External composition

Abstract

To provide technology for improving the stability of vitamin D3 in a topical composition containing vitamin D3 even with increased water content in the topical composition.SOLUTION: A topical composition contains vitamin D3, a nonionic surfactant A that is a polyoxyalkylene hydrogenated castor oil in which the average added number of moles of alkylene oxide is 55 or less, and a nonionic surfactant B that is a nonionic surfactant other than the polyoxyalkylene hydrogenated castor oil.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to compositions for external use. [Background technology]

[0002] Psoriasis is a skin disease whose main symptoms are skin keratinization, scales, thickening of the skin, red rash, etc., and there are hundreds of thousands of patients in Japan. It is known that vitamin D3 is used as an external medicine for the skin symptoms of psoriasis. It is also known that vitamin D3 and glucocorticoids are used in combination as external medicines for psoriasis (Patent Document 1). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Special Publication No. 2021-518409 Summary of the Invention [Problem to be solved by the invention]

[0004] Although vitamin D3 has excellent medicinal properties, its stability decreases when dissolved in water, and the stability problem becomes greater as the water content increases.

[0005] Therefore, an objective of the present invention is to provide a technology for further improving the stability of vitamin D3 in an external use composition containing vitamin D3, even when the water content in the external use composition is increased. [Means for solving the problem]

[0006] The present inventors have conducted intensive research in view of the above problems, and have found that the above problems can be solved by a composition for external use that contains vitamin D3, glucocorticoid, nonionic surfactant A which is polyoxyalkylene hydrogenated castor oil, and nonionic surfactant B which is a nonionic surfactant other than polyoxyalkylene hydrogenated castor oil. Based on this finding, the present inventors have conducted further research, and have completed the present invention. That is, the present invention includes the following aspects.

[0007] Item 1. A composition for external use comprising vitamin D3, nonionic surfactant A which is a polyoxyalkylene hydrogenated castor oil having an average number of alkylene oxide added moles of 55 or less, and nonionic surfactant B which is a nonionic surfactant other than polyoxyalkylene hydrogenated castor oil.

[0008] Item 2. The composition for external use according to Item 1, wherein the nonionic surfactant B is at least one selected from the group consisting of polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbite fatty acid esters, and polyglycerin fatty acid esters.

[0009] Item 3. The composition for external use according to Item 1 or 2, wherein the HLB value of the nonionic surfactant B is 6 or more.

[0010] Item 4. The composition for external use according to any one of Items 1 to 3, wherein the total content of the nonionic surfactant A and the nonionic surfactant B in the composition for external use is 0.5% by mass or more and 10% by mass or less.

[0011] Item 5. The composition for external use according to any one of Items 1 to 4, wherein the content of the nonionic surfactant A in the total of the nonionic surfactant A and the nonionic surfactant B is 10% by mass or more and 99.9% by mass or less.

[0012] Item 6. The composition for external use according to any one of Items 1 to 5, which contains an ester oil.

[0013] Item 7. The composition for external use according to Item 6, wherein the ester oil contains at least glycerin triisooctanoate.

[0014] Item 8. The nonionic surfactant B is at least one selected from the group consisting of polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbite fatty acid esters, and polyglycerin fatty acid esters; The nonionic surfactant B has an HLB value of 6 or more, The total content of the nonionic surfactant A and the nonionic surfactant B in the composition for external use is 1% by mass or more and 10% by mass or less, The content of the nonionic surfactant A in the total of the nonionic surfactant A and the nonionic surfactant B is 10% by mass or more and 99.9% by mass or less, and Item 8. The composition for external use according to any one of items 1 to 7, comprising an ester oil.

[0015] Item 9. The composition for external use according to any one of Items 1 to 8, wherein the vitamin D3 is at least one selected from the group consisting of calcipotriol, maxacalcitol, alphacalcidol, falecalcitriol, tacalcitol, and calcitriol.

[0016] Item 10. The composition for external use according to any one of Items 1 to 9, wherein the vitamin D3 is calcipotriol, the glucocorticoid is betamethasone dipropionate, the polyoxyalkylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil, and the nonionic surfactant B is at least one selected from the group consisting of polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbite fatty acid esters, and polyglycerin fatty acid esters.

[0017] Item 11. The composition for external use according to any one of Items 1 to 10, wherein the nonionic surfactant B is one or more selected from polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene lauryl ether, polyoxyethylene polyoxypropylene glycol, polyethylene glycol monostearate, polyoxyethylene sorbitol tetraoleate, and polyglyceryl monolaurate.

[0018] Item 12. The composition for external use according to any one of Items 1 to 11, further comprising water.

[0019] Item 13. The composition for external use according to Item 12, wherein the content of the water in the composition for external use is 40% by mass or more.

[0020] Item 14. The composition for external use according to Item 12, wherein the content of water in the composition for external use is 75% by mass or more.

[0021] Item 15. The composition for external use according to any one of Items 1 to 14, wherein the content of vitamin D3 in the composition for external use is from 0.0001% by mass to 0.2% by mass.

[0022] Item 16. The composition for external use according to any one of Items 1 to 15, further comprising an antioxidant. Item 17. The composition for external use according to any one of Items 1 to 16, which is in the form of a gel, liquid, aerosol, mist, or foam.

[0023] Item 18. The composition for external use according to any one of Items 1 to 17, which is used for preventing or ameliorating psoriasis. Effect of the Invention

[0024] According to the present invention, it is possible to provide a composition for external use which contains vitamin D3 and has improved stability of vitamin D3 even when the water content in the composition is high. [Brief description of the drawings]

[0025] [Figure 1]The vertical axis shows the residual ratios (upper part) of vitamin D3 and glucocorticoids (lower part) when the liquid compositions (Example 1, Comparative Example 1, and Comparative Example 2) were allowed to stand at 60° C. The horizontal axis shows the number of weeks since the start of standing at 60° C. [Diagram 2] The vertical axis shows the residual ratios (upper part) of vitamin D3 and glucocorticoids (lower part) when the liquid compositions (Example 2, Comparative Example 1, and Comparative Example 3) were allowed to stand at 60° C. The horizontal axis shows the number of weeks since the start of standing at 60° C. [Diagram 3] The vertical axis shows the residual ratios (upper part) of vitamin D3 and glucocorticoids (lower part) when the liquid compositions (Example 3, Comparative Example 1, and Comparative Example 4) were allowed to stand at 60° C. The horizontal axis shows the number of weeks since the start of standing at 60° C. [Figure 4] The vertical axis shows the residual ratios (upper part) of vitamin D3 and glucocorticoids (lower part) when the liquid compositions (Example 4, Comparative Example 1, and Comparative Example 5) were allowed to stand at 60° C. The horizontal axis shows the number of weeks since the start of standing at 60° C. [Diagram 5] The vertical axis shows the residual ratios (upper part) of vitamin D3 and glucocorticoids (lower part) when liquid compositions (Example 5, Comparative Example 1, and Comparative Example 6) were allowed to stand at 60° C. The horizontal axis shows the number of weeks since the start of standing at 60° C. [Figure 6] The vertical axis shows the residual ratios (upper part) of vitamin D3 and glucocorticoids (lower part) when the liquid compositions (Example 6, Comparative Example 1, and Comparative Example 7) were allowed to stand at 60° C. The horizontal axis shows the number of weeks since the start of standing at 60° C. [Figure 7] The vertical axis shows the residual rate of vitamin D3 (upper row) and glucocorticoid (lower row) when the liquid compositions (Example 7, Comparative Example 8, and Comparative Example 9) were allowed to stand at 60° C. The horizontal axis shows the number of weeks elapsed since the start of standing at 60° C. [Figure 8] The vertical axis shows the residual ratios (upper part) of vitamin D3 and glucocorticoids (lower part) when liquid compositions (Example 8, Comparative Example 8, and Comparative Example 10) were allowed to stand at 60° C. The horizontal axis shows the number of weeks since the start of standing at 60° C. [Figure 9]The vertical axis shows the residual ratios (upper part) of vitamin D3 and glucocorticoids (lower part) when liquid compositions (Example 9, Comparative Example 8, and Comparative Example 11) were allowed to stand at 60° C. The horizontal axis shows the number of weeks since the start of standing at 60° C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] In this specification, the expressions "contain" and "comprise" include the concepts of "contain", "include", "consist essentially of" and "consist only of".

[0027] In this specification, the number of carbon atoms of "alkylene" is, for example, 2 to 4, preferably 2 to 3, and more preferably 2.

[0028] In one aspect, the present invention relates to a composition for external use (sometimes referred to as the "composition for external use of the present invention" in this specification) that contains vitamin D3, a nonionic surfactant A that is a polyoxyalkylene hydrogenated castor oil having an average number of moles of alkylene oxide added of 55 or less, and a nonionic surfactant B that is a nonionic surfactant other than polyoxyalkylene hydrogenated castor oil. This will be described below.

[0029] Vitamin D3 is not particularly limited as long as it can be used in an active vitamin D3 preparation. Examples of vitamin D3 include calcipotriol (1α,24(OH)2-22-ene-24-cyclopropyl-vitamin D3), maxacalcitol (22-oxa-1α,25-dihydroxyvitamin D3), alphacalcidol, falecalcitriol (1,25-dihydroxy-26,27-hexafluoro-vitamin D3), tacalcitol (1α,24(R)-dihydroxyvitamin D3), and calcitriol (1,25-dihydroxyvitamin D3). These components include free form, salts, and solvates (e.g., hydrates). Among these, calcipotriol and maxacalcitol are preferred from the viewpoint of the stability of the drug (especially vitamin D3). In one aspect of the present invention, the vitamin D3 is particularly preferably maxacalcitol. In another embodiment of the invention, the vitamin D3 is calcipotriol.

[0030] Vitamin D3 can be used alone or in any combination of two or more types.

[0031] The content of vitamin D3 in the composition for external use of the present invention is not particularly limited, and can be, for example, 0.0001% by mass or more and 0.2% by mass or less. The content is preferably 0.0002% by mass or more and 0.1% by mass or less, preferably 0.0005% by mass or more and 0.05% by mass or less, preferably 0.001% by mass or more and 0.02% by mass or less, and preferably 0.0015% by mass or more and 0.01% by mass or less.

[0032] The polyoxyalkylene hydrogenated castor oil (nonionic surfactant A) is obtained by addition polymerization of alkylene oxide to hydrogenated castor oil, and is not particularly limited as long as the average number of moles of alkylene oxide added is 55 or less. From the viewpoint of the stability of vitamin D3, the average number of moles of ethylene oxide added is more preferably 10 or more and 55 or less, even more preferably 20 or more and 55 or less, even more preferably 30 or more and 50 or less, and particularly preferably 35 or more and 45 or less. As the polyoxyalkylene hydrogenated castor oil, particularly preferred is polyoxyethylene hydrogenated castor oil. Specific examples of polyoxyethylene hydrogenated castor oil include polyoxyethylene (5) hydrogenated castor oil (also referred to as polyoxyethylene hydrogenated castor oil 5), polyoxyethylene (10) hydrogenated castor oil (also referred to as polyoxyethylene hydrogenated castor oil 10), polyoxyethylene (20) hydrogenated castor oil (also referred to as polyoxyethylene hydrogenated castor oil 20), polyoxyethylene (30) hydrogenated castor oil (also referred to as polyoxyethylene hydrogenated castor oil 30), polyoxyethylene (40) hydrogenated castor oil (also referred to as polyoxyethylene hydrogenated castor oil 40), polyoxyethylene (50) hydrogenated castor oil (also referred to as polyoxyethylene hydrogenated castor oil 50), and the like.

[0033] The nonionic surfactant A may be used alone or in any combination of two or more kinds.

[0034] The content of nonionic surfactant A in the topical composition of the present invention is not particularly limited, but is, for example, 0.1% by mass or more and 20% by mass or less. From the viewpoints of the stability of vitamin D3, reduction in stickiness of the topical composition, etc., the content is preferably 0.2% by mass or more and 15% by mass or less, more preferably 0.5% by mass or more and 10% by mass or less, even more preferably 1% by mass or more and 8% by mass or less, still more preferably 1.5% by mass or more and 6% by mass or less, and particularly preferably 2% by mass or more and 5% by mass or less.

[0035] The nonionic surfactant B is a nonionic surfactant other than polyoxyalkylene hydrogenated castor oil, and is not particularly limited thereto. Examples of the nonionic surfactant B include polyoxyalkylene alkyl ether, polyoxyalkylene glycol, polyoxyalkylene fatty acid ester, polyoxyalkylene sorbitol fatty acid ester, polyglycerin fatty acid ester, etc.

[0036] Examples of polyoxyalkylene alkyl ethers include polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene myristyl ether, polyoxyethylene palmityl ether, polyoxyethylene isostearyl ether, polyoxyethylene hexyldecyl ether, polyoxyethylene behenyl ether, polyoxyethylene linolyl ether, polyoxyethylene capryl ether, polyoxyethylene dodecyl ether, polyoxyethylene tridecyl ether, polyoxyethylene isotridecyl ether, polyoxyethylene pentadecyl ether, polyoxyethylene cholestanol ether, polyoxyethylene octyldodecyl ether, and polyoxyethylene polyoxypropylene decyltetradecyl ether.

[0037] The polyoxyalkylene glycol includes, for example, polyoxyethylene polyoxypropylene glycol.

[0038] Examples of polyoxyalkylene fatty acid esters include polyethylene glycol monostearate, polyethylene glycol distearate, polyethylene glycol monooleate, polyethylene glycol dioleate, polyethylene glycol monoisostearate, and polyethylene glycol diisostearate.

[0039] Examples of polyoxyalkylene sorbitol fatty acid esters include polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitol hexastearate, polyoxyethylene sorbitol monolaurate, and polyoxyethylene sorbitol beeswax.

[0040] Examples of polyglycerol fatty acid esters include diglyceryl monocaprylate, decaglyceryl monocaprylate, hexaglyceryl monocaprate, tetraglyceryl monolaurate, hexaglyceryl monolaurate, decaglyceryl monolaurate, polyglyceryl monolaurate, decaglyceryl monomyristate, decaglyceryl monostearate, decaglyceryl monoisostearate, polyglyceryl monostearate, diglyceryl monooleate, hexaglyceryl monooleate, diglyceryl sesquioleate, polyglyceryl diisostearate, polyglyceryl distearate, diglyceryl triisostearate, and polyglyceryl tristearate.

[0041] Other examples of nonionic surfactants B besides those mentioned above include glycerin fatty acid esters, sorbitan fatty acid esters, and alkyl glyceryl ethers (ethers formed by the reaction of higher alcohols with glycerin).

[0042] From the viewpoint of more effectively improving the stability of the drug (especially vitamin D3), the HLB (Hydrophilic-Lipophilic Balance) value of the nonionic surfactant is preferably 6 or more, more preferably 6.5 or more, even more preferably 7 or more, still more preferably 7 to 19, and particularly preferably 7 to 18.

[0043] The nonionic surfactant B may be used alone or in any combination of two or more kinds.

[0044] The content of nonionic surfactant B in the composition for external use of the present invention is not particularly limited, but is, for example, 0.002% by mass or more and 10% by mass or less. From the viewpoint of the stability of vitamin D3, reduction of stickiness of the composition for external use, etc., the content is preferably 0.005% by mass or more and 10% by mass or less, more preferably 0.01% by mass or more and 10% by mass or less, even more preferably 0.02% by mass or more and 10% by mass or less, even more preferably 0.05% by mass or more and 8% by mass or less, particularly preferably 0.1% by mass or more and 6% by mass or less, especially preferably 0.2% by mass or more and 4% by mass or less, and especially more preferably 0.5% by mass or more and 3% by mass or less.

[0045] The total content of the nonionic surfactant A and the nonionic surfactant B in the topical composition of the present invention is not particularly limited, but is, for example, 0.1% by mass or more and 20% by mass or less. From the viewpoints of the stability of vitamin D3, reduction in stickiness of the topical composition, etc., the content is preferably 0.5% by mass or more and 15% by mass or less, more preferably 1% by mass or more and 12% by mass or less, even more preferably 2% by mass or more and 10% by mass or less, still more preferably 3% by mass or more and 8% by mass or less, and preferably 4% by mass or more and 6% by mass or less.

[0046] The content of nonionic surfactant A in the total of nonionic surfactant A and nonionic surfactant B is not particularly limited, but is, for example, 10% by mass or more and 99.9% by mass or less. From the viewpoints of the stability of vitamin D3, reduction in stickiness of the topical composition, etc., the content is preferably 20% by mass or more and 99.5% by mass or less, more preferably 30% by mass or more and 99% by mass or less, even more preferably 40% by mass or more and 95% by mass or less, still more preferably 45% by mass or more and 92% by mass or less, and particularly preferably 45% by mass or more and 90% by mass or less.

[0047] The topical composition of the present invention preferably contains ester oil. The ester oil can further improve the stability of vitamin D3. The ester oil is an oily component consisting of an ester of a fatty acid and an alcohol, and is not particularly limited as long as it is liquid at room temperature (20°C).

[0048] Specific examples of the ester oil include the following:

[0049] Dibasic acid ester oils such as dioctyl succinate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, diethyl sebacate, diisopropyl sebacate, and dioctyl sebacate.

[0050] Ester oils having a hydroxyl group, such as lauryl lactate, myristyl lactate, cetyl lactate, octyldodecyl lactate, trioctyl citrate, triisocetyl citrate, trioctyldodecyl citrate, and diisostearyl malate; Ester oils of straight-chain fatty acids and lower alcohols, such as isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, butyl stearate, ethyl oleate, ethyl linoleate, and isopropyl linoleate; ester oils of straight-chain fatty acids and straight-chain higher alcohols, such as cetyl caprate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, cetyl palmitate, stearyl stearate, decyl oleate, and oleyl oleate; ester oils of straight-chain fatty acids and branched alcohols, such as perilla laurate, isotridecyl myristate, isocetyl myristate, isostearyl myristate, octyldodecyl myristate, 2-ethylhexyl palmitate, isocetyl palmitate, isostearyl palmitate, 2-ethylhexyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl oleate, and octyldodecyl ricinoleate; Ester oils of branched fatty acids and lower alcohols, such as ethyl isostearate and isopropyl isostearate; Ester oils of branched fatty acids and linear higher alcohols, such as cetyl 2-ethylhexanoate, cetostearyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, hexyl isostearate, and 2-hexyldecyl isostearate; Ethylene glycol dioctanoate, ethylene glycol dioleate, propylene glycol dicaprylate, propylene glycol dicaprylate-caprate, propylene glycol dicaprate, dipropylene glycol dioleate, neopentyl glycol dicaprate, neopentyl glycol dioctanoate, glyceryl tricaprylate, glyceryl tri-2-ethylhexanoate, glycerin triisooctanoate, glyceryl tricaprylate-caprate, glyceryl triisopalmitate, glyceryl triisostearate, trimethylolpropane triisostearate, pentaerythritol tetraisostearate, pentaerythritol tetraisostearate, pentaerythritol tetraisostearate, pentaerythritol tetraethylhexanoate, and other fatty acid and polyhydric alcohol ester oils; Ester oils of branched chain fatty acids and branched chain alcohols, such as octyldodecyl neopentanoate, isocetyl octanoate, isostearyl octanoate, 2-ethylhexyl isopelargonate, hexyldecyl dimethyloctanoate, octyldodecyl dimethyloctanoate, 2-ethylhexyl isopalmitate, isocetyl isostearate, isostearyl isostearate, and octyldodecyl isostearate.

[0051] Among the above specific examples, the topical composition of the present invention may preferably contain an ester oil of a dibasic acid from the viewpoint of the stability of vitamin D3, etc. From the same viewpoint, the ester oil of a dibasic acid may more preferably contain a diester (preferably a symmetric diester) of a dicarboxylic acid (preferably a linear dicarboxylic acid) having 4 to 8 (preferably 5 to 7) carbon atoms in the main chain and an alkyl alcohol (preferably an alkyl alcohol having 2 to 10, preferably 3 to 10, more preferably 3 to 6 carbon atoms).

[0052] In one embodiment of the present invention, the ester oil may contain at least glycerin triisooctanoate.

[0053] The ester oil may be used alone or in any combination of two or more kinds.

[0054] When the topical composition of the present invention contains ester oil, the content of the ester oil in the topical composition of the present invention is not particularly limited, and is, for example, more than 0% by mass and 10% by mass or less. From the viewpoint of the stability of vitamin D3, the content is preferably 0.005% by mass or more and 10% by mass or less, more preferably 0.05% by mass or more and 10% by mass or less, even more preferably 0.1% by mass or more and 8% by mass or less, even more preferably 0.2% by mass or more and 6% by mass or less, particularly preferably 0.5% by mass or more and 4% by mass or less, and particularly preferably 1% by mass or more and 2% by mass or less.

[0055] The topical composition of the present invention preferably contains a glucocorticoid. According to the present invention, a topical composition in which vitamin D3 is more stable and the glucocorticoid is also stable can be provided.

[0056] The glucocorticoid is not particularly limited as long as it can be used in steroid preparations. Examples of glucocorticoids include cortisones such as cortisone, hydrocortisone, cortisol, and corticosterone, prednisolones such as prednisolone and methylprednisolone, dexamethasone, betamethasone, and derivatives thereof. Examples of derivatives include esters such as phosphate ester, valerate ester, butyrate ester, and propionate ester, and the ester may be an ester of one acid or an ester of mixed acids. Among these, betamethasone or its ester is preferred. Among esters, betamethasone dipropionate, betamethasone butyrate ester propionate, and the like are preferred.

[0057] The glucocorticoids may be used alone or in any combination of two or more kinds.

[0058] When the topical composition of the present invention contains a glucocorticoid, the content of the glucocorticoid in the topical composition of the present invention is not particularly limited and can be, for example, 0.001% by mass to 2% by mass, preferably 0.002% by mass to 1% by mass, preferably 0.005% by mass to 0.5% by mass, preferably 0.01% by mass to 0.2% by mass, and preferably 0.015% by mass to 0.1% by mass.

[0059] The composition for external use of the present invention usually contains water. The content of water in the composition of the present invention is, for example, 40% by mass or more, preferably 50% by mass or more, more preferably 60% by mass or more, even more preferably 70% by mass or more, even more preferably 75% by mass or more, particularly preferably 80% by mass or more, particularly preferably 85% by mass or more, and particularly preferably 90% by mass or more. The upper limit of the content can be, for example, 95% by mass, 90% by mass, 85% by mass, or 80% by mass. The above lower limit and upper limit can be arbitrarily combined. The composition for external use of the present invention can effectively improve the stability of vitamin D3 even in a situation where the content of water is higher and the problem of the stability of vitamin D3 becomes greater.

[0060] When the topical composition of the present invention contains water, the pH of the topical composition of the present invention is preferably 6 to 8, more preferably 6.5 to 7.5, even more preferably 6.7 to 7.3, even more preferably 6.8 to 7.2, and particularly preferably 6.9 to 7.1, from the viewpoint of the stability of vitamin D3, etc.

[0061] In one embodiment of the present invention, the composition for external use of the present invention may contain other components other than those described above. Examples of other components include hydrocarbons (e.g., liquid paraffin (e.g., light liquid paraffin), squalane, etc.), solvents (e.g., benzyl alcohol, methyl ethyl ketone, N-alkylpyrrolidone, alkylene carbonate, acetone, ethanol, isopropanol, propylene glycol, 1,3-butylene glycol, concentrated glycerin, polyethylene glycol, hexylene glycol, propylene carbonate, etc.), water-soluble polymers (e.g., carboxyvinyl polymer, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, chitosan, povidone, polyvinyl alcohol, gelatin, casein, carrageenan, etc.), antioxidants, pH adjusters, preservatives, preservatives, stabilizers, amino acids, chelating agents, etc. These may be used alone or in combination of any two or more. In addition, the topical composition of the present invention may contain other ingredients, such as medicinal ingredients other than the above-mentioned vitamin D3 and glucocorticoid, such as moisturizers, anti-inflammatory agents, vitamins, antibacterial agents, germicides, antiviral agents, steroids, antibiotics, antipruritic agents, anti-immunosuppressants, local anesthetics, and whitening agents.

[0062] In one embodiment of the present invention, the topical composition of the present invention contains hydrocarbons (hydrocarbon oils).

[0063] In one embodiment of the present invention, the topical composition of the present invention contains an antioxidant.

[0064] The content of other components in the composition for external use of the present invention is not particularly limited as long as it does not significantly impair the effects of the present invention. The content is, for example, 0% by mass to 10% by mass, 0% by mass to 5% by mass, 0% by mass to 2% by mass, 0% by mass to 1% by mass, or 0% by mass to 0.1% by mass.

[0065] The topical composition of the present invention can be used for application to the skin. The topical composition of the present invention can be for application to the skin (excluding those for application to hair (e.g., shampoo, rinse)). The topical composition of the present invention is preferably in the form of a topical composition for the skin, such as a skin topical medicine or cosmetic. The topical composition of the present invention is used in a manner that is not removed after application, and is distinguished from a cleanser that is intended to be removed with water (e.g., washed off) after lathering.

[0066] The composition for external use of the present invention is not particularly limited in the form of the drug, and can be in the form of a known cosmetic or quasi-drug.Among such known forms, for example, liquid, suspension, emulsion, cream, gel, liniment, lotion, aerosol, powder, cataplasm, sheet impregnated with a drug solution in a sheet such as nonwoven fabric, and emulsion for lips can be mentioned.Among them, liquid, suspension, emulsion, cream, gel, and lotion are preferred in terms of good usability, and liquid (with transparency) is particularly preferred.

[0067] In one embodiment of the present invention, the formulation of the topical composition of the present invention is a gel, liquid, aerosol, mist, or foam.

[0068] The composition for external use of the present invention can be prepared by mixing each component with a solvent. The composition of the present invention is preferably in a solubilized state. The solubilized state refers to a state in which the surfactant forms micelles, dissolves transparently and uniformly, and becomes a one-phase solution. The solubilized state also includes a microemulsion state. A microemulsion is a thermodynamically stable micellar solution consisting of emulsion particles with a fine particle size of 100 nm or less. The solubilized state can be confirmed by the transparent appearance. The solubilized state can also be confirmed by measuring the particle size by a conventional method. The solubilized composition can be obtained by dissolving each component under heating as necessary, and then cooling.

[0069] The composition for external use of the present invention is preferably a composition filled in a non-gas type foam discharger. Here, the non-gas type foam discharger means a device equipped with a mechanism for foaming without relying on a propellant. That is, the composition for external use of the present invention is preferably one for foaming by a non-gas type foam discharger. An example of a non-gas type foam discharger is a screen type foam discharger. A screen type foam discharger means a device having a mechanism for pressurizing a liquid and passing it through a net-like screen (mesh) to mix it with air and foam it. Examples of the screen type foam discharger include a pump type foam discharger, a tube type foam discharger, and a squeeze type foam discharger. Among these, a pump type foam discharger is preferable.

[0070] As the non-gas type foam discharge device, known devices, commercially available devices, etc. can be used. For example, in the case of a pump type foam discharge device, those described in JP 2012-45525 A, JP 2008-307478 A, etc. can be used.

[0071] The topical composition of the present invention can be used, for example, to prevent or improve psoriasis.

[0072] The term "amelioration" includes not only attenuation or elimination of symptoms, but also suppression of the degree of exacerbation of symptoms or cessation of the exacerbation of symptoms when the exacerbation of symptoms continues.

[0073] Psoriasis is not particularly limited, and examples thereof include psoriasis vulgaris, psoriatic arthritis, guttate psoriasis, erythrodermic psoriasis, and pustular psoriasis.

[0074] The topical composition of the present invention can be applied to mammals, including humans, for example, once every day or once every few days, and is preferably applied continuously. When the topical composition of the present invention is applied continuously, the application period is preferably 2 weeks or more, more preferably 3 weeks or more, and even more preferably 4 weeks or more. EXAMPLES

[0075] The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

[0076] material Details of the materials used in the following test examples are as follows: POE means polyoxyethylene, and POP means polyoxypropylene.

[0077] (a1. Active pharmaceutical ingredient: Vitamin D3) Calcipotriol monohydrate Maxacalcitol.

[0078] (a2. Drug substance: glucocorticoid) Betamethasone dipropionate · Betamethasone butyrate propionate.

[0079] (b. Nonionic Surfactant A) Polyoxyethylene hydrogenated castor oil 40 (HLB value 12.5). "40" indicates the average number of moles of ethylene oxide added.

[0080] (c1. Nonionic surfactant B: Polyoxyalkylene alkyl ether) POE(20) POP(4) Cetyl ether (HLB value 12.5) -POE lauryl ether (HLB value 14.5).

[0081] (c2. Nonionic surfactant B: polyoxyalkylene glycol) · POEPOP Glycol (HLB value 10.9).

[0082] (c3. Nonionic surfactant B: polyoxyalkylene fatty acid ester) ·Polyethylene glycol monostearate (HLB value 17.5).

[0083] (c4. Nonionic surfactant B: polyoxyalkylene sorbite fatty acid ester) -Polyoxyethylene sorbitol tetraoleate (HLB value 15.5).

[0084] (c5. Nonionic surfactant B: Polyglycerol fatty acid ester) ·Polyglyceryl monolaurate (HLB value 15.5).

[0085] (d. Ester oil) Diisopropyl adipate Glyceryl triisooctanoate.

[0086] (e. pH adjuster) Sodium hydroxide ·Sodium citrate hydrate Citric acid hydrate.

[0087] Test Example 1. Evaluation test of drug substance stability 1 Liquid compositions (Examples 1 to 9, Comparative Examples 1 to 11) were prepared according to the formulations shown in Tables 1 and 2 (the units of numbers are mass %, and blanks indicate 0). Specifically, the above-mentioned group a (a1 and a2) and group d1 were dissolved, and then group c (c1 or c2 or c3 or c4 or c5) was added and dissolved again. Thereafter, water was added and stirred to dissolve, thereby obtaining a liquid composition. The pH of the liquid composition was adjusted to pH 7.0 by adding a pH adjuster (the appropriate amount in the tables is 0.002 to 0.01 mass %) as shown in Tables 1 and 2.

[0088] The stability of vitamin D3 and glucocorticoid in the obtained liquid composition was measured. Specifically, the liquid composition was left to stand at 60°C, and the contents of vitamin D3 and glucocorticoid after 1 week, 2 weeks, and 3 weeks were analyzed by HPLC, and the peak areas of the samples were measured by automatic integration, and the remaining ratios of vitamin D3 and glucocorticoid were calculated.

[0089] [Table 1]

[0090] [Table 2]

[0091] The results are shown in Figures 1 to 9. It was found that a synergistic effect was obtained in improving the stability of vitamin D3 by combining nonionic surfactant A, which is a polyoxyalkylene hydrogenated castor oil, with nonionic surfactant B, which is a nonionic surfactant other than polyoxyalkylene hydrogenated castor oil. It was also found that this combination did not adversely affect the stability of glucocorticoids.

Claims

1. A composition for topical use, comprising: The composition contains vitamin D3, a nonionic surfactant A which is a polyoxyalkylene hydrogenated castor oil having an average number of alkylene oxide moles added of 55 or less, a nonionic surfactant B which is a nonionic surfactant other than polyoxyalkylene hydrogenated castor oil, and water, The vitamin D3 is at least one selected from the group consisting of calcipotriol, maxacalcitol, alphacalcidol, falecalcitriol, tacalcitol, and calcitriol; and The content of the water in the composition for external use is 40% by mass or more. External composition.

2. The composition for external use according to claim 1, wherein the nonionic surfactant B is at least one selected from the group consisting of polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbite fatty acid esters, and polyglycerin fatty acid esters.

3. The composition for external use according to claim 1 , wherein the HLB value of the nonionic surfactant B is 6 or higher.

4. The topical composition according to claim 1, wherein the total content of the nonionic surfactant A and the nonionic surfactant B in the topical composition is 0.5% by mass or more and 10% by mass or less.

5. The composition for external use according to claim 1, wherein the content of said nonionic surfactant A in the total of said nonionic surfactant A and said nonionic surfactant B is 10% by mass or more and 99.9% by mass or less.

6. The topical composition according to claim 1 , which contains an ester oil.

7. The topical composition according to claim 6, wherein the ester oil contains at least glycerin triisooctanoate.

8. the nonionic surfactant B is at least one selected from the group consisting of polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbite fatty acid esters, and polyglycerin fatty acid esters; The nonionic surfactant B has an HLB value of 6 or more, The total content of the nonionic surfactant A and the nonionic surfactant B in the composition for external use is 1% by mass or more and 10% by mass or less, The content of the nonionic surfactant A in the total of the nonionic surfactant A and the nonionic surfactant B is 10% by mass or more and 99.9% by mass or less, and The topical composition according to claim 1 , which contains an ester oil.

9. The composition for external use according to claim 1, wherein the vitamin D3 is at least one selected from the group consisting of calcipotriol and maxacalcitol.

10. The composition for external use according to claim 1, wherein the vitamin D3 is calcipotriol, the glucocorticoid contains betamethasone dipropionate, the polyoxyalkylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil, and the nonionic surfactant B is at least one selected from the group consisting of polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbite fatty acid esters, and polyglycerin fatty acid esters.

11. The composition for external use according to claim 1, 2, 8 or 10, wherein the nonionic surfactant B is one or more selected from polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene lauryl ether, polyoxyethylene polyoxypropylene glycol, polyethylene glycol monostearate, polyoxyethylene sorbitol tetraoleate, and polyglyceryl monolaurate.

12. An external composition described in any one of claims 1 to 10, wherein the water content in the external composition is 50 mass% or more.

13. The composition for external use according to claim 12, wherein the content of said water in said composition for external use is 60% by mass or more.

14. The composition for external use according to claim 12, wherein the content of said water in said composition for external use is 75% by mass or more.

15. The composition for external use according to any one of claims 1 to 10, wherein the content of vitamin D3 in the composition for external use is 0.0001% by mass or more and 0.2% by mass or less.

16. The composition for external use according to any one of claims 1 to 10, further comprising an antioxidant.

17. The composition for external use according to any one of claims 1 to 10, which is in the form of a gel, liquid, aerosol, mist, or foam.

18. The composition for external use according to any one of claims 1 to 10, which is used for preventing or improving psoriasis.

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