In the phase diagram, the boundaries of the plotted portions of the compositions for which each compatibility score was obtained are indicated by lines (contour lines). In addition, in the phase diagram for 0% by mass of cholesterol, the plotted points of the compatibility scores of the composition 10A-3 are highlighted as an example. In addition, Figure 9b summarizes the phase diagrams created based on the compatibility scores of each component listed in Tables 10B to 10D. This is shown.

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

[0098] Furthermore, in the formulation shown in the table below (values ​​indicate mass %), medium-chain fatty acid triglyceride (MCT) and light liquid paraffin were further mixed with diethylene glycol monoethyl ether. Mixed compositions were prepared by mixing polyethylene glycol (PEG400), propylene carbonate, or propylene glycol, and the compatibility of each component was examined in the same manner as above. The compatibility scores for each mixed composition are also shown in the table below.

[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 compatibilizing diethylene glycol monoethyl ether and hydrocarbons, which are immiscible. Therefore, it was considered that this effect is particularly preferably obtained when diethylene glycol monoethyl ether is used.

[0101] Examination of propellants used in aerosol preparations The components used as propellants for aerosol formulations were investigated.

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

[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 composition ratio) was filled into this, and the solubility of difamilast at 5°C and 25°C was evaluated. The results are also shown in the table below.

[0104] [Table 11]

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

[0106] The prepared aerosol formulation was thoroughly shaken and then allowed to stand at 5°C or 25°C for 3 days, and the state of dissolution was visually confirmed. Those in which the difamilast-containing liquid composition remained dissolved were rated as +, and those in which the difamilast-containing liquid composition precipitated or deposited were rated as -. The evaluation results are also shown in the table below (NA indicates not performed).

[0107] [Table 12]

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

[0109] Stability study of high-concentration difamilast formulations According to the formulations shown in the table below (component amounts are in mass %), liquid compositions (oil lotions) containing 1 mass % or 2 mass % of difamilast were prepared in the same manner as above.

[0110] [Table 13A]

[0111] The composition of Example 13-1 was used as a 1% formulation concentrate, and the composition of Example 13-2 was used as a 2% formulation concentrate, and if necessary, difamilast bulk powder was further added to these to adjust the difamilast content of the formulation concentrate (see the table below).

[0112] [Table 13B]

[0113] Then, in the same manner as above, aerosol formulations were prepared by combining the concentrate and propellant (dimethyl ether: DME) in the ratios shown in the table below. The aerosol formulations were visually inspected for dissolution at 25°C. After standing at 5°C for approximately 3 months, the dissolution was inspected again visually. Those that maintained dissolution were evaluated as +, those that showed precipitation or deposition were evaluated as -, and those that showed phase separation were evaluated as ±. When inspected visually, those that showed the entire formulation reflecting blue, purple, yellow, etc. due to dispersion were evaluated as "phase separation." The results are also shown in the table below.

[0114] [Table 13C]

[0115] Examination of foaming properties of foam agents A liquid composition (oil lotion) containing 1% by mass of difamilast was prepared in the same manner as above, according to the formulation shown in the table below (component amounts are in mass%). A predetermined amount of this was then placed in an aerosol can, a valve was attached, the can was vacuum-clinched, and a propellant was added to prepare an aerosol formulation. Dimethyl ether was used as the propellant, and a mass ratio of dimethyl ether to liquid composition (formulation concentrate) of 20:80, 30:70, or 40:60 was prepared.

[0116] [Table 14]

[0117] The aerosol formulations prepared from all liquid compositions produced good foam immediately after spraying (foaming properties), and there were no problems with coolness or dripping. Regarding foam stability (foam retention time), the thickeners containing dextrin palmitate were particularly preferable.

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

[0119] It was found that the foaming properties of foam agents can be increased by using thickeners (especially dextrin palmitate).

[0120] Consideration of each composition According to the compositions in the following table (component amounts are in mass%), a liquid composition (Example D) and foams (specifically, aerosol formulations) (Examples A to C) were prepared in the same manner as above. Furthermore, 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 in the following table and Figure 11a.

[0121] [Table 15A] In addition, foams (specifically aerosol formulations) (Examples E to H, Comparative Example A) were prepared in the same manner as above according to the compositions in the following table (component amounts are in mass%), and 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 in the following table and Figure 11b. [Table 15B] In Example E, a foam preparation (specifically, an aerosol preparation) was prepared in the same manner as in Example E, except that the amount of diethylene glycol monoethyl ether was 2.5% by mass and the amount of liquid paraffin was 58.74% by mass. Furthermore, the skin permeability of difamilast was evaluated by an IVPT test using human skin in the same manner as above. The cumulative permeation amount over 24 hours was 0.32 μg / cm. 2 It was. Compared to Comparative Example A (formulation without diethylene glycol monoethyl ether), the skin permeability of each example in which diethylene glycol monoethyl ether was added was higher. This suggests that adding diethylene glycol monoethyl ether improves skin permeability even in human skin.

Claims

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; (C) a liquid hydrocarbon; and (D) fats and oils; Contains Liquid composition.

2. (A) difamilast, (B) at least one selected from the group consisting of diethylene glycol monoethyl ether and N-methyl-2-pyrrolidone (NMP); (C) a liquid hydrocarbon; and (D) fats and oils; Contains Liquid composition.

3. (A) difamilast, (B) diethylene glycol monoethyl ether, (C) a liquid hydrocarbon; and (D) fats and oils; Contains Liquid composition.

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 esters, vegetable fatty oils, and animal fatty oils; 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; (D) is at least one selected from the group consisting of triacetin, fatty acid esters, vegetable fatty oils, and animal fatty oils; The liquid composition according to any one of claims 1 to 4.

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): Contains 1 to 25 parts by mass of (B) per part by mass of (A). (II): Contains 60 to 400 parts by mass of (C) and (D) in total per part by mass of (A).

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

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

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

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

11. 11. An aerosol formulation comprising the liquid composition according to any one of claims 1 to 10 and a propellant filled in a pressure-resistant container.

12. 12. The aerosol formulation of 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 a composition for external use.

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