External components

Abstract

The object of this disclosure is to provide a topical composition comprising ceramide 2 and retinols that can suppress creaming due to storage. [Solution] The topical composition containing (A) ceramide 2, (B) retinols, and (C) glycyrrhizic acid derivatives has been found to suppress creaming during storage.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to an external composition containing ceramide 2 and retinoids, which is capable of suppressing creaming. BACKGROUND ART

[0002] The stratum corneum is mainly composed of corneocytes and intercellular lipids that form a lamellar structure, and the lamellar structure of the intercellular lipids in the stratum corneum plays a critical role in the barrier function and moisturizing function. It is known that about 50% of the intercellular lipids in the stratum corneum are composed of ceramides, and a decrease in the ceramide content in the stratum corneum leads to deterioration of the barrier function and moisturizing function.

[0003] Accordingly, external compositions formulated with ceramides have been conventionally developed for the purpose of maintaining the functions of the stratum corneum by replenishing ceramides in the stratum corneum. For example, Patent Document 1 reports that an emulsion composition containing a ceramide, a specific monoalkyl glyceryl ether or monoalkenyl glyceryl ether, a higher fatty acid, and a polyhydric alcohol has high stability and excellent usability. PRIOR ART DOCUMENTS PATENT DOCUMENT

[0004] PATENT DOCUMENT 1 Japanese Unexamined Patent Publication No. 2014-237595 SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION

[0005] Ceramides are broadly classified into human-type ceramides, animal-derived ceramides, plant-derived ceramides, and pseudo-ceramides. Of these, human-type ceramides have the same structure as ceramides found in human skin and have excellent affinity with the skin. Among human-type ceramides, ceramide 2 is the most abundant in human skin and has a function that supports moisturizing, so it is used in topical compositions. On the other hand, retinols are a type of vitamin known to be involved in the regenerative function of normal epithelial tissue such as skin, and are used in topical compositions. The inventors of this invention proceeded with research to develop a topical composition containing ceramide 2 and retinols, but encountered the problem that creaming occurs during storage in topical compositions containing ceramide 2 and retinols.

[0006] Therefore, the object of this disclosure is to provide a topical composition containing ceramide 2 and retinols that can suppress creaming due to storage. [Means for solving the problem]

[0007] The inventors conducted diligent research to solve the aforementioned problems and found that creaming due to storage can be suppressed by including glycyrrhizic acid in an external composition containing ceramide 2 and retinols. This disclosure was completed by further research based on this finding.

[0008] In other words, this disclosure provides external compositions in the following embodiments. Item 1. A topical composition containing (A) ceramide 2, (B) retinol and / or its derivatives, and (C) glycyrrhizic acid, its derivatives, and / or salts thereof. Item 2. The topical composition according to Item 1, wherein the content of component (B) per 1 g of component (A) is 10,000 to 30 million IU. Item 3. The topical composition according to item 1 or 2, wherein the content of component (C) per 1,000,000 IU of component (B) is 0.01 to 50 g. Item 4. The external composition according to any one of items 1 to 3, wherein the content of component (C) per 1 part by weight of component (A) is 0.01 to 50 parts by weight. Item 5. The topical composition according to any one of items 1 to 4, wherein the content of component (A) is 0.01 to 10% by weight. Item 6. The topical composition according to any one of items 1 to 5, wherein the content of component (C) is 0.001 to 5% by weight. Item 7. An emulsified composition, which is an external composition according to any one of items 1 to 6. Item 8. The topical composition described in Item 7, which is an oil-in-water type. [Effects of the Invention]

[0009] The topical compositions disclosed herein contain ceramide 2 and retinols, yet can suppress creaming due to storage. Furthermore, in preferred embodiments, the topical compositions disclosed herein also have improved usability. [Modes for carrying out the invention]

[0010] The topical composition disclosed herein is characterized by containing (A) ceramide 2 (hereinafter also referred to as "component (A)"), (B) retinol and / or its derivatives (hereinafter also referred to as "component (B)" or "retinols"), and (C) glycyrrhizic acid and / or its derivatives (hereinafter also referred to as "component (C)" or "glycyrrhizic acids"). The topical composition disclosed herein has suppressed creaming due to storage. In this disclosure, creaming is a phenomenon in which the dispersed phase is partially concentrated due to the floating (if the dispersed phase is an oil phase) or sedimentation (if the dispersed phase is an oil phase) of the continuous phase and dispersed phase. The degree of suppression of creaming due to storage can be confirmed by diluting the topical composition 100 times with water to create harsh conditions, and by checking the presence or absence of a concentrated area of ​​the dispersed phase due to creaming, or the degree of its thickness. In a preferred embodiment, the topical composition disclosed herein further has improved usability (specifically, good spreadability). The topical compositions disclosed herein will be described in detail below. In this disclosure, the numerical range "X~Y" refers to a range of X or more and Y or less.

[0011] [(A) Ceramide 2] The topical composition disclosed herein contains ceramide 2 as component (A). Conventionally, when ceramide 2 is incorporated into topical compositions together with retinols, it causes creaming during storage, but the topical composition disclosed herein suppresses creaming during storage. Furthermore, conventionally, when ceramide 2 is incorporated into topical compositions together with retinols, it worsens the feel of use, but in a preferred embodiment of the topical composition disclosed herein, the feel of use can also be improved.

[0012] Ceramide 2 is N-stearoyldihydrosphingosine, a type of human-type ceramide.

[0013] The content of component (A) in the topical composition of this disclosure is not particularly limited and can be appropriately set according to the desired degree of creaming suppression and / or improvement of usability, the formulation form, etc., but examples include 0.001 to 10% by weight, or 0.002 to 10% by weight, preferably 0.01 to 10% by weight, 0.01 to 8% by weight, or 0.01 to 5% by weight, more preferably 0.01 to 3% by weight, even more preferably 0.1 to 3% by weight, even more preferably 0.2 to 1.5% by weight, 0.3 to 1% by weight, 0.4 to 0.8% by weight, or 0.45 to 0.6% by weight.

[0014] [(B) Retinols] The topical composition disclosed herein contains retinols as component (B). Conventionally, when retinols are incorporated into topical compositions together with ceramide 2, creaming occurs during storage, but the topical composition disclosed herein suppresses creaming during storage. Furthermore, conventionally, when retinols are incorporated into topical compositions together with ceramide 2, the feel of the product deteriorates, but in a preferred embodiment of the topical composition disclosed herein, the feel of the product can also be improved.

[0015] Retinols are known as a type of vitamin that is involved in the regenerative function of normal epithelial tissue such as skin.

[0016] Retinol is a type of vitamin A, and is sometimes also called vitamin A alcohol.

[0017] Retinol derivatives are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, but examples include retinol esters (fatty acid esters of retinol, short-chain fatty acid esters of retinol, etc.), retinol oxides, and esters of retinol oxides.

[0018] Examples of fatty acid esters of retinol include esters of retinol with fatty acids having 6 to 30 carbon atoms, preferably 6 to 18 carbon atoms. Specific examples of fatty acid esters of retinol include retinol octylate, retinol laurate, retinol palmitate, retinol stearate, retinol myristate, retinol oleate, retinol linolenate, retinol linoleate, and the like. These fatty acid esters of retinol may be used alone or in combination of two or more thereof.

[0019] Examples of short-chain fatty acid esters of retinol include esters of retinol with short-chain fatty acids having 1 to 5 carbon atoms. Specific examples of short-chain fatty acid esters of retinol include retinol acetate, retinol propionate, retinol butyrate, and the like. These short-chain fatty acid esters of retinol may be used alone or in combination of two or more thereof.

[0020] Specific examples of retinol oxides include retinoic acid (sometimes referred to as "tretinoin"), retinal, and the like. These retinol oxides may be used alone or in combination of two or more thereof.

[0021] Specific examples of esters of retinol oxides include methyl retinoate, ethyl retinoate, retinyl retinoate, tocopheryl retinoate (tocopherol may be any of α, β, γ, or δ), and the like. These esters of retinol oxides may be used alone or in combination of two or more thereof.

[0022] The retinol is not particularly limited in terms of its raw material, production method, purification method, etc., and may be one isolated and purified by oneself from animals or the like, or a commercially available product may be used. In addition, in the external composition of the present disclosure, as component (B), one selected from retinol and retinol derivatives may be used, or two or more may be used in combination. In the external composition of the present disclosure, among component (B), retinol derivatives are preferred, fatty acid esters of retinol are more preferred, and retinol palmitate is even more preferred.

[0023] Further, in the external composition of the present disclosure, the retinol may be used in a state of being dissolved in an oil such as vegetable oil. Such a product obtained by dissolving retinol in oil is known as "vitamin A oil". Vitamin A oil can be produced, for example, according to the method described in the Japanese Pharmacopoeia. As the vitamin A oil, those having a content of retinol and / or a derivative thereof of usually 100,000 to 2,000,000 I.U. / g, preferably 500,000 to 1,700,000 I.U. / g, and more preferably 800,000 to 1,200,000 I.U. / g can be used. In this specification, the unit "I.U." for the content of retinol and / or a derivative thereof refers to International Unit.

[0024] The content of component (B) in the external composition of the present disclosure is not particularly limited, and may be appropriately set according to the required degree of creaming suppression and / or feeling improvement upon use, the formulation form, etc., and the content of the component (B) per 100 g of the external composition is, for example, 10,000 to 5,000,000 I.U., preferably 100,000 to 3,000,000 I.U., more preferably 50,000 to 2,000,000 I.U., further preferably 100,000 to 1,000,000 I.U., and particularly preferably 300,000 to 700,000 I.U..

[0025] (B) When vitamin A oil is used in the formulation of component (B), the content of vitamin A oil in the topical composition of the present disclosure should be set so that the amount of retinols in the topical composition of the present disclosure satisfies the aforementioned amount, depending on the content of retinols in the vitamin A oil. Specifically, when using vitamin A oil containing 1 million IU / g of retinols, the content of vitamin A oil in the topical composition of the present disclosure can be, for example, 0.001 to 5% by weight, preferably 0.01 to 3% by weight, more preferably 0.05 to 2% by weight, even more preferably 0.1 to 1% by weight, and particularly preferably 0.3 to 0.7% by weight.

[0026] In the topical composition disclosed herein, the ratio of component (A) to component (B) is determined according to the content of each component, but from the viewpoint of enhancing the effect of suppressing creaming and / or improving the feel of use, the content of component (B) per 1 g of component (A) is preferably 10,000 to 30 million IU, more preferably 100,000 to 25 million IU, even more preferably 300,000 to 20 million IU, even more preferably 400,000 to 15 million IU, 400,000 to 10 million IU, 400,000 to 7 million IU, and 400,000 to 6 million IU.

[0027] [(C) Glycyrrhizic acid derivatives] The topical compositions of this disclosure contain glycyrrhizic acid, its derivatives, and / or salts thereof as component (C). Conventionally, topical compositions containing ceramide 2 and retinols tend to cream upon storage, but in the topical compositions of this disclosure, creaming due to storage can be suppressed by using glycyrrhizic acid derivatives in combination with ceramide 2 and retinols. Furthermore, conventional topical compositions containing ceramide 2 and retinols have a poor feel upon use, but in preferred embodiments of the topical compositions of this disclosure, the feel upon use can also be improved by using glycyrrhizic acid derivatives in combination with ceramide 2 and retinols.

[0028] Glycyrrhizic acid is a well-known component that is known to have anti-inflammatory and anti-allergic effects.

[0029] Derivatives of glycyrrhizic acid are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, but specific examples include methyl glycyrrhizate and stearyl glycyrrhizate. These derivatives of glycyrrhizic acid may be used individually or in combination of two or more.

[0030] The salts of glycyrrhizic acid and / or its derivatives are not particularly limited as long as they are pharmaceutically or cosmetically acceptable, but specifically, examples include alkali metal salts such as sodium salts and potassium salts; and ammonium salts. These salts may be used individually or in combination of two or more.

[0031] In the topical compositions of this disclosure, one of glycyrrhizic acid, its derivatives, and salts thereof may be selected as component (C), or two or more may be used in combination. Among component (C), glycyrrhizinate salts are preferred, and dipotassium glycyrrhizinate is particularly preferred, from the viewpoint of further enhancing the creaming-inhibiting and / or gloss-improving effects when prepared as a cream.

[0032] The content of component (C) in the topical composition of this disclosure is not particularly limited and may be set appropriately depending on the desired degree of creaming suppression and / or improvement of usability, the formulation, etc., but examples include 0.001 to 5% by weight, preferably 0.01 to 5% by weight, 0.1 to 4% by weight, or 0.3 to 3% by weight, more preferably 0.5 to 2% by weight, even more preferably 0.8 to 1.5% by weight, or 0.9 to 1.5% by weight.

[0033] In the topical composition of the present disclosure, the ratio of component (A) to component (C) is determined according to the content of each component, but from the viewpoint of enhancing the effect of suppressing creaming and / or improving the feel of use, the content of component (C) per 1 part by weight of component (A) is preferably 0.01 to 50 parts by weight, or 0.05 to 40 parts by weight, more preferably 0.1 to 30 parts by weight, or 0.5 to 20 parts by weight, and even more preferably 0.8 to 12 parts by weight, 1 to 8 parts by weight, or 1.5 to 5 parts by weight.

[0034] In the topical composition of the present disclosure, the ratio of component (B) to component (C) is determined according to the content of each component, but from the viewpoint of enhancing the effect of suppressing creaming and / or improving the feel of use, the content of component (C) per 100 I.U. of component (B) is preferably 0.01 to 50 g or 0.1 to 40 g, more preferably 0.5 to 30 g, 1 to 20 g or 1.4 to 15 g, and even more preferably 1.7 to 10 g, 1.8 to 6 g or 1.8 to 4 g.

[0035] [water] The topical compositions of this disclosure contain water for preparation into a desired formulation. The water content in the topical compositions of this disclosure may be set appropriately depending on the formulation, etc., but examples include 20 to 97% by weight, preferably 30 to 95% by weight, more preferably 40 to 90% by weight, and even more preferably 50 to 85% by weight.

[0036] [Oily base] The topical compositions disclosed herein include an oily base (oil) for preparation into a desired formulation. The type of oily base is not particularly limited as long as it is pharmaceutically acceptable, but examples include mineral oil, higher monohydric alcohol, fatty acid alkyl ester, vegetable oil, animal oil, cholesterol, higher fatty acids having 12 to 34 carbon atoms, silicone oil, etc.

[0037] Among these oily bases, mineral oils and higher monohydric alcohols are good examples. Specific examples of mineral oils include paraffin, hydrogenated polyisobutene, liquid paraffin, gelling hydrocarbons (such as Plastibase), ceresin, microcrystalline wax, and petrolatum. Higher monohydric alcohols are monohydric alcohols with 6 to 34 carbon atoms. Preferably, higher monohydric alcohols have 10 to 18 carbon atoms, and specific examples include octyl alcohol, decyl alcohol, lauryl alcohol, myristyl alcohol, cetanol, stearyl alcohol, oleyl alcohol, and eicosanol.

[0038] These oily bases may be used individually or in combination of two or more.

[0039] A preferred example of an oily base used in the external compositions of this disclosure is a combination of mineral oil and a higher monohydric alcohol. When mineral oil and a higher monohydric alcohol are used in combination, the ratio is not particularly limited, but for example, per 100 parts by weight of mineral oil, the higher monohydric alcohol may be 0.1 to 1000 parts by weight, preferably 0.1 to 500 parts by weight, more preferably 1 to 200 parts by weight, even more preferably 5 to 100 parts by weight, even more preferably 10 to 50 parts by weight, and particularly preferably 20 to 40 parts by weight.

[0040] The content of the oily base in the topical composition of this disclosure may be set appropriately depending on the formulation form, etc., but for example, the total amount of the oily base may be 1 to 80% by weight, preferably 3 to 60% by weight, more preferably 5 to 40% by weight, even more preferably 10 to 20% by weight, and particularly preferably 10 to 15% by weight.

[0041] [Polyhydric alcohols] The topical compositions disclosed herein may optionally contain polyhydric alcohols. The type of polyhydric alcohol is not particularly limited, as long as it is pharmaceutically acceptable, but examples include dihydric alcohols such as ethylene glycol, 1,3-butylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, and polypropylene glycol; and trihydric alcohols such as glycerin. Among these polyhydric alcohols, 1,3-butylene glycol is preferred. These polyhydric alcohols may be used individually or in combination of two or more.

[0042] When a polyhydric alcohol is included in the topical composition of this disclosure, the amount is not particularly limited, but for example, it may be 1 to 20% by weight, preferably 4 to 15% by weight, and more preferably 6 to 10% by weight.

[0043] [Surfactants] The topical compositions disclosed herein may contain surfactants for preparation into desired formulations. The surfactant may be a nonionic surfactant, anionic surfactant, cationic surfactant, or amphoteric surfactant, but a nonionic surfactant is preferred.

[0044] The types of nonionic surfactants are not particularly limited, as long as they are pharmaceutically acceptable, but examples include polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, polyethylene glycol fatty acid esters, lecithin derivatives, etc.

[0045] Among these nonionic surfactants, polyoxyethylene sorbitan fatty acid esters and glycerin fatty acid esters are preferred, and self-emulsifying glyceryl monostearate (glyceryl stearate (SE)) and polyoxyethylene sorbitan monostearate (polysorbate 60) are preferred.

[0046] These nonionic surfactants may be used individually or in combination of two or more.

[0047] A preferred example of a surfactant used in the topical composition of this disclosure is a combination of polyoxyethylene sorbitan fatty acid ester and glycerin fatty acid ester. When using polyoxyethylene sorbitan fatty acid ester and glycerin fatty acid ester in combination, the ratio is not particularly limited, but for example, per 100 parts by weight of glycerin fatty acid ester, the amount of polyoxyethylene sorbitan fatty acid ester can be 1 to 1000 parts by weight, preferably 10 to 500 parts by weight, more preferably 20 to 200 parts by weight, even more preferably 30 to 100 parts by weight, even more preferably 40 to 80 parts by weight, and particularly preferably 50 to 70 parts by weight.

[0048] When a surfactant is included in the topical composition of this disclosure, the amount can be appropriately set depending on the formulation form, the type of surfactant used, etc., but for example, the total amount of surfactant can be 0.1 to 20% by weight, preferably 0.5 to 15% by weight, more preferably 1 to 10% by weight, even more preferably 2 to 7% by weight, and particularly preferably 3 to 5% by weight.

[0049] [Other ingredients] The topical compositions disclosed herein may or may not contain other commonly used additives in addition to the components described above, as needed. Examples of such optional additives include one or more monohydric lower alcohols, pH adjusters, buffers, thickeners, solubilizers, antioxidants, stabilizers, fragrances, colorants, etc. When other additives are included in the topical compositions disclosed herein, their content may be appropriately determined depending on the type of additive used.

[0050] Furthermore, the topical compositions disclosed herein may contain other pharmacological components in addition to the components described above. Examples of such other pharmacological components, whether present or absent, include one or more of the following: antihistamines, local anesthetics, moisturizers, bactericides, antibacterial agents, antipruritics, skin protectants, blood circulation promoters, vitamins, etc. When other pharmacological components are included in the topical compositions disclosed herein, their concentrations may be appropriately set according to the type of pharmacological component used, the expected effect, etc.

[0051] [Formulation form / dosage type] The topical compositions disclosed herein may be emulsified formulations such as oil-in-water emulsions and water-in-oil emulsions, or non-emulsified formulations such as solubilized formulations and aqueous ointments. In the prior art, when ceramide 2 and retinols are included in emulsified formulations (especially oil-in-water emulsions), creaming due to storage tends to be significant. In contrast, the topical compositions disclosed herein can effectively suppress creaming due to storage, even when they are emulsified formulations. In view of these effects, emulsified formulations, and more preferably oil-in-water emulsions, are preferred as topical compositions of the disclosure.

[0052] Furthermore, the topical compositions of this disclosure are used as topical dermatological pharmaceuticals or quasi-drugs, and are preferably used as topical dermatological pharmaceuticals. Specific formulations of the topical compositions of the present invention include creams, lotions, gels, emulsions, liquids, poultices, patches, liniments, aerosols, aqueous ointments, packs, and the like. Among these, creams and emulsions are preferred, and creams are more preferred.

[0053] [Manufacturing method] The topical compositions disclosed herein can be manufactured according to known formulation methods corresponding to their formulation form. For example, if the topical composition disclosed herein is an emulsified formulation, it can be prepared by separating the components to be contained into water-soluble components and oily components, preparing an aqueous phase containing the water-soluble components and an oil phase containing the oily components, and emulsifying these according to known methods. [Examples]

[0054] The present disclosure will be explained in more detail below with reference to examples, but the present disclosure is not limited to these examples.

[0055] Test example Topical compositions (oil-in-water emulsion compositions, creams) shown in Tables 1 and 2 were prepared. Specifically, an oil-phase composition consisting of components [1] and [2] and an aqueous-phase composition consisting of component [3] were dissolved at 75-86°C. Both the oil-phase and aqueous-phase compositions were in a dissolved state. The oil-phase and aqueous-phase compositions were mixed at 80°C, stirred, and cooled to room temperature to prepare the topical compositions.

[0056] <Evaluation of creaming suppression> Naturally, the more uniform and small the emulsion particles are, the higher the stability of the emulsion. Conversely, if the emulsion particles are non-uniform or large, the emulsion state deteriorates, leading to creaming. It is well known from Stokes' sedimentation equation that creaming is more likely to occur when the viscosity of the continuous phase is low. In this test example, in order to evaluate the degree of creaming of the topical composition, the emulsion was subjected to harsh conditions by forcibly lowering the viscosity of the continuous phase through dilution, thereby allowing for a more nuanced evaluation of the difference in emulsion stability of the topical composition before dilution. Specifically, the prepared topical composition was diluted 100 times with water, placed in a vial, and mixed by inversion. The degree of creaming was evaluated from the appearance after 20 minutes.

[0057] The degree of creaming in the diluted topical composition was evaluated on a 10-point scale, with a score of "1" indicating no creaming and a score of "10" indicating significant creaming. More specifically, the degree of creaming was evaluated according to the ratio of the thickness of the creaming phase (the region where the dispersed phase (oil phase) is concentrated due to creaming) (the length from the lower end of the concentrated region to the upper surface of the topical composition) to the height of the diluted topical composition in the vial. A larger ratio of this thickness (i.e., a higher score) indicates a greater degree of creaming when the topical composition was stored before dilution. The results are shown in Tables 1 and 2.

[0058] <Evaluation of user experience> Regarding the feel of the topical composition immediately after preparation, expert panelists evaluated the degree of spreadability of the topical composition when applied to the skin on a 5-point scale: "5" for poor spreadability, "4" for slightly poor spreadability, "3" for neither, "2" for slightly good spreadability, and "1" for good spreadability. The results are shown in Tables 1 and 2.

[0059] [Table 1]

[0060] [Table 2]

[0061] As shown in Table 1, no creaming occurred in topical compositions that did not contain components (A) to (C) (Reference Example 1), and no significant creaming was observed in topical compositions containing either component (A) or component (B) (Reference Examples 2 and 3). However, significantly more pronounced creaming occurred in topical compositions containing both components (A) and (B) (Comparative Example 1). In contrast, as shown in Table 2, creaming was suppressed and storage stability improved in topical compositions containing all of components (A) to (C) (Examples 1 to 6). In particular, no creaming was observed in the topical compositions of Examples 1, 3 to 6, and storage stability was significantly improved.

[0062] Furthermore, as shown in Table 1, topical compositions without components (A) to (C) showed good usability (Reference Example 1), and topical compositions containing either component (A) or component (B) did not exhibit problematic usability (Reference Examples 2 and 3). However, topical compositions containing both components (A) and (B) showed a deterioration in usability (Comparative Example 1). In contrast, as shown in Table 2, topical compositions containing all of components (A) to (C) showed improved usability (Examples 1 to 6). In particular, the topical compositions of Examples 1, 4 to 6 showed improved usability to a level comparable to Reference Example 1.

Claims

1. A topical composition containing (A) ceramide 2, (B) retinol and / or its derivatives, and (C) glycyrrhizic acid, its derivatives, and / or salts thereof.

2. The topical composition according to claim 1, wherein the content of component (B) per gram of component (A) is 10,000 to 30 million I.U.

3. The topical composition according to claim 1 or 2, wherein the content of component (C) per 1 million I.U. of component (B) is 0.01 to 50 g.

4. The external composition according to claim 1 or 2, wherein the content of component (C) per 1 part by weight of component (A) is 0.01 to 50 parts by weight.

5. The topical composition according to claim 1 or 2, wherein the content of component (A) is 0.01 to 10% by weight.

6. The topical composition according to claim 1 or 2, wherein the content of component (C) is 0.001 to 5% by weight.

7. The external composition according to claim 1 or 2, which is an emulsified composition.

8. The topical composition according to claim 7, wherein it is an oil-in-water type.

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