Composition for external use

Abstract

Provided is a technique for further improving the stability of vitamin D3 in a composition for external use containing vitamin D3 and glucocorticoid, even if the water content in the composition for external use is increased. The composition for external use contains vitamin D3, glucocorticoid, a nonionic surfactant (A) that is polyoxyalkylene hydrogenated castor oil, and a nonionic surfactant (B) that is a nonionic surfactant other than polyoxyalkylene hydrogenated castor oil.

Description

TECHNICAL FIELD

[0001] The present application relates to an external composition or the like. BACKGROUND

[0002] Psoriasis is a skin disease in which the main symptoms are skin keratosis, scaling, skin thickening, and red rash, and there are several hundred thousand patients in Japan. For the skin symptoms of psoriasis, it is known to use vitamin D3 as an external agent. In addition, for psoriasis, it is known to use vitamin D3 and a glucocorticoid together as an external agent (Patent Literature 1).

[0003] PRIOR ART DOCUMENTS PATENT LITERATURE Patent Literature 1: Japanese Patent Application Laid-Open No. 2021-518409 SUMMARY

[0004] PROBLEMS TO BE SOLVED BY THE INVENTION Although vitamin D3 is excellent in terms of its efficacy, when it is dissolved in water, the stability decreases, and therefore, when the water content is increased, the problem of stability becomes greater.

[0005] Therefore, the problem to be solved by the present application is to provide a technology that, in an external composition containing vitamin D3 and a glucocorticoid, can further improve the stability of vitamin D3 even if the water content in the external composition is increased.

[0006] Item 1. An external composition containing vitamin D3, a glucocorticoid, a nonionic surfactant A that is a polyoxyalkylene hydrogenated castor oil, and a nonionic surfactant B that is a nonionic surfactant other than a polyoxyalkylene hydrogenated castor oil.

[0007] Item 2. The external composition according to Item 1, wherein the nonionic surfactant B is at least one selected from the group consisting of a polyoxyalkylene alkyl ether, a polyoxyalkylene glycol, a polyoxyalkylene fatty acid ester, a polyoxyalkylene sorbitol fatty acid ester, and a polyglycerin fatty acid ester.

[0008] Item 3. The external composition according to Item 1 or 2, wherein the nonionic surfactant B has an HLB value of 6 or more.

[0009] Item 4. The external composition 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 external composition is 0.5 mass% or more and 10 mass% or less.

[0010] Item 5. The topical composition 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.

[0011] Item 6. The topical composition as described in any one of items 1 to 5, comprising an ester oil.

[0012] Item 7. The topical composition as described in Item 6, wherein the ester oil comprises at least triisooctanoic acid glycerol.

[0013] Item 8. The topical composition according to any one of items 1 to 7, wherein the nonionic surfactant B is selected from at least one of polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbitol fatty acid esters, and polyglycerol fatty acid esters. The nonionic surfactant B mentioned above has an HLB value of 6 or higher. The total content of the above-mentioned nonionic surfactant A and nonionic surfactant B in the above-mentioned topical composition is more than 1% by mass and less than 10% by mass. The content of nonionic surfactant A in the total of the above-mentioned nonionic surfactant A and nonionic surfactant B is 10% by mass or more and 99.9% by mass or less, and, The above-mentioned topical composition contains ester oil.

[0014] Item 9. The topical composition as described in any one of Items 1 to 8, wherein the vitamin D3 is selected from at least one of calcipotriol, masalcalcidol, alfacalcidol, fluorotriol, tacalcitol, and calcitriol.

[0015] Item 10. The topical composition as described in 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 polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbitol fatty acid esters, and polyglycerol fatty acid esters.

[0016] Item 11. The topical composition according to any one of items 1 to 10, wherein the nonionic surfactant B is selected from one or more of polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene lauryl ether, polyoxyethylene polyoxypropylene glycol, polyethylene glycol monostearate, polyoxyethylene sorbitol tetraoleate, and polyglycerol monolaurate.

[0017] Item 12. The topical composition as described in any one of items 1 to 11, wherein the average molar number of epoxides added to the polyoxyalkylene hydrogenated castor oil is less than 60.

[0018] Item 13. The topical composition as described in Item 12, wherein the epoxy alkyl group is ethylene oxide.

[0019] Item 14. The topical composition as described in any one of items 1 to 13, wherein the average molar number of ethylene oxide additions in the above-mentioned polyoxyethylene hydrogenated castor oil is less than 60.

[0020] Item 15. The topical composition as described in any one of items 1 to 14, further comprising water.

[0021] Item 16. The topical composition as described in Item 15, wherein the water content in the topical composition is 40% by mass or more.

[0022] Item 17. The topical composition as described in Item 15, wherein the water content in the topical composition is 75% by mass or more.

[0023] Item 18. The topical composition as described in any one of items 1 to 17, wherein the content of the vitamin D3 in the topical composition is more than 0.0001% by mass and less than 0.2% by mass.

[0024] Item 19. The topical composition as described in any one of items 1 to 18, wherein the content of the glucocorticoid in the topical composition is more than 0.001% by mass and less than 2% by mass.

[0025] Item 20. The topical composition as described in any one of items 1 to 19, wherein the topical composition further contains an antioxidant.

[0026] Item 21. The topical composition as described in any one of items 1 to 20, wherein the dosage form is a gel, liquid, aerosol, mist, or foam.

[0027] Item 22. The topical composition as described in any one of items 1 to 21, used for the prevention or improvement of psoriasis.

[0028] Technical solutions for solving technical problems The inventors of this invention, having conducted meticulous research in view of the aforementioned technical problems, discovered that a topical composition containing vitamin D3, glucocorticoids, nonionic surfactant A (as a polyoxyalkylene hydrogenated castor oil), and nonionic surfactant B (as a nonionic surfactant other than polyoxyalkylene hydrogenated castor oil) can solve these problems. Based on this insight, the inventors of this invention further conducted research, and as a result, completed this invention. That is, this invention includes the following embodiments.

[0029] Invention Effects Using the present invention, a topical composition is provided that contains vitamin D3 and glucocorticoids, and the stability of vitamin D3 can be further improved even when the water content in the composition is increased. Attached Figure Description

[0030] Figure 1 The vertical axis represents the residual rates of vitamin D3 (upper section) and glucocorticoids (lower section) in the liquid compositions (Example 1, Comparative Example 1, Comparative Example 2) when they are left to stand at 60°C. The horizontal axis represents the number of weeks elapsed since the start of the standing process at 60°C.

[0031] Figure 2 The vertical axis represents the residual rates of vitamin D3 (upper section) and glucocorticoids (lower section) in the liquid compositions (Example 2, Comparative Example 1, Comparative Example 3) after standing at 60°C. The horizontal axis represents the number of weeks elapsed from the start of standing at 60°C.

[0032] Figure 3 The vertical axis represents the residual rates of vitamin D3 (upper section) and glucocorticoids (lower section) in the liquid compositions (Example 3, Comparative Example 1, Comparative Example 4) when they were left to stand at 60°C. The horizontal axis represents the number of weeks elapsed since the start of the standing process at 60°C.

[0033] Figure 4 The vertical axis represents the residual rates of vitamin D3 (upper section) and glucocorticoids (lower section) in the liquid compositions (Example 4, Comparative Example 1, Comparative Example 5) after standing at 60°C. The horizontal axis represents the number of weeks elapsed from the start of standing at 60°C.

[0034] Figure 5 The vertical axis represents the residual rates of vitamin D3 (upper section) and glucocorticoids (lower section) in the liquid compositions (Example 5, Comparative Example 1, Comparative Example 6) when they were left to stand at 60°C. The horizontal axis represents the number of weeks elapsed since the start of the standing process at 60°C.

[0035] Figure 6The vertical axis represents the residual rates of vitamin D3 (upper section) and glucocorticoids (lower section) in the liquid compositions (Example 6, Comparative Example 1, Comparative Example 7) when they were left to stand at 60°C. The horizontal axis represents the number of weeks elapsed since the start of the standing process at 60°C.

[0036] Figure 7 The vertical axis represents the residual rates of vitamin D3 (upper section) and glucocorticoids (lower section) in the liquid compositions (Examples 7, Comparative Examples 8, and Comparative Examples 9) when they were left to stand at 60°C. The horizontal axis represents the number of weeks elapsed since the start of the standing process at 60°C.

[0037] Figure 8 The vertical axis represents the residual rates of vitamin D3 (upper section) and glucocorticoids (lower section) in the liquid compositions (Example 8, Comparative Example 8, Comparative Example 10) after standing at 60°C. The horizontal axis represents the number of weeks elapsed from the moment the liquid compositions (Example 8, Comparative Example 8, Comparative Example 10) began to stand at 60°C.

[0038] Figure 9 The vertical axis represents the residual rates of vitamin D3 (upper section) and glucocorticoids (lower section) in the liquid compositions (Example 9, Comparative Example 8, Comparative Example 11) after standing at 60°C. The horizontal axis represents the number of weeks elapsed from the moment the liquid compositions (Example 9, Comparative Example 8, Comparative Example 11) began to stand at 60°C.

[0039] Figure 10 The vertical axis represents the residual rate of vitamin D3 when the liquid composition (Example 3, Example 3A) is allowed to stand at 60°C. The horizontal axis represents the number of weeks elapsed since the start of the standing process at 60°C.

[0040] Figure 11 The vertical axis represents the residual rate of vitamin D3 when the liquid composition (Example 6, Example 6A) is left to stand at 60°C. The horizontal axis represents the number of weeks elapsed since the start of the standing process at 60°C. Detailed Implementation

[0041] In this specification, the expressions “containing” and “comprising” include the concepts of “containing”, “comprising”, “substantially constituted by” and “consisting solely of”.

[0042] In this specification, the number of carbon atoms in "alkylene" is, for example, 2 to 4, preferably 2 to 3, and more preferably 2.

[0043] In one embodiment, this invention relates to a topical composition containing vitamin D3, a glucocorticoid, a nonionic surfactant A (as a polyoxyalkylene hydrogenated castor oil), and a nonionic surfactant B (other than the polyoxyalkylene hydrogenated castor oil) (sometimes referred to in this specification as "the topical composition of this invention"). It will be described below.

[0044] There are no particular limitations on vitamin D3 as long as it is a compound that can be used in an active vitamin D3 formulation. Examples of vitamin D3 include calcipotriol (1α,24(OH)2-22-en-24-cyclopropyl-vitamin D3), mascalcitriol (22-oxa-1α,25-dihydroxyvitamin D3), alfacalcitriol, fluorocalcitriol (1,25-dihydroxy-26,27-hexafluoro-vitamin D3), tacalcitriol (1α,24(R)-dihydroxyvitamin D3), and calcitriol (1,25-dihydroxyvitamin D3). These components include free forms, salts, and solvates (e.g., hydrates). Among these, calcipotriol and mascalcitriol are preferred from the viewpoint of pharmaceutical stability (especially vitamin D3). In one embodiment of the invention, mascalcitriol is particularly preferred as vitamin D3. In another embodiment of the invention, calcipotriol is used as vitamin D3.

[0045] Vitamin D3 can be used alone or in combination with any two or more types.

[0046] The content of vitamin D3 in the topical composition of the present invention is not particularly limited, and can be set to 0.0001% by mass or more and 0.2% by mass or less. This content is preferably 0.0002% by mass or more and 0.1% by mass, preferably 0.0005% by mass or more and 0.05% by mass, preferably 0.001% by mass or more and 0.02% by mass, and preferably 0.0015% by mass or more and 0.01% by mass or less.

[0047] There are no particular restrictions on glucocorticoids as long as they are compounds that can be used in steroid preparations. Examples of glucocorticoids include cortisone, hydrocortisone, cortisol, corticosterone and other cortisone derivatives, prednisolone, methylprednisolone and other prednisolone derivatives, dexamethasone, betamethasone and their derivatives. Examples of derivatives include esters such as phosphate esters, valerate esters, butyrate esters, propionate esters, etc., which can be esters of a single acid or esters of mixed acids. Among these, betamethasone or its esters are preferred. Among esters, betamethasone dipropionate and betamethasone butyrate propionate are preferred.

[0048] Glucocorticoids can be used alone or in combination of any two or more.

[0049] The content of glucocorticoids in the topical composition of the present invention is not particularly limited, and can be set to 0.001% by mass or more and 2% by mass or less. This content is preferably 0.002% by mass or more and 1% by mass or less, preferably 0.005% by mass or more and 0.5% by mass or less, preferably 0.01% by mass or more and 0.2% by mass or less, and preferably 0.015% by mass or more and 0.1% by mass or less.

[0050] Polyoxyalkylene hydrogenated castor oil (nonionic surfactant A) is a compound formed by the addition polymerization of an alkylene oxide and hydrogenated castor oil. As a nonionic surfactant, there are no particular limitations as long as it can be used. The average molar number of the alkylene oxide addition is not particularly limited, for example, it is 5 to 100. From the viewpoint of pharmaceutical stability (especially vitamin D3), this average molar number of addition is particularly preferred to be 55 or less, more preferably 10 to 55 or less, further preferably 20 to 55 or less, even more preferably 30 to 50 or less, and particularly preferably 35 to 45 or less. Polyoxyalkylene hydrogenated castor oil is particularly preferred as a polyoxyalkylene hydrogenated castor oil. Specific examples of polyoxyethylene hydrogenated castor oil include polyoxyethylene (5) hydrogenated castor oil (also known as polyoxyethylene hydrogenated castor oil 5), polyoxyethylene (10) hydrogenated castor oil (also known as polyoxyethylene hydrogenated castor oil 10), polyoxyethylene (20) hydrogenated castor oil (also known as polyoxyethylene hydrogenated castor oil 20), polyoxyethylene (30) hydrogenated castor oil (also known as polyoxyethylene hydrogenated castor oil 30), and polyoxyethylene (40) hydrogenated castor oil. Hydrogenated castor oil (also known as polyoxyethylene hydrogenated castor oil 40), polyoxyethylene (50) hydrogenated castor oil (also known as polyoxyethylene hydrogenated castor oil 50), polyoxyethylene (60) hydrogenated castor oil (also known as polyoxyethylene hydrogenated castor oil 60), polyoxyethylene (80) hydrogenated castor oil (also known as polyoxyethylene hydrogenated castor oil 80), polyoxyethylene (100) hydrogenated castor oil (also known as polyoxyethylene hydrogenated castor oil 100), etc.

[0051] Nonionic surfactant A can be used alone or in combination with any two or more.

[0052] The content of nonionic surfactant A in the topical composition of the present invention is not particularly limited, for example, it is 0.1% by mass or more and 20% by mass or less. From the viewpoint of the stability of the pharmaceutical agent (especially vitamin D3) and reducing the viscosity of the topical composition, this 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, further preferably 1% by mass or more and 8% by mass or less, even 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.

[0053] There are no particular restrictions on nonionic surfactant B, as long as it is not a polyoxyalkylene hydrogenated castor oil. Examples of nonionic surfactant B include polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbitol fatty acid esters, polyglycerol fatty acid esters, polyoxyalkylene glycerol fatty acid esters, and polyoxyalkylene sorbitan fatty acid esters.

[0054] Examples of polyoxyalkylene 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 benzyl ether, polyoxyethylene linoleyl ether, polyoxyethylene octyl ether, polyoxyethylene dodecyl ether, polyoxyethylene tridecyl ether, polyoxyethylene isotridecyl ether, polyoxyethylene pentadecyl ether, polyoxyethylene cholesterol alcohol ether, polyoxyethylene octyl dodecyl ether, and polyoxyethylene polyoxypropylene decyl tetradecyl ether.

[0055] Examples of polyoxyalkylene glycols include polyoxyethylene polyoxypropylene glycol.

[0056] Examples of polyoxyalkylene fatty acid esters include polyethylene monostearate, polyethylene distearate, polyethylene monooleate, polyethylene dioleate, polyethylene monoisostearate, and polyethylene diisostearate.

[0057] Examples of polyoxyalkylene sorbitol fatty acid esters include tetraoleic polyoxyethylene sorbitol ester, hexastearate polyoxyethylene sorbitol ester, monolaurate polyoxyethylene sorbitol ester, and polyoxyethylene sorbitol beeswax.

[0058] Examples of polyglycerol fatty acid esters include monocaprylic acid diglyceride, monocaprylic acid decaglyceride, monocapric acid hexaglyceride, monolauric acid tetraglyceride, monolauric acid hexaglyceride, monolauric acid decaglyceride, monolauric acid polyglyceride, monomyristate decaglyceride, monostearate decaglyceride, monoisostearate decaglyceride, monostearate polyglyceride, monooleic acid diglyceride, monooleic acid hexaglyceride, sesquioleic acid diglyceride, diisostearate polyglyceride, distearate polyglyceride, triisostearate diglyceride, and tristearate polyglyceride.

[0059] Examples of polyoxyalkylene glycerol fatty acid esters include, for example, polyoxyethylene monostearate.

[0060] Examples of polyoxyalkylene sorbitan esters include polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan tristearate, and polyoxyethylene sorbitan trioleate.

[0061] In addition to the above, other nonionic surfactants B can also include fatty acid glycerides, sorbitan fatty acid esters, and alkyl glycerol ethers (ethers formed by the reaction of higher alcohols with glycerol) as examples.

[0062] From the viewpoint of being able to more effectively improve the stability of the agent (especially vitamin D3), the HLB (Hydrophilic-Lipophilic Balance) value of the nonionic surfactant is preferably 6 or more, more preferably 6.5 or more, further preferably 7 or more, even more preferably 7 to 19, and particularly preferably 7 to 18.

[0063] Nonionic surfactant B can be used alone or in combination with any two or more.

[0064] The content of nonionic surfactant B in the topical composition of the present invention is not particularly limited, for example, it is 0.002% by mass or more and 10% by mass or less. From the viewpoint of the stability of the pharmaceutical agent (especially vitamin D3) and reducing the viscosity of the topical composition, this 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, further 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, particularly more preferably 0.2% by mass or more and 4% by mass or less, and particularly more preferably 0.5% by mass or more and 3% by mass or less.

[0065] The total content of the above-mentioned nonionic surfactant A and nonionic surfactant B in the topical composition of the present invention is not particularly limited, for example, it is 0.1% by mass or more and 20% by mass or less. From the viewpoint of the stability of the pharmaceutical agent (especially vitamin D3) and reducing the viscosity of the topical composition, this 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, further preferably 2% by mass or more and 10% by mass or less, even 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.

[0066] The content of nonionic surfactant A in the total of nonionic surfactant A and nonionic surfactant B is not particularly limited, for example, it is 10% by mass or more and 99.9% by mass or less. From the viewpoint of the stability of the pharmaceutical agent (especially vitamin D3) and reducing the viscosity of the topical composition, this 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, further preferably 40% by mass or more and 95% by mass or less, even 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.

[0067] The topical composition of the present invention preferably contains ester oil. Using ester oil can further improve the stability of the pharmaceutical preparation (especially vitamin D3). Ester oil is an oily component containing esters of fatty acids and alcohols, and there are no particular limitations as long as it is liquid at room temperature (20°C).

[0068] As ester oils, specific examples can be listed below.

[0069] Ester oils of dicarboxylic acids such as dioctyl succinate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, diethyl sebacate, diisopropyl sebacate, and dioctyl sebacate.

[0070] Ester oils containing hydroxyl groups include lauryl lactate, myristyl lactate, cetyl lactate, octyl dodecyl lactate, trioctyl citrate, triisoceryl 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 decanoate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, cetyl palmitate, stearyl stearate, decyl oleate, and oleic acid ester; ester oils of straight-chain fatty acids and branched alcohols, such as isostearyl laurate, isotriadecyl myristate, isocetyl myristate, isostearyl myristate, octyl dodecyl myristate, 2-ethylhexyl palmitate, isocetyl palmitate, isostearyl palmitate, 2-ethylhexyl stearate, isocetyl stearate, isocetyl oleate, and octyl dodecyl ricinoleate. Ester oils containing branched fatty acids and lower alcohols, such as ethyl isostearate and isopropyl isostearate. Ester oils containing branched fatty acids and straight-chain higher alcohols, such as 2-ethylhexanoate cetearyl, 2-ethylhexanoate cetearyl, 2-ethylhexanoate stearyl, hexyl isostearate, and 2-hexyldecyl isostearate. Ester oils of fatty acids and polyols, including ethylene glycol dioctanoate, ethylene glycol dioleate, propylene glycol dioctanoate, propylene glycol di(octanoic acid / decanoic acid), propylene glycol didecanoate, dipropylene glycol dioleate, neopentyl glycol didecanoate, neopentyl glycol dioctanoate, tricaprylic acid glycerides, tri(2-ethylhexanoic acid) glycerides, triisocaprylic acid glycerides, tri(octanoic acid / decanoic acid) glycerides, triisopalmitoyl triglycerides, triisostearate, trimethylolpropane triisostearate, pentaerythritol tetra(2-ethylhexanoic acid), pentaerythritol tetraisostearate, and pentaerythritol tetra(2-ethylhexanoic acid). Ester oils of branched fatty acids and branched alcohols, including octyl dodecyl isopentyl octanoate, isocetyl isostearate, 2-ethylhexyl isononanoate, hexyl decyl dimethyl octanoate, octyl dodecyl dimethyl octanoate, 2-ethylhexyl isopalmitoate, isocetyl isostearate, isostearate, and octyl dodecyl isostearate.

[0071] From the viewpoint of pharmaceutical stability (especially vitamin D3), the topical composition of the present invention preferably contains an ester oil of a diacid in the above-described specific examples. From the same viewpoint, it is more preferable that the ester oil of the diacid contains a diester (preferably a symmetrical diester) of a dicarboxylic acid (preferably a linear dicarboxylic acid) with a main chain having 4 to 8 (preferably 5 to 7) carbon atoms and an alkyl alcohol (preferably an alkyl alcohol with 2 to 10 carbon atoms, preferably 3 to 10, more preferably 3 to 6 carbon atoms).

[0072] In one embodiment of the invention, the ester oil may contain at least triisooctanoic acid glycerol.

[0073] Ester oils can be used alone or in combination of any two or more types.

[0074] When the topical composition of the present invention contains ester oil, the content of ester oil in the topical composition of the present invention is not particularly limited, for example, greater than 0% by mass and less than 10% by mass. From the viewpoint of the stability of the pharmaceutical agent (especially vitamin D3), this content is preferably 0.005% by mass or more and less than 10% by mass, more preferably 0.05% by mass or more and less than 10% by mass, further preferably 0.1% by mass or more and less than 8% by mass, even more preferably 0.2% by mass or more and less than 6% by mass, particularly preferably 0.5% by mass or more and less than 4% by mass, and particularly more preferably 1% by mass or more and less than 2% by mass.

[0075] The topical composition of the present invention typically contains water. The water content 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, further preferably 70% by mass or more, even more preferably 75% by mass or more, particularly preferably 80% by mass or more, particularly more preferably 85% by mass or more, and particularly preferably 90% by mass or more. The upper limit of this content can be, for example, 95% by mass, 90% by mass, 85% by mass, or 80% by mass. The above lower and upper limits can be combined arbitrarily. Even when the water content is higher and the stability problem of vitamin D3 becomes greater, the topical composition of the present invention can effectively improve the stability of vitamin D3.

[0076] When the topical composition of the present invention contains water, from the viewpoint of the stability of the pharmaceutical agent (especially vitamin D3), 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.

[0077] In one embodiment of the invention, the topical composition of the invention may contain other ingredients besides those described above. Examples of other ingredients include hydrocarbons (e.g., liquid paraffin, light liquid paraffin, squalane, etc.), solvents (e.g., benzyl alcohol, methyl ethyl ketone, N-alkylpyrrolidone, alkylene carbonate, acetone, ethanol, isopropanol, propylene glycol, 1,3-butanediol, concentrated glycerol, polyethylene glycol, hexanediol, propylene carbonate, etc.), water-soluble polymers (e.g., carboxyvinyl polymers, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, chitosan, povidone, polyvinyl alcohol, gelatin, casein, carrageenan, sodium hyaluronate, 2-methacryloyloxyethyl phosphocholine / butyl methacrylate copolymer, xanthan gum, polyethylene glycol, etc.), antioxidants, pH adjusters, preservatives, storage agents, stabilizers, amino acids, chelating agents, and amphoteric surfactants such as hydrogenated lecithin. These can be used individually or in combination of any two or more. In addition, the topical composition of the present invention may contain other pharmacological ingredients besides the aforementioned vitamin D3 and glucocorticoids, such as moisturizers, anti-inflammatory agents, vitamins, antibacterial agents, bactericides, antiviral agents, steroids, antibiotics, antipruritic agents, antiimmunosuppressants, local anesthetics, whitening agents, etc.

[0078] In one embodiment of the invention, the topical composition of the invention contains hydrocarbons (hydrocarbon oils).

[0079] In one embodiment of the invention, the topical composition of the invention contains an antioxidant.

[0080] Examples of antioxidants include fat-soluble antioxidants and water-soluble antioxidants. Examples of fat-soluble antioxidants include: butylated phenols such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA); nordihydroguaiac acid (NDGA); ascorbic acid esters such as ascorbate palmitate, ascorbate stearate, ascorbate aminopropyl phosphate, ascorbate tocopheryl phosphate, dl-α-tocopherol, d-δ-tocopherol, tocopheryl acetate, ascorbate triphosphate, and ascorbate palmitate; gallic acid esters such as ethyl gallate, propyl gallate, octyl gallate, and dodecyl gallate; propyl gallate; 3-butyl-4-hydroxyquinoline-2-one; cucurbitacin-like compounds such as lutein and astaxanthin; polyphenols such as anthocyanins, catechins, tannins, and curcumin; and CoQ10. Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (sodium ascorbate-2-sulfate, sodium ascorbate, magnesium ascorbate-2-phosphate, sodium ascorbate-2-phosphate, etc.), sodium bisulfite, sodium sulfite, sodium metabisulfite, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA) or its salts (sodium EDTA, disodium EDTA, tetrasodium EDTA), etc. Lipid-soluble antioxidants are preferred, among which phenols containing butyl groups are more preferred, and butylated hydroxytoluene is particularly preferred.

[0081] When the topical composition of the present invention contains an antioxidant, the antioxidant content in the topical composition of the present invention is, for example, 0.001 to 5% by mass, preferably 0.01 to 2% by mass, and more preferably 0.05 to 0.5% by mass.

[0082] The content of other components in the topical composition of the present invention is not particularly limited, provided that it does not significantly impair the effect of the present invention. Such content is, for example, 0% to 10% by mass, 0% to 5% by mass, 0% to 2% by mass, 0% to 1% by mass, or 0% to 0.1% by mass.

[0083] The topical composition of the present invention can be applied to the skin. The topical composition of the present invention can be a substance applied to the skin (excluding substances applied to hair (e.g., shampoos, conditioners)). The topical composition of the present invention is preferably in the form of a topical skin medicine, cosmetic, or other topical skin composition. The topical composition of the present invention is used in a form that does not require removal after application, unlike cleansing agents that require removal with water (e.g., rinsing) after foaming.

[0084] The pharmaceutical form of the topical composition of the present invention is not particularly limited, and can take any form known as a cosmetic or quasi-drug product. Examples of such known forms include liquids, suspensions, emulsions, ointments, gels, liniments, lotions, aerosols, powders, pastes, tablets made by impregnating a sheet of nonwoven fabric with the pharmaceutical solution, and lip emulsions. From the perspective of good user experience, liquids, suspensions, emulsions, ointments, gels, and lotions are preferred, with liquids (having transparency) being particularly preferred.

[0085] In one embodiment of the invention, the dosage form of the topical composition of the invention is a gel, liquid, aerosol, mist, or foam.

[0086] The topical composition of the present invention can be prepared by mixing the components with a solvent. The composition of the present invention is preferably in a soluble state. A soluble state refers to a state in which the surfactant forms micelles, dissolves transparently and uniformly to form a single-phase solution. Additionally, a soluble state includes a microemulsion state. Microemulsions consist of emulsion particles with a diameter of less than 100 nm and are thermodynamically stable micellar solutions. A soluble state can be confirmed by its transparent appearance. Furthermore, the soluble state can also be confirmed by measuring the particle size using common methods. A soluble composition can be obtained by dissolving the components under heating as needed, followed by cooling.

[0087] The external application composition of the present invention is preferably a composition filled in a non-gaseous foam dispensing device. A non-gaseous foam dispensing device refers to a device having a mechanism for foaming without relying on a propellant. That is, the external application composition of the present invention is preferably used by foaming using a non-gaseous foam dispensing device. Examples of non-gaseous foam dispensing devices include, for example, screen-type foam dispensing devices. A screen-type foam dispensing device refers to a mechanism that pressurizes a liquid, passes it through a mesh screen (mesh opening), and thereby mixes it with air to create foam. Examples of screen-type foam dispensing devices include, for example, pump-type foam dispensing devices, tube-type foam dispensing devices, and extrusion-type foam dispensing devices. Among these, pump-type foam dispensing devices are preferred.

[0088] As a non-gas-type foam ejection device, known devices and commercially available devices can be used. For example, when it is a pump-type foam ejection device, devices described in Japanese Patent Application Publication No. 2012-45525 and Japanese Patent Application Publication No. 2008-307478 can be used.

[0089] The topical compositions of the present invention can be used, for example, for the prevention or improvement of psoriasis.

[0090] "Improvement" includes not only reducing or eliminating symptoms, but also inhibiting the degree of symptom worsening or preventing the symptoms from worsening when they are in a state of continuous deterioration.

[0091] There are no particular restrictions on what constitutes psoriasis; for example, common psoriasis, psoriatic arthritis, guttate psoriasis, erythrodermic psoriasis, pustular psoriasis, etc., can be listed.

[0092] The topical composition of the present invention can be applied to mammals, including humans, for example, once daily or every few days, preferably continuously. When applying the topical composition of the present invention continuously, the application period is preferably 2 weeks or more, more preferably 3 weeks or more, and even more preferably 4 weeks or more.

[0093] Example The present invention will now be described in detail based on embodiments, but the present invention is not limited to these embodiments.

[0094] Material The details of the materials used in the following test examples are as follows. POE refers to polyoxyethylene, and POP refers to polyoxypropylene.

[0095] (a1. Original drug: Vitamin D3) ·Calcipitol monohydrate • Mascalciferol.

[0096] (a2. Original drug: glucocorticoid) Betamethasone dipropionate • Betamethasone butyrate propionate.

[0097] (b. Nonionic surfactant A) • Polyoxyethylene hydrogenated castor oil 40 (HLB value 12.5). “40” indicates the average number of moles of ethylene oxide added.

[0098] (c1. Nonionic surfactant B: polyoxyalkylene alkyl ether) ·POE(20)POP(4)Cetyl ether (HLB value 12.5) • POE lauryl ether (HLB value 14.5).

[0099] (c2. Nonionic surfactant B: polyoxyalkylene glycol) ·POEPOP diol (HLB value 10.9).

[0100] (c3. Nonionic surfactant B: polyoxyalkylene fatty acid ester) • Polyethylene glycol monostearate (HLB value 17.5).

[0101] (c4. Nonionic surfactant B: polyoxyalkylene sorbitol fatty acid ester) • Tetraoleic oleate polyoxyethylene sorbitan ester (HLB value 15.5).

[0102] (c5. Nonionic surfactant B: polyglycerol fatty acid ester) • Polyglycerol monolaurate (HLB value 15.5).

[0103] (d. Ester oil) Diisopropyl adipic acid • Triisooctanoic acid glyceride.

[0104] (e. pH adjuster) Sodium hydroxide Sodium citrate hydrate • Citric acid hydrate.

[0105] Test Example 1. Evaluation of the stability of the active ingredient 1 Liquid compositions (Examples 1-9, Comparative Examples 1-11) were prepared according to the formulations shown in Tables 1 and 2 (numbers are in % by mass, blank columns indicate 0). Specifically, groups a (a1 and a2) and d were dissolved, and then groups b and c (c1 or c2 or c3 or c4 or c5) were added and dissolved again. Water was then added and stirred to dissolve, yielding the liquid composition. As shown in Tables 1 and 2, the pH of the liquid composition was adjusted to pH 7.0 by adding a pH adjuster (in the tables, the appropriate amount is 0.002-0.01% by mass).

[0106] The stability of vitamin D3 and glucocorticoids in the obtained liquid composition was determined. Specifically, the liquid composition was allowed to stand at 60°C, and the contents of vitamin D3 and glucocorticoids were determined by HPLC after 1 week, 2 weeks, and 3 weeks. The peak area of ​​the test sample was determined using an automatic integration method, and the residual rates of vitamin D3 and glucocorticoids were calculated.

[0107] [Table 1] [Table 2] The results are shown in Figures 1-9 It is known that combining nonionic surfactant A (used in polyoxyalkylene hydrogenated castor oil) with nonionic surfactant B (used in other nonionic surfactants besides polyoxyalkylene hydrogenated castor oil) achieves a synergistic effect in improving the stability of vitamin D3. It is also known that this combination does not adversely affect the stability of glucocorticoids.

[0108] Test Example 2. Evaluation of the stability of the active ingredient, Test 2 An antioxidant (butylated hydroxytoluene) was added to a concentration of 0.1% by mass, and the liquid compositions (Examples 3A and 6A) were prepared in the same manner as in Examples 3 and 6 of the present invention. The vitamin D3 stability of the obtained liquid compositions was determined according to the method described in Test Example 1.

[0109] The results are shown in Figure 10 and Figure 11 This indicates that antioxidants did not adversely affect the stability of vitamin D3; on the contrary, they could improve its stability.

Claims

1. A topical composition, characterized in that: It contains vitamin D3, glucocorticoids, nonionic surfactant A (as a polyoxyalkylene hydrogenated castor oil), and nonionic surfactant B (as a nonionic surfactant other than polyoxyalkylene hydrogenated castor oil).

2. The topical composition as described in claim 1, characterized in that: The nonionic surfactant B is selected from at least one of polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbitol fatty acid esters, and polyglycerol fatty acid esters.

3. The topical composition as described in claim 1, characterized in that: The nonionic surfactant B has an HLB value of 6 or higher.

4. The topical composition as described in claim 1, characterized in that: The total content of the nonionic surfactant A and the nonionic surfactant B in the topical composition is more than 0.5% by mass and less than 10% by mass.

5. The topical composition as claimed in claim 1, characterized in that: The content of nonionic surfactant A in the total of nonionic surfactant A and nonionic surfactant B is more than 10% by mass and less than 99.9% by mass.

6. The topical composition as claimed in claim 1, characterized in that: It contains ester oil.

7. The topical composition as described in claim 6, characterized in that: The ester oil contains at least triisooctanoic acid glyceride.

8. The topical composition as claimed in claim 1, characterized in that: The nonionic surfactant B is selected from at least one of polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbitol fatty acid esters, and polyglycerol fatty acid esters. The nonionic surfactant B has an HLB value of 6 or higher. The combined content of the nonionic surfactant A and the nonionic surfactant B in the topical composition is more than 1% by mass and less than 10% by mass. The content of nonionic surfactant A in the total of nonionic surfactant A and nonionic surfactant B is 10% by mass or more and 99.9% by mass or less, and, The topical composition contains ester oil.

9. The topical composition as claimed in claim 1, characterized in that: The vitamin D3 is selected from at least one of calcipotriol, masalcalciferol, alfacalciferol, fluorotriol, tacalciferol, and calcitriol.

10. The topical composition as claimed in claim 1, characterized in that: 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 selected from at least one of polyoxyalkylene alkyl ethers, polyoxyalkylene glycols, polyoxyalkylene fatty acid esters, polyoxyalkylene sorbitol fatty acid esters, and polyglycerol fatty acid esters.

11. The topical composition as described in claim 1, 2, 8, or 10, characterized in that: The nonionic surfactant B is selected from one or more of polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene lauryl ether, polyoxyethylene polyoxypropylene glycol, polyethylene monostearate, polyoxyethylene sorbitol tetraoleate, and polyglycerol monolaurate.

12. The topical composition as claimed in claim 1, characterized in that: The average molar number of epoxide additions in the polyoxyalkylene hydrogenated castor oil is less than 60.

13. The topical composition as claimed in claim 12, characterized in that: The epoxy alkyl group is ethylene oxide.

14. The topical composition as claimed in claim 10, characterized in that: The average molar addition of ethylene oxide to the polyoxyethylene hydrogenated castor oil is less than 60.

15. The topical composition according to any one of claims 1 to 10 and 12 to 14, characterized in that: It also contains water.

16. The topical composition as claimed in claim 15, characterized in that: The water content in the external composition is 40% by mass or more.

17. The topical composition as claimed in claim 15, characterized in that: The water content in the external composition is 75% by mass or more.

18. The topical composition according to any one of claims 1 to 10 and 12 to 14, characterized in that: The content of vitamin D3 in the topical composition is more than 0.0001% by mass and less than 0.2% by mass.

19. The topical composition according to any one of claims 1 to 10 and 12 to 14, characterized in that: The glucocorticoid content in the topical composition is more than 0.001% by mass and less than 2% by mass.

20. The topical composition according to any one of claims 1 to 10 and 12 to 14, characterized in that: The topical composition also contains antioxidants.

21. The topical composition according to any one of claims 1 to 10 and 12 to 14, characterized in that: The dosage form is gel, liquid, aerosol, mist, or foam.

22. The topical composition according to any one of claims 1 to 10 and 12 to 14, characterized in that: Used for the prevention or improvement of psoriasis.

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