JP2005104962A - Dermal external agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a dermal external agent for stably blending vitamin A and its derivatives. <P>SOLUTION: This dermal external agent is characterized by blending the following components (a)-(c); (a) vitamin A and/or its derivatives, (b) a medicine having ≥75 % removal rate of superoxides and (c) an oil soluble antioxidant. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an external preparation for skin containing vitamin A and its derivatives, a drug having a superoxide removal rate of 75% or more, and an oil-soluble antioxidant, and more specifically, stabilizes vitamin A and its derivatives. It is related with the skin external preparation which can be mix | blended with.

  Vitamin A and its derivatives have an action of promoting normal keratinization of epidermal cells and are known to be effective for abnormal keratinization of epidermal cells. In dermal cells, it is also known to promote extracellular matrix production and be effective for tissue repair. Therefore, vitamin A and its derivatives are blended as active ingredients in various skin external preparations having these purposes as effective ingredients for prevention and treatment of skin keratosis and the like, as well as prevention and recovery of skin aging. (For example, see Non-Patent Document 1 etc.).

However, vitamin A and its derivatives are extremely unstable substances that cause various isomerizations, decompositions, and polymerizations by acid, air, light, heat, metal ions, and the like, thereby causing discoloration and coloring. For this reason, the technique for mix | blending vitamin A and its derivative stably conventionally is examined. Specifically, the technique which uses antioxidant, a chelating agent, etc. together is mentioned (for example, refer patent documents 1-3 etc.).
Yoshio Hamada et al., Fragrance Journal, April issue, page 75, 1998 Japanese Patent No. 3014780 (pages 1 to 17) JP 2001-011441 A (pages 1 to 15) Japanese Patent No. 3280712 (pages 1 to 5)

  However, the technique using an antioxidant, a chelating agent or the like cannot sufficiently eliminate discoloration or coloring of vitamin A and its derivatives.

  In view of such a situation, the present inventor has made extensive studies to solve the above problems, and as a stabilizer for vitamin A and / or its derivatives, by using a drug having a superoxide removal rate of 75% or more, The inventors have found that coloring and discoloration over time can be effectively prevented, and the present invention has been completed.

That is, the present invention includes the following components (a) to (c);
(A) Vitamin A and / or a derivative thereof (b) A drug having a superoxide removal rate of 75% or more and (c) an oil-soluble anti-oxidant are provided.

  Furthermore, the skin external preparation is provided, wherein the drug of component (b) is selected from one or more of a mykaika extract, an age extract, a goldfish extract, and a tea extract. And a component (a) is 0.01-1 mass%, a component (b) is 0.0001-0.1 mass% in conversion of solid content, respectively, and the compounding mass ratio (a) / (b) is. The external preparation for skin is characterized by being 10 to 1000. Further, the present invention provides any one of the above-mentioned external preparations for skin, wherein the drug of component (b) is a plant extract extracted with an aqueous solvent.

  Since the external preparation for skin of the present invention can remarkably improve the stability of vitamin A and / or its derivatives, it has an excellent advantage of preventing coloration and odor change over time.

  The component (a) used in the external preparation for skin of the present invention is vitamin A and / or a derivative thereof, vitamin A (retinoic acid), vitamin A alcohol (retinol), vitamin A acetate (retinol acetate), vitamin A palmitate. (Retinol palmitate), vitamin A propionate (retinol propionate), vitamin A linoleate (retinol linoleate), β-carotene, astaxanthin, and the like can be used, and one or more of these can be used.

  Among the substances described above, component (a) is preferably a vitamin A fatty acid ester such as vitamin A palmitate, vitamin A acetate, vitamin A propionate, or vitamin A linoleate from the viewpoint of stability and effectiveness.

  Although the compounding quantity of the component (a) in the skin external preparation of this invention is not specifically limited, 0.01-1 mass% (Hereinafter, it only describes as [%]) is preferable. When component (a) is blended in this range, a skin external preparation superior in stability and effectiveness can be obtained.

  On the other hand, the component (b) used in the external preparation for skin of the present invention is a drug having a superoxide removal rate of 75% or more determined by a superoxide removal activity measurement test. The component (b) drug used in the present invention must have a superoxide removal rate of 75% or more, and if it is less than 75%, the component (a) cannot be stabilized.

  The agent having a superoxide removal rate of 75% or more of the component (b) is not particularly limited, and examples thereof include plant extracts such as a mica squid extract, ages extract, goldfish extract, and tea extract. 1 type or 2 types or more can be used from these. The said plant extract is extracted from the following plant, respectively, The production area, the cultivation method, etc. are not specifically limited. Specifically, Mikaika extract is a flower bud of Rosa rugosa Thunb., And Ages extract is a fruit of Rosa multiflora Thunb. The honeysuckle (Lonicera japonica Thunb.) Honeysuckle (Lonicera japonica Thunb.) And tea extract are extracted from the leaf stem of the camellia evergreen tree (Camellia sinensis).

  The extraction method in the plant extract is not particularly limited. For example, after various plants are appropriately treated, such as drying, chopping, pressing, or fermentation, the solvent is used at low temperature or from room temperature to warming. The extraction method can be mentioned. Next, purification such as filtration, adsorption, and decolorization with an ion exchange resin or the like may be performed as necessary.

  In addition, the solvent for extracting the plant is not particularly limited. For example, lower monohydric alcohols (methyl alcohol, ethyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.) , Polyhydric alcohols (glycerin, propylene glycol, 1,3-butylene glycol, etc.), other aqueous solvents, lower alkyl esters (such as ethyl acetate), hydrocarbons (benzene, hexane, pentane, etc.), ketones (acetone, methyl ethyl ketone) Etc.), ethers (diethyl ether, tetrahydrofuran, dipropyl ether, etc.), acetonitrile, other hydrophobic solvents, etc., and one or more of these can be used. Among these solvents, the aqueous solvent is particularly preferable in order to blend the vitamin A of component (a) and / or its derivative more stably.

  Such component (b) is a commercially available product of Mykaika extract LA (ethanol aqueous solution extraction, manufactured by Maruzen Pharmaceutical Co., Ltd., solid content concentration: about 2.5%), Agetsu extract (ethanol aqueous solution extraction, manufactured by Maruzen Pharmaceutical Co., Ltd.) Solid content concentration of about 8.5%), goldfish extract NO.80 (ethanol aqueous solution extraction, manufactured by Nagaoka Fragrance Co., Ltd., solid content concentration of about 4.5%), green tea liquid (ethanol aqueous solution extraction, manufactured by Ichimaru Falcos, solid content) Concentration of about 0.1%), black tea liquid (ethanol aqueous solution extraction, manufactured by Ichimaru Falcos, solid content concentration of about 2.3%), red oolongcha extract BG (1,3-butylene glycol aqueous solution extraction, manufactured by Maruzen Pharmaceutical Co., Ltd.) , Solid content concentration of about 1%) and the like, and can be used as it is for the external preparation for skin of the present invention.

  Although the compounding quantity of the component (b) in the skin external preparation of this invention is not specifically limited, 0.0001-0.1% is preferable in conversion of solid content, and 0.0005-0. 05% is particularly preferred. When component (b) is blended in this range, a skin external preparation superior in stability and effectiveness can be obtained.

  The blending mass ratio (a) / (b) of the component (a) and the component (b) in the external preparation for skin of the present invention is not particularly limited, but is preferably 10 to 1000. When component (a) and component (b) are blended in this range, an external preparation for skin with particularly remarkable stability and effectiveness can be obtained.

  Furthermore, the component (c) used for the external preparation for skin of the present invention is an oil-soluble antioxidant. Specifically, dibutylhydroxytoluene (hereinafter abbreviated as “BHT”), butylhydroxyanisole (hereinafter abbreviated as “BHA”), sorbic acid, rutin, propyl gallate, vitamin E (α, β, γ, δ) -Tocopherol), vitamin E acetate (tocopherol acetate), oil-soluble vitamin E derivatives such as vitamin E linoleate (tocopherol linoleate), oil-soluble vitamin C derivatives such as tetrahexyldecanoic acid ascorbyl, ascorbic acid dipalmitate, etc. 1 type, or 2 or more types can be used.

  Although the compounding quantity of the component (c) in the skin external preparation of this invention is not specifically limited, 0.01 to 5% is preferable. When component (c) is blended in this range, a skin external preparation superior in stability and effectiveness can be obtained.

  In addition to the essential components described above, the skin external preparation of the present invention includes various components that are usually used in cosmetics, quasi-drugs, external medicines, etc., that is, water, lower alcohols, polyhydric alcohols, oily components, interfaces. Activators, thickeners, powders, chelating agents, pH adjusters, preservatives, medicinal agents, extracts derived from animals and plants / microorganisms, pigments, fragrances, and the like can be added as long as the effects of the present invention are not impaired. .

  The topical skin preparation of the present invention comprehensively represents cosmetics such as lotion, cosmetic liquid, milky lotion, cream, cosmetic oil, and external medicines such as quasi-drugs, ointments, liniments, and poultices. . The dosage form may be any of an emulsified type such as oil-in-water, water-in-oil, water-in-oil-in-water, solubilized type, aqueous liquid type, oily liquid type, etc. The shape is an oil-in-water type. Further, the form may be any of liquid, emulsion, cream, solid, aerosol, patch and the like.

  The method for producing the skin external preparation of the present invention is not particularly limited as long as components (a) to (c) can be added to a base material such as cosmetics, quasi drugs, and external medicines. .

  Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Superoxide removal activity measurement test method and test examples:
Table 1 shows the superoxide removal rates of various drugs determined by the superoxide removal activity measurement test method shown below.

(Superoxide removal activity measurement test method)
Substrate solution [3.0 mM xanthine (dissolved in 0.05 M sodium carbonate buffer)] 0.1 mL, 3.0 mM EDTA 0.1 mL, 0.15 in 2.4 mL of 0.05 M sodium carbonate buffer (pH 10.2) % (W / v) bovine serum albumin 0.1 mL, 0.75 mM nitroblue tetrazolium 0.1 mL and each test sample 0.1 mL were mixed and allowed to stand at 25 ° C. for 10 minutes. Next, 0.1 mL of an enzyme solution [xanthine oxidase solution (diluted to about 0.04 units / mL with purified water)] was added to start the reaction. After incubation at 25 ° C. for 20 minutes, 0.1 mL of 6 mM CaCl ₂ was added. In addition, the reaction is stopped. Next, the absorbance (A) at 560 nm is measured.

Absorbance (B) of the sample in which purified water was added instead of the test sample for the control, and 0.1 mL of xanthine oxidase was added to the blank of each test sample after adding 0.1 mL of 6 mM CaCl ₂ and stopping the reaction. The absorbance (C) of the sample is measured, and the superoxide removal rate of each test sample is calculated from Equation 1 below.

A: Absorbance due to enzyme reaction of sample B: Absorbance due to enzyme reaction of control C: Absorbance due to enzyme-free reaction of sample

Examples 1 to 6 and Comparative Examples 1 to 3: Oil-in-water creams An oil-in-water cream having the composition shown in Table 2 was prepared by the following production method, evaluated by the evaluation method shown below, and the results are shown in Tables 2 and 3 together. It was shown to. In addition, the compounding quantity of each chemical | medical agent of the components (15) to (18) in a table | surface is a compounding quantity in conversion of solid content.

(Production method)
A. Components (1) to (8) are heated and dissolved at 70 ° C.
B. Components (9) to (14) and (21) are mixed and heated to 70 ° C.
C. Add A to B and emulsify.
D. C is cooled to room temperature, and components (15) to (20) are added and mixed uniformly.
E. D was filled into a container to obtain an oil-in-water cream.

[Evaluation Method 1: Retinol Palmitate Remaining Rate]
The retinol palmitate content immediately after the production of the examples and comparative examples was set to 100%, and the retinol palmitate content after each sample was stored in a constant temperature bath at 40 ° C. for 6 months was measured. (%) Was calculated. In the present invention, it is determined that the stability is good when the residual ratio is 80% or more.

[Evaluation Method 2: Change in Odor and Discoloration over Time]
The oil-in-water creams of the examples and comparative examples were stored in a constant temperature bath at 40 ° C. and 5 ° C. for 6 months each, and the 40 ° C. stored products were compared relative to the 5 ° C. stored products, and in accordance with the evaluation criteria shown below. evaluated.
(Evaluation criteria)
Evaluation result: Judgment No change: ◎
There are minor changes: ○
There is a slight change: △
There is considerable change: ×

  As is apparent from the results in Table 2, the oil-in-water creams of Examples 1 to 6 according to the present invention have a good residual ratio of retinol palmitate even when stored at 40 ° C. for 6 months, It was an excellent external preparation for skin that does not cause odor or discoloration. On the other hand, as is apparent from the results of Table 3, Comparative Example 1 not containing the oil-soluble antioxidant of component (c), which is an essential component of the present invention, has a retinol palmitate residual ratio as low as 75%, and Also, odor change and discoloration occurred, and the stability was poor. Further, in Comparative Example 2 which does not contain a drug having a superoxide removal rate of 75% or more of the component (b) which is an essential component of the present invention, the residual rate of retinol palmitate is as low as 79%, and odor and color change Also occurred and the stability was poor. Further, in Comparative Example 3 using L-ascorbic acid sulfate disodium having a superoxide removal rate of 4.6% instead of component (b), which is an essential component of the present invention, the residual rate of retinol palmitate was 77. %, And odor and discoloration also occurred, resulting in poor stability.

Example 7: Oil-in-water emulsion (component) (%)
(1) Sorbitan monostearate 0.3
(2) Polyoxyethylene sorbitan monooleate (20E.O.) 0.1
(3) Lipophilic glyceryl monostearate 0.2
(4) Stearic acid 0.5
(5) Cetanol 0.5
(6) Squalane 3.0
(7) Liquid paraffin 4.0
(8) Glyceryl tri-2-ethylhexanoate 2.0
(9) Methylpolysiloxane 1.0
(10) Retinol acetate 0.2
(11) dl-α-tocopherol 0.01
(12) Paraben 0.2
(13) Carboxyvinyl polymer 1.0
(14) Sodium hydroxide 0.05
(15) Glycerin 5.0
(16) 1,3-butylene glycol 7.0
(17) Purified water remaining amount (18) ethyl alcohol 5.0
(19) Black tea extract * 5 0.001
(20) Perfume appropriate amount * 5 Black tea liquid (ethanol aqueous solution extraction, manufactured by Ichimaru Falcos). The above compounding amount is a solid content conversion amount.

(Manufacturing method)
A. Ingredients (13) to (17) are heated and mixed and maintained at 70 ° C.
B. Ingredients (1) to (12) are heated and mixed and maintained at 70 ° C.
C. Add B to A, mix and uniformly emulsify.
D. (18)-(20) is added after cooling C, and it mixes uniformly.
E. D was filled into a container to obtain an oil-in-water emulsion.

  The oil-in-water emulsion of Example 7 was an excellent external preparation for skin having a good residual ratio of retinol acetate even when stored at 40 ° C. for 6 months and causing no odor change or discoloration over time.

Example 8: Oil-in-water ointment (component) (%)
(1) Stearic acid 18.0
(2) Cetanol 4.0
(3) BHA 0.2
(4) Vitamin A 0.5
(5) Paraben appropriate amount (6) Triethanolamine 2.0
(7) Glycerin 5.0
(8) Purified water remaining amount (9) Green tea extract * 6 0.005
(10) Yeast extract 0.5
* 6 Green tea liquid (ethanol aqueous solution extraction, manufactured by Ichimaru Falcos). The above compounding amount is a solid content conversion amount.

(Manufacturing method)
A. A part of components (6), (7) and (8) are heated and mixed and kept at 75 ° C.
B. Ingredients (1) to (5) are heated and mixed and maintained at 75 ° C.
C. Gradually add A to B.
D. While cooling C, add (9) to (10) dissolved in the remainder of (8) and mix uniformly.
E. D was filled into a container to obtain an oil-in-water ointment.

The oil-in-water ointment of Example 8 was an excellent skin external preparation that had a good residual ratio of vitamin A even when stored at 40 ° C. for 6 months, and did not cause odor or discoloration over time.
The ointment obtained in Example 8 was an ointment having excellent temporal stability and a high skin beautifying effect.

Claims (4)

The following components (a) to (c);
(A) Vitamin A and / or a derivative thereof (b) A skin external preparation characterized by containing a drug (c) oil-soluble antioxidant having a superoxide removal rate of 75% or more. The skin external preparation according to claim 1, wherein the drug of component (b) is one or more selected from a mica squid extract, an age extract, a goldfish extract, and a tea extract. The component (a) is blended in an amount of 0.01 to 1% by mass, the component (b) is blended in an amount of 0.0001 to 0.1% by mass in terms of solid content, and the blending mass ratio (a) / (b) is 10 to 10%. The skin external preparation according to claim 1, wherein the skin external preparation is 1000. The external preparation for skin according to any one of claims 1 to 3, wherein the drug of component (b) is a plant extract extracted with an aqueous solvent.