JP2014144929A - Composition containing vitamins for preventing or treating acne - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a skin composition for external application which includes retinol and has excellent effect of preventing or treating acne.SOLUTION: A skin composition for external application that prevents or treats acne includes vitamin A, vitamin C, vitamin D, and vitamin E as active ingredients.

Description

  The present invention relates to an external composition for skin having a high acne prevention or treatment effect.

  Acne (acne vulgaris) is an inflammatory disease of the skin that develops when the hair follicles are clogged with sebum and cause inflammation. It develops mainly in puberty, and skin eruptions are observed on the back of the face, chest and back, matching the pores. There are two stages of acne onset: comedone formation and inflammation, which includes increased sebum secretion, abnormal keratinization in the hair follicle funnel, and bacteria in the hair follicle [especially Propionibacterium acnes] In the process of inducing inflammation, it has been reported that an extracellular inflammation-inducing substance derived from Aspergillus oryzae is involved (see, for example, Non-Patent Document 1). In addition to improving face washing and lifestyle habits, these acne can be prevented and treated with sulfur-containing preparations and adapalene (trade name: Differin (registered trademark) gel, an external medicine containing naphthoic acid derivatives having a retinoid-like action as active ingredients) 0.1%) (for example, see Non-Patent Document 2), antibacterial agents and the like are used.

  Retinoic acid (vitamin A acid), which is a metabolite of vitamin A, is one of the physiologically active substances of vitamin A, and promotes the proliferation of epidermal cells and fibroblasts (see Non-patent Document 3, for example), hyaluronic acid Various physiological actions such as production promoting action (see, for example, Non-Patent Document 3), keratinization improving action (see, for example, Non-Patent Document 4), and anti-acne action (see Non-Patent Document 5) are known. However, retinoic acid has a drawback that it is strongly irritating, and is a component that cannot be added to cosmetics. On the other hand, retinol, which has weaker pharmacological activity than retinoic acid but has no irritation, is used for the treatment of acne (see, for example, Patent Document 1).

As for vitamins other than vitamin A, vitamin E has an inhibitory action on the production of lipid peroxide, one of the onset factors of acne, due to its antioxidant action, and is used as an adjuvant therapy for acne (for example, non-patented Reference 6). In addition, ascorbic acid (for example, see Patent Document 2), ether derivatives or ester derivatives of ascorbic acid have an anti-acne action (for example, see Patent Document 3), and vitamin D has a comedone-dissolving action (for example, non-patent documents). 7).
Furthermore, it is known that a composition for external use containing vitamin C, carotene and vitamin E and not containing retinoic acid is effective in treating acne as a combination of vitamins (see, for example, Patent Document 4). ). In addition, an external composition for preventing skin aging containing vitamin A, vitamin B6, vitamin C, vitamin D and vitamin E as active ingredients is also known (see, for example, Patent Document 5).
However, it is not known that an external composition for skin containing vitamin A, vitamin C, vitamin D and vitamin E as active ingredients is effective for acne.

JP 7-165567 A JP-A-9-110628 JP 11-79930 A JP-T-2006-525945 JP 2011-12055 A

MB Derma. No. 170, 6-7, 2010. Pharmaceutical package insert Differin (R) gel 0.1% J. Invest. Dermatol. Symp. Proc. Vol. 3, 57-60, 1998. Arch. Dermatol. Res. Vol. 291, 346-353, 1999. J. Am. Acad. Dermatol. Vol. 17, 251-254, 1987. Forefront of acne, edited by Yoshiki Miyaji, Medical Review, Inc., 115 pages British J. of Dermatol. Vol. 155, 895-901, 2006.

  Retinoic acid, which is a metabolite of vitamin A, and adapalene, which is a naphthoic acid derivative having a retinoid-like action, have excellent therapeutic effects on acne, but have strong side effects such as irritation. Retinol, on the other hand, is less irritating and relatively safe, but alone is not satisfactory in its therapeutic effect. Under such circumstances, an object of the present invention is to find an external composition for skin containing retinol and having an excellent preventive or therapeutic effect for acne.

As a result of intensive studies, the present inventors have found that a composition for external use containing vitamin A, vitamin C, vitamin D, and vitamin E has an excellent effect as a preventive or therapeutic agent for acne. Completed the invention.
That is, the present invention provides the following (1) to (3).
(1) A composition for external use for preventing or treating acne, comprising vitamin A, vitamin C, vitamin D, and vitamin E as active ingredients.
(2) The external composition for skin according to (1), wherein vitamin C is fat-soluble vitamin C.
(3) The external composition for skin according to (1), wherein vitamin A is retinol palmitate, vitamin C is ascorbyl tetra-2-hexyldecanoate, vitamin D is cholecalciferol, and vitamin E is tocopherol acetate. object.

  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a composition for external use for the prevention or treatment of acne that is excellent in effectiveness with few side effects.

Since the side effects of retinoid topical agents are thought to be mainly mediated by RARγ, the expression level of retinoic acid receptor γ (RARγ) mRNA in the human epidermal keratinocytes of each test substance is expressed in the untreated group. It is the figure compared as relative evaluation when is set to 1.

  “Vitamin A” in the present invention means retinol, retinol fatty acid esters, retinol organic acid esters, retinol inorganic acid diester complex, etc., specifically, retinol; retinol fatty acid esters include retinol palmitic Acid esters, retinol stearates, retinol acetates; retinol organic acid esters, retinol lactate esters, retinol glycolate esters; retinol inorganic acid diester conjugates, retinol phosphate diester conjugates, retinol pyrophosphate diester conjugates Body, retinol sulfate diester complex, and the like. In the present invention, “vitamin A” includes all-trans retinol and its isomer, all-trans retinal and its isomer, all-trans retinoic acid and its isomer, their 3-dehydro form, and 3,4-didehydro Retinol palmitate, which is widely commercially available and relatively stable, is preferred; retinol palmitate is particularly preferred. These vitamin A may be a chemically synthesized product, a product obtained from a natural extract, or a purified natural extract.

  “Vitamin C” in the present invention means ascorbic acid, calcium ascorbate, sodium ascorbate, ascorbyl palmitate, ascorbyl tetra-2-hexyldecanoate, and the like. As the “vitamin C” in the present invention, “fat-soluble vitamin C” is preferable from the viewpoint of the effect of preventing or treating keratin permeability and thus acne. “Fat-soluble vitamin C” used in the present invention is not particularly limited as long as it is fat-soluble vitamin C. For example, ascorbyl palmitate and ascorbyl tetra-2-hexyldecanoate are preferable. These vitamin Cs may be chemically synthesized products, those obtained from natural extracts, or those obtained by purifying natural extracts.

  In the present invention, “vitamin D” means cholecalciferol, ergocalciferol and the like, and cholecalciferol is preferable. Such vitamin D is commercially available and can be easily obtained.

  “Vitamin E” in the present invention means tocopherol, tocopherol succinate, tocopherol acetate, etc., and tocopherol acetate is preferred. Such vitamin E is commercially available and can be easily obtained.

The amount of vitamin A blended in the composition for external use of the present invention is usually 0.00001 to 10% by weight, preferably 0.0005 to 5% by weight, and 0.0001 to 1% by weight of the whole preparation. Is more preferable.
The amount of vitamin C blended in the external composition for skin of the present invention is usually 0.00001 to 50% by weight, preferably 0.0001 to 10% by weight, and preferably 0.0005 to 5% by weight of the whole preparation. Is more preferable.
The amount of vitamin D to be blended in the external composition for skin of the present invention is usually 0.00001 to 10% by weight, preferably 0.0001 to 1% by weight, preferably 0.0001 to 0.1% of the whole preparation. Weight percent is more preferred.
The amount of vitamin E blended in the external composition for skin of the present invention is usually 0.0001 to 10% by weight, preferably 0.001 to 5% by weight, and preferably 0.005 to 2% by weight of the whole preparation. Is more preferable.

  In addition to the above vitamin A, vitamin C, vitamin D, and vitamin E, the composition for external use of the skin is an ingredient effective for preventing or treating acne, and an ingredient that enhances an ingredient effective for preventing or treating acne Can be blended within a range that does not impair the effects (effectiveness and safety) of the present invention. For example, vitamins such as vitamin B2 and vitamin B6; anti-inflammatory agents such as dipotassium glycyrrhizinate, glycyrrhizic acid, allantoin and ibuprofenpiconol; exfoliating agents such as salicylic acid, benzoyl peroxide and sulfur; nadifloxacin, clindamycin, erythromycin And bactericides and antibiotics such as chloramphenicol and benzoic acid.

The composition for external use of the skin of the present invention is used for the prevention or treatment of acne (acne vulgaris, acne), and particularly suppresses the formation of comedones.
The skin external composition of the present invention is not particularly limited as long as it is a composition used by being applied to the skin. For example, it is a medical skin external composition or cosmetic composition. In this composition, in addition to active ingredients such as vitamin A; vitamin C; vitamin D and vitamin E, components usually used in medical compositions for external skin use such as pharmaceuticals, quasi drugs and cosmetics, for example, aqueous Ingredients, oily ingredients, powder ingredients, alcohols, humectants, thickeners, UV absorbers, whitening agents, preservatives, antioxidants, surfactants, fragrances, pigments, etc. may be added as necessary. it can. Such a blending method can be performed according to the method described in the Japanese Pharmacopoeia General Rules.

  The “dosage form” of the external composition for skin of the present invention is not particularly limited as long as it is a dosage form that can be applied to the skin, but it is a coating agent such as a cream, ointment, liquid, gel, or lotion, a poultice, Patches such as tapes and patches are preferred, and creams are more preferred. Further, the composition for external use of the skin of the present invention can be used as a pharmaceutical product, a quasi-drug, a cosmetic product, etc., and when the composition for external use of the skin is a coating agent, as its method of use, take an appropriate amount, It may be applied to the skin once to several times a day.

  Examples of the present invention are described below, but are not limited thereto.

1. (Test Example 1) Examination of effectiveness using acne vulgaris model mouse 1-1. Test method The test was carried out using rhino mice, which are acne vulgaris model mice. The rhino mouse is a model for evaluating the epidermal thickening effect and the comedone-suppressing action of various drugs used for the treatment of acne. Rhino mice have follicles in the skin and their openings can be widened with horned material, the structure resembles human microcomedones and is called vesicles or pseudocomedones.
That is, in this study, male and female mice (RHJ / LeJ) used as a model for acne vulgaris were used, and the histological evaluation of the skin was conducted at the end of the treatment period after the test substance was administered dermally for 21 days. The effect of suppressing comedones was evaluated in five levels (Table 1) using visual evaluation of the face state of the mouse surface as an index.

1-2. Test substances In Example 1, Comparative Example 1 and Comparative Example 2, test compositions were prepared using the components shown in Table 2. In the preparation method, Group A and Group B were each heated to 80 ° C., and Group A was added and emulsified while stirring Group B. Thereafter, the obtained composition was cooled to 35 ° C. In addition, adapalene and all-trans retinoic acid were known to show significant activity and were used as positive controls in rhino mice. For Comparative Example 3 and Comparative Example 4, tri (caprylic acid / capric acid) glyceryl (obtained so that the final concentrations of all-trans retinoic acid (source: Nacalai Tesque) were 0.01% and 0.0001%, respectively. (Previously: Nikko Chemical Co., Ltd.)). In Comparative Example 5, a commercially available formulation [Differin (registered trademark) gel (gel containing 0.1% adapalene; source: Shionogi & Co., Ltd.) was used as it was.

1-3. Test animals Rhino mice (RHJ / LeJ, males 6-11 weeks old, females 8-11 weeks old, source: The Jackson Laboratory) were used as test animals. 12 males and 12 females of rhino mice were divided into 6 groups, 4 animals per group, and used for the test after acclimatization.

1-4. Test results The results are shown in Table 3.
As a result of this test, the vitamin ACDE combination group showed a higher effect of suppressing comedones compared with the control adapalene group in the visual evaluation of the face state of the mouse surface layer. In retinoic acid, a remarkable effect was observed in the retinoic acid 0.01% group, but skin damage was not severely detectable in 3 out of 4 mice, and in the lower concentration retinoic acid 0.0001% group, comedones The inhibitory effect was insufficient.
In addition, in the adapalene group, 1 out of 4 mice could not be determined due to skin damage, whereas in the vitamin ACDE combination group, no skin damage was observed, and all 4 individuals exhibited a comedone suppressing effect. .
Adapalene, a topical comedone solubilizer currently on the market, is unsuitable for continuous use because of its dryness and skin irritation. It is clear that the composition containing vitamin A, vitamin C, vitamin D and vitamin E that we have developed this time has no skin irritation, moisturizing effect, and exhibits high acne prevention and treatment effects when used daily. Became.

2. (Test Example 2) Safety test using human epidermal keratinocytes 2-1. Test Method Human epidermal keratinocytes were added to the test substance, and the expression level of retinoic acid receptor γ (RARγ) mRNA was compared with the untreated group. Skin inflammation (desquamation, erythema, irritation) is known as a side effect of retinoid topical agents, and this is thought to be mainly mediated by RARγ.
Normal human epidermal keratinocytes (Kurabo) were seeded in a 96-well plate at a density of 10,000 cells / well in HuMedia KG-2 medium (Kurabo). 1 day later, concentrations of retinol palmitate (vitamin A) alone, vitamin C + vitamin D + vitamin E (VC + VD + VE), vitamin A + vitamin C + vitamin D + vitamin E (VA + VC + VD + VE), all-trans retinoic acid, and adapalene as shown in Table 4 The medium was replaced with HuMedia KB-2 medium (Kurabo) supplemented with a high concentration) and a 10-fold dilution (low concentration) thereof, and then cultured for 2 days. The untreated group was replaced with HuMedia KB-2 medium.

  The test was performed in real time using TaqMan® Fast Cells-to-CT® Kit (Applied Biosystems), TaqMan® Probe (Assay ID Hs01559234_m1) and TaqMan® Probe (Human GAPDH). RT-PCR was performed. The expression level of RARγ mRNA is expressed by the following (Formula 1), ΔΔCt method (the calculation method is “Real-time PCR experiment guide well understood from the principle”) (edit: Hirohiko Kitajo, publisher: Yodosha Co., Ltd.) page 34 The relative expression level was calculated when the untreated group was set to 1. The results (average value of n = 2) are shown in FIG.

2-2. Test results
From the graph of FIG. 1, the expression levels of vitamin A + vitamin C + vitamin D + vitamin E were almost the same in the high-concentration group and the low-concentration group as in the untreated group, but the expression levels were high in all-trans retinoic acid and adapalene. In this test, the concentrations of vitamin A (retinol palmitate), all-trans retinoic acid and adapalene were adjusted to 1 μM (high concentration group) and 0.1 μM (low concentration group), respectively.
From the above results, it was found that the combination of vitamin A, vitamin C, vitamin D and vitamin E was safer than all-trans retinoic acid and adapalene.

3. Formulation Example (Formulation Example 1) Cosmetic liquid The ingredients listed in Table 5 were mixed by a conventional method to produce a cosmetic liquid.

(Formulation example 2) Cosmetic liquid The ingredients listed in Table 6 were mixed by a conventional method to produce a cosmetic liquid.

(Formulation Example 3) Emulsion The ingredients listed in Table 7 were mixed by a conventional method to produce an emulsion.

(Formulation Example 4) Emulsion The ingredients listed in Table 8 were mixed by a conventional method to produce an emulsion.

  The composition of the present invention combines excellent efficacy and high safety for the prevention or treatment of acne. Therefore, such an external composition for skin is useful as an external composition for prevention or treatment of acne.

Claims (3)

  A composition for external use for the prevention or treatment of acne, comprising vitamin A, vitamin C, vitamin D and vitamin E as active ingredients.   The external composition for skin according to claim 1, wherein the vitamin C is fat-soluble vitamin C.   The external composition for skin according to claim 1, wherein vitamin A is retinol palmitate, vitamin C is ascorbyl tetra-2-hexyldecanoate, vitamin D is cholecalciferol, and vitamin E is tocopherol acetate.