JP2014040399A - Skin external agent or cosmetic composition with accelerated permeation of active ingredient into skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide accelerated permeation, into skin, of a skin active ingredient having relatively low absorption into skin.SOLUTION: A skin external agent or cosmetic composition contains (A) a skin active ingredient having a molecular weight of 500 to 1500 and a distribution coefficient Log P of 5.0 to 30.0; and (B) a hydrocarbon oil where the surface tension of a skin permeation acceleration-effective dose of the ingredient (A) is 29.5 mN/m or less at a temperature of 32°C. Examples of the ingredient (A) are stearyl glycyrrhetinate, astaxanthin, coenzyme Q10 and ascorbyl tetrahexyldecanoate.

Description

  The present invention relates to a technique for promoting the penetration of active ingredients used in cosmetics and the like into the skin. The present invention is particularly useful for enhancing the transdermal permeability of a component having a partition coefficient Log P value of a certain level or more, represented by stearyl glycyrrhetinate. The present invention is useful in the fields of life science, cosmetic production, and beauty.

A compound that is considered to have good skin absorbability in the pharmaceutical field has a molecular weight of 500 or less and a Log P value (octanol / water partition coefficient) of 1 to 3 (Non-patent Documents 1 and 2).
However, there are many components that are effective against the skin outside these ranges. Particularly in the cosmetics field, useful effects have been found for ingredients with relatively high molecular weight, such as ingredients derived from natural products and vitamin derivatives, and ingredients that do not easily penetrate the skin due to their relatively high or low polarity. ing.
On the other hand, the present inventors have heretofore applied an infinite dose system and a small amount of practical use for stearyl glycyrrhetinate (for example, Japanese Patent No. 3513861) used in cosmetics as a component exhibiting an anti-inflammatory action. Skin penetration in the system has been investigated using different types of oils. And infinite dose system, stearyl glycyrrhetinate hardly penetrates the skin, but in small amount application system, it was found that it penetrated into the skin, which may be related to the physicochemical properties of the base. Reported that there is. (Non Patent Literature 3)

Japanese Patent No. 3513861

Wester RC et.al Percutaneous absorption. Mechanisms-methodology-drug-delivery New York 107-23,1983 Yano T, et al Life Sci. 39, 1043-50, 1986 Osamu Sakata et al., Effect of oil on skin permeability of stearyl glycyrrhetinate, Japan Pharmaceutical Association 132nd Annual Meeting (2012), 30E16-pm06,

  Even if it is a component that has a molecular weight of 500 or less and has a log P value of 1 to 3 that is considered to have good skin absorbability, and if there is a means to increase skin permeability, a more effective external use for skin Agents and cosmetic compositions can be expected.

  The present inventors disperse stearyl glycyrrhetinate as a representative active ingredient having relatively low skin permeability in liquid paraffin (molecular weight of 245 to 500) having different physical properties, and examined the influence on skin permeability. As a result of analyzing the relationship between the physicochemical properties of liquid paraffin used in the experiment and the skin permeability, it was found that the surface tension of liquid paraffin was greatly involved in the skin penetration of stearyl glycyrrhetinate. completed.

The present invention provides the following:
[1] (A) an active skin ingredient having a molecular weight of 500-1500 and a partition coefficient Log P value of 5.0-30.0; and (B) an effective amount for promoting skin penetration of component (A) A skin external preparation or cosmetic composition containing a hydrocarbon oil having a surface tension of 29.5 mN / m or less at a temperature of 32 ° C.
[2] The external skin preparation or cosmetic composition according to [1], wherein the component (A) is one or more selected from the group consisting of stearyl glycyrrhetinate, astaxanthin, coenzyme Q10, and ascorbyl tetrahexyldecanoate.
[3] The skin external preparation or cosmetic composition according to any one of [1] to [3], wherein the distribution coefficient Log P value of the component (A) is 10.0 to 25.0.
[4] Any of [1] to [3], wherein the mass ratio of component (A) / component (B) is 1 / (10 to 250) as an effective amount for promoting skin penetration of component (A) The skin external preparation or cosmetic composition according to 1.
[5] Effective penetration of the active ingredient (A) into the skin with an effective skin ingredient (A) having a molecular weight of 500 to 1500 and a partition coefficient Log P value of 5.0 to 30.0 is effective. A method of promoting by simultaneously using a quantity of hydrocarbon oil (B) having a surface tension at a temperature of 32 ° C. of 29.5 mN / m or less.
[6] A method for producing a topical skin preparation or cosmetic composition in which penetration of an active skin ingredient into the skin is promoted:
Skin active ingredient (A) is selected using as an index that the molecular weight is 500-1500 and the partition coefficient Log P value is 5.0-30.0;
The hydrocarbon oil (B) is selected with the surface tension at a temperature of 32 ° C. being 29.5 mN / m or less as an index; and an effective amount of hydrocarbon oil for promoting skin penetration of the component (A) ( A manufacturing method including the process containing B).
[7] Skin of component (A) for promoting penetration of skin active ingredient (A) having a molecular weight of 500-1500 and a partition coefficient Log P value of 5.0-30.0 into the skin An agent comprising a hydrocarbon oil (B) having a surface tension at a temperature of 32 ° C. of 29.5 mN / m or less in an effective amount for promoting penetration.

  According to the present invention, penetration of an active skin ingredient having a specific distribution coefficient into the skin can be promoted.

The amount of stearyl glycyrrhetinate permeated into the stratum corneum and / or epidermis depending on the type of liquid paraffin. Stearyl glycyrrhetinate was suspended at 2% w / v in liquid paraffin having different physicochemical properties, applied to YMP skin at 2.5 μL / cm ² , and the amount of penetration after 24 hours was evaluated. DiI amount penetrating into the stratum corneum and / or epidermis depending on the type of liquid paraffin. DiI was dissolved at 0.1% w / v in liquid paraffin having different physicochemical properties and applied to YMP skin, and evaluated after 2 hours. (A) Photograph, (b) Penetration amount. The amount of Nile Red penetrating into the stratum corneum and / or epidermis depending on the type of liquid paraffin. Nile Red was dissolved in liquid paraffin having different physicochemical properties to 0.1% w / v and applied to YMP skin and evaluated after 2 hours. (A) Photograph, (b) Penetration amount.

  Hereinafter, the present invention will be described in detail. In the present specification, “skin penetration promotion” means to promote penetration into the stratum corneum and epidermis unless otherwise specified. Moreover, when a range is represented by "-" in this specification, except the case where it describes especially, both ends are included. In the present invention, the values shown for the ratio or ratio (%, etc.) are values based on mass, unless otherwise specified. “W / v” represents the ratio (%) of the mass (weight) of the solute in the volume of the solvent.

  The “Log P value” in the present invention refers to an octanol / water partition coefficient using n-octanol and water as a solvent. When the Log P value is indicated in the present invention, it is 25 ° C. unless otherwise specified. Is the value at.

The present invention relates to promoting penetration of an active skin ingredient (component (A)) into the skin.
The “active skin ingredient” as used in the present invention refers to an ingredient that is expected to be effective when administered to the skin.

  The present invention can be applied to an active skin ingredient having a molecular weight of 500-1500, preferably 510-1500, more preferably 590-1150, and further preferably 650-790.有効 The active skin ingredient used in the invention has a partition coefficient Log P value of 5.0 to 30.0, more preferably 10.0 to 30.0, regardless of the molecular weight. More preferably, it is 15.0-25.0.

  Specific examples of active skin ingredients that can be used in the present invention are stearyl glycyrrhetinate, astaxanthin, coenzyme Q10, and ascorbyl tetrahexyldecanoate. The molecular weights and Log P values of these components are shown in the table below.

  Stearyl glycyrrhetinic acid (Glycyrrhetinic Acid) is a compound obtained by esterifying stearic acid to the hydroxyl group of glycyrrhetinic acid obtained by hydrolysis of glycyrrhizic acid contained in licorice and the like, and is represented by the following formula.

  The molecular structure of glycyrrhetinic acid has planarity and has anti-inflammatory action because the 3rd and 11th positions are similar to cortisone. Stearyl glycyrrhetinate has been widely used as an anti-inflammatory component in technical fields such as external preparations for skin and cosmetics where safety is required because stearic acid is added to enhance safety.

  Astaxanthin is known as a component that has an antioxidant effect, an anti-inflammatory effect, a skin aging prevention effect, a whitening effect, and the like, and can impart an excellent emollient effect, skin aging prevention effect and antioxidant effect. In the present invention, “astaxanthin” refers to astaxanthin in the narrow sense (3,3′-dihydroxy-β, β-carotene-4,4′-dione, free form), fatty acid, and the like unless otherwise specified. Derivatives thereof (including monoester type and diester type). The fatty acid ester may be a long-chain fatty acid ester such as palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, EPA, or DHA, or may be an ester of a medium-chain fatty acid. Astaxanthin used in the present invention is not limited in its origin and production method as long as it is acceptable as an additive for external preparations for skin or cosmetic compositions. For example, red yeast Phaffia, green algae hematococcus, marine bacteria In addition to those derived from plants such as Adonis Palestine and natural products such as krill, any of those obtained according to conventional methods may be used.

  Coenzyme Q10 is a biological component widely present in living organisms, and plays an important role in ATP production in humans as a component of the electron transport system of the inner mitochondrial membrane. It also exists in membrane systems other than mitochondria, such as cell membranes, Golgi apparatus, and lysosomes, and functions as an antioxidant. Coenzyme Q10 is widely used as a drug for the treatment of congestive heart failure, health food, cosmetics and the like. Coenzyme Q10 can be produced by a synthesis method, a fermentation method using microorganisms, or the like, and any of them can be used in the present invention as long as it is acceptable as an additive to an external preparation for skin or a cosmetic composition. good. In addition, there are two types of forms, oxidized ubiquinone and reduced ubiquinol, and any of them may be used in the present invention as long as it is acceptable as an additive to an external preparation for skin or a cosmetic composition. good.

  Ascorbyl tetrahexyl decanoate is an esterification of all hydroxyl groups of ascorbic acid with branched fatty acids, without damaging the effects of ascorbic acid such as whitening, skin quality improvement, collagen production, antioxidant action, cell activation effect, etc. , Improved stability and solubility in oil. Ascorbyl tetrahexyldecanoate used in the present invention is not limited in its production method and origin as long as it is acceptable as an additive for external preparations for skin or cosmetic compositions.

  The content of the component (A) in the external preparation for skin or cosmetic composition of the present invention can be appropriately determined in such an amount that the expected effect of the component (A) can be expected. The content can be appropriately determined by those skilled in the art. For example, when stearyl glycyrrhetinate is used as the component (A), it can be contained, for example, in an amount of 0.01 to 10% by mass. It is more preferable to contain, and it is more preferable to contain by 0.2-2 mass%.

  In the present invention, the penetration of skin active ingredients into the skin is facilitated by hydrocarbon oils having specific physicochemical properties. According to the study by the present inventors, a high correlation was found between the amount of stearyl glycyrrhetinate penetrated into the skin and the surface tension of the hydrocarbon oil used.

The hydrocarbon oil used in the present invention has a surface tension at a temperature of 20 ° C. of 29.5 mN / m or less. The surface tension is preferably 28.5 mN / m or less, more preferably 28 mN / m or less. The lower the surface tension, the more easily the hydrocarbon oil spreads on the skin surface, and accordingly, the skin permeability of the target component is further promoted. As the surface tension decreases, the permeability of the target component to the skin tends to increase. However, according to our study using stearyl glycyrrhetinate, the surface tension of hydrocarbon oil is 29.5 mN / m or less. As a result, it is known that the acceleration effect is rapidly increased.

  From the viewpoint of effects, there is no particular limitation on the lower limit value of the surface tension, but generally the lower limit value of the surface tension of the hydrocarbon oil is about 16.0 N / m. Therefore, if the lower limit of the hydrocarbon oil used in the present invention is defined, it is 16.0 N / m or more, for example, 23.0 N / m or more.

  In the present invention, when a value is indicated for the surface tension, it is a value measured by the pendant drop method, unless otherwise specified.

  According to the study by the present inventors, at least stearyl glycyrrhetinate and stearyl glycyrrhetinate, a fluorescent dye DiI (1,1′-Dioctadecyl-3,3,3 ′, 3′-tetramethylindo-carbocyanine having a molecular weight and a Log P value approximate to each other. perchlorate, molecular weight: 834.41, Log P value: 23.2), the surface tension of the hydrocarbon oil used at the same time affected the skin penetration, but the molecular weight was 318.37 and the Log P value was 3. No. 8 fluorescent dye, Nile Red (9- (Diethylamino) -5H-benzo [a] phenoxazin-5-one), the surface tension of the hydrocarbon oil used at the same time did not affect the permeability to the skin. Therefore, the selection of an oil agent as a base based on surface tension is particularly effective for active skin ingredients whose distribution coefficient is within a specific range, and the contribution of the surface tension of the oil agent as a base is as follows: It is presumed that the active ingredient is not only adsorbed to the skin grooves and fine irregularities on the skin stratum corneum surface when transferring to the skin.

  The hydrocarbon oil (component (B)) used in the present invention is not particularly limited as long as the surface tension is in the range described above and is a specification that can be added to an external preparation for skin or a cosmetic composition. However, it is preferably liquid at 20 ° C. Specific examples include isododecane, isohexadecane, hydrogenated polyisobutene, light liquid isoparaffin, liquid paraffin, squalane, petrolatum, polyisobutylene, polybutene, and the like. These can be used alone or in combination. When used in combination, the surface tension of the mixture may be in the range described above.

  In the present invention, the hydrocarbon oil (component (B)) is used in an amount that promotes penetration of the skin active ingredient (component (A)) into the skin, that is, an effective amount for promoting skin penetration of the component (A). It is done. According to the study by the present inventors, when stearyl glycyrrhetinate is suspended in the component (B) so as to be 2% w / v (≈2% by mass), the skin permeability of stearyl glycyrrhetinate is sufficient. Promoted to. Therefore, if the mass ratio of component (A) / component (B) is 1 / (10-250), it is considered that the penetration of component (A) can be effectively promoted, and 1 / (15- 250) is preferable, and 1 / (25 to 250) is more preferable.

  The content of the component (B) in the external preparation for skin or cosmetic composition of the present invention can be appropriately determined, for example, 0.1 to 99% by mass, and 1 to 50% by mass. It is more preferable to contain 2 to 20% by mass.

  The method for producing the external preparation for skin or cosmetic composition of the present invention is not particularly limited as long as it can effectively promote the penetration of component (A). Various production methods for the external preparation for skin or cosmetic composition can be applied.

  The skin external preparation or cosmetic composition of the present invention is contained in the skin external preparation and cosmetics together with the component (A), and promotes the skin permeability of the component (A) when applied to the skin. Therefore, the component (A) can be efficiently stored in the target site (skin layer or epidermis) in the skin. Thereby, the effect | action of a component (A) can be improved more.

  In the external preparation for skin or cosmetic composition of the present invention, components that are usually used in preparations such as cosmetics, that is, water (purified water, hot spring water), as long as the effects of the present invention are not impaired as required. , Deep water, etc.), alcohol, oil agent, surfactant, metal soap, gelling agent, powder, alcohol, water-soluble polymer, film-forming agent, resin, UV protection agent, inclusion compound, antibacterial agent, perfume , Deodorant, salt, pH adjuster, freshener, animal / microbe-derived extract, plant extract, blood circulation promoter, astringent, antiseborrheic agent, whitening agent, anti-inflammatory agent, active oxygen scavenger, cell Activators, moisturizers, chelating agents, keratolytic agents, enzymes, hormones, vitamins and the like can be added.

  The properties of the external preparation for skin or cosmetic composition of the present invention may be any of liquid, gel, cream, semi-solid, solid, stick, powder, etc., emulsion, cream, lotion, Forms belonging to skin cosmetics such as cosmetic liquids, packs, face wash, makeup cosmetics, etc .; forms relating to hair cosmetics such as shampoos, hair treatments, hair styling agents, hair nourishing agents, hair restorers, etc. The skin penetration enhancer and stearyl glycyrrhetinate can be contained in various cosmetics as described above, and can also be contained in external medicines such as dispersions, ointments, aerosols, patches, poultices and liniments.

  Hereinafter, the present invention will be described in more detail with reference to test examples for evaluating the action of the skin penetration enhancer of the present invention. However, the present invention is not limited to these examples.

[Examination of factors affecting skin permeability]
1. Method After removing the subcutaneous tissue and fat of Yucatan micropig (YMP) skin (Nippon Charles River) according to the method of Fujii et al. Described in the Journal of Cosmetic Society, 31 (1), 1-7 (2007) This was set in a mold cell, and stearyl glycyrrhetinate (GS) suspended in liquid paraffin at a concentration of 2% w / v was applied at 2.5 μL / cm ² .

  After 24 hours, the skin was separated into three layers, epidermis, dermis and stratum corneum, and GS contained in each part was quantified by HPLC. This experiment was conducted with reference to “OECD In Vitro Percutaneous Absorption Test Method” and “Bioequivalence Test Guidelines for Generic Drugs for Topical Skin Application”.

  The viscosity of liquid paraffin is measured at 32 ° C. using Viscometer SV-10 (A & D), and the surface tension is pendant drop method (ds / de method) using Dropmaster DM-500 (manufactured by Kyowa Interface Science Co., Ltd.). , 20 ° C.).

Skin penetration evaluation of DiI (1,1'-Dioctadecyl-3,3,3 ', 3'-tetramethylindo-carbocyanine perchlorate) and Nile Red (9- (Diethylamino) -5H-benzo [a] phenoxazin-5-one) Was performed by observing with CLSM (Olympus, FV-1000) after containing DiI or Nile Red at 0.1% w / v in 2.5 μL / cm ² of the sample solution and absorbing for 2 hours. . These molecular weights and Log P are shown in the table below.

2. Results (1) Liquid paraffin The physicochemical parameters of liquid paraffin (manufactured by Kaneda Corporation) used for evaluation are shown in the table below.

(2) Amount of penetration of GS into YMP skin The results are shown in FIG. As the molecular weight of liquid paraffin decreased, the amount of GS transferred to the skin increased.

(3) Multiple regression analysis Regarding the relationship between the amount of GS skin transfer and the viscosity, surface tension and molecular weight of liquid paraffin used in the experiment, software (JMP 9.03 (SAS Institute Japan), analysis mode: Stepwise method) Using, regression analysis was performed for each of molecular weight, viscosity, and surface tension. As a result, a high correlation was observed for the surface tension. The analysis results are summarized in the table below.

  It was shown that the surface tension of liquid paraffin was the most involved in the skin migration of GS.

Evaluation of penetration depth into YMP skin using (4) FIG. 2 shows the results for DiI, and FIG. 3 shows the results for Nile Red. As in the case of GS, when DiI having a large molecular weight and Log P value was used, the penetration depth of DiI decreased as the molecular weight of liquid paraffin increased. However, for Nile Red having a small molecular weight and Log P value, there was no correlation between the molecular weight of liquid paraffin and the penetration depth of Nile Red into the skin.

  It was suggested that the surface tension of liquid paraffin plays an important role in the skin permeability of active ingredients having a large molecular weight and Log P value including stearyl glycyrrhetinate.

[Preparation Example of Cosmetic Composition]
Beauty oil A beauty oil having the following composition was prepared according to the following production method.
(Ingredient) (mass%)
1. Stearyl glycyrrhetinate 0.5
2. Liquid paraffin (surface tension 27.6 mN / m) 10.0
3. Isotridecyl isononanoate 5.0
4). Dimethylpolysiloxane 5.0
5. Natural vitamin E 0.1
6). Jojoba oil

(Production method)
A: Dissolve component 1 in component 3 B: After components 2 and 4-6 were uniformly dissolved, A was added to obtain a beauty oil.

Claims (7)

(A) an active skin ingredient having a molecular weight of 500-1500 and a partition coefficient Log P value of 5.0-30.0; and (B) an effective amount for promoting skin permeation of component (A) at a temperature of 32 A skin external preparation or cosmetic composition comprising a hydrocarbon oil having a surface tension at 2 ° C. of 29.5 mN / m or less. The skin external preparation or cosmetic composition according to claim 1, wherein the component (A) is one or more selected from the group consisting of stearyl glycyrrhetinate, astaxanthin, coenzyme Q10, and ascorbyl tetrahexyldecanoate. The skin external preparation or cosmetic composition according to any one of claims 1 to 3, wherein the distribution coefficient Log P value of the component (A) is 10.0 to 25.0. The mass ratio of component (A) / component (B) is 1 / (10 to 250) as an effective amount for promoting skin penetration of component (A), according to any one of claims 1 to 3. Skin external preparation or cosmetic composition.   Permeation of the skin active ingredient (A) having a molecular weight of 500 to 1500 and a partition coefficient Log P value of 5.0 to 30.0 into the skin is effective in promoting skin penetration of the ingredient (A), The method of promoting by using simultaneously hydrocarbon oil (B) whose surface tension in the temperature of 32 degreeC is 29.5 mN / m or less. A method for producing a topical skin preparation or cosmetic composition in which penetration of an active skin ingredient into the skin is promoted:
Skin active ingredient (A) is selected using as an index that the molecular weight is 500-1500 and the partition coefficient Log P value is 5.0-30.0;
The hydrocarbon oil (B) is selected with the surface tension at a temperature of 32 ° C. being 29.5 mN / m or less as an index; and an effective amount of hydrocarbon oil for promoting skin penetration of the component (A) ( A manufacturing method including the process containing B).   Promoting skin penetration of component (A) for promoting penetration of skin active ingredient (A) having a molecular weight of 500 to 1500 and a partition coefficient Log P value of 5.0 to 30.0 into the skin An agent comprising an effective amount of a hydrocarbon oil (B) having a surface tension of 29.5 mN / m or less at a temperature of 32 ° C.

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