JP2008303185A - Agent for promoting formation and maturation of cornified envelope - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent for promoting the formation and maturation of cornified envelope (hereinafter referred as CE). <P>SOLUTION: This agent for promoting the formation and maturation of CE comprises a pyrrolidone derivative represented by the general formula (1) (wherein, R is H, a 1-4C straight chain or branched alkyl having zero to three hydroxy groups, or a 3-7C cycloalkyl groups having zero to five hydroxy groups) and/or its salt. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a CE formation / maturation promoter that promotes the formation and / or maturation of a cornified envelope (cornified thickened membrane; hereinafter abbreviated as CE) comprising a pyrrolidone derivative and / or a salt thereof.

  The stratum corneum is composed of keratinocytes formed by terminal differentiation of epidermal keratinocytes and intercellular lipids surrounding them. Intercellular lipids form a lamellar structure with ceramide, cholesterol, fatty acids and the like as components. On the other hand, keratinocytes are composed of CE containing keratin fibers as the main component and enveloping them. CE is formed by cross-linking and insolubilizing a plurality of CE precursor proteins produced in cells according to the differentiation of epidermal keratinocytes. Furthermore, it has been suggested that ceramide and the like are covalently bonded to a part of the structure and have a hydrophobic structure, thereby supplying a base of the lamellar structure of the intercellular lipid described above.

  CE boiled epidermal tissue or cultured skin cells in a solution containing a surfactant such as sodium dodecyl sulfate and a reducing agent such as mercaptoethanol, and an insoluble fraction from which soluble components have been removed by means such as centrifugation. It can be prepared by obtaining. By observing the form with a microscope, the property can be evaluated. Michel et al. Report that there are more CEs with a fragile structure deeper in the stratum corneum than in the outermost layer of the stratum corneum (J. Invest. Dermatol. 91: 11-15, 1988). Furthermore, it is said that fragile CE is also found in the outermost layer in psoriasis and phylloid ichthyosis (Br. J. Dermatol. 122: 15-21, 1990).

  The present inventors have studied to elucidate the state of the skin, particularly the stratum corneum, from the properties of CE. As a result, in addition to the morphology of CE, for example, the hydrophobicity of CE is examined by Nile Red staining, and the stratum corneum modulation is captured by examining the antigenicity of involucrin, which is a constituent element, by immunostaining. I found that I can do it.

  Furthermore, it has also been found that the formation or maturity of CE in cultured keratinocytes can be evaluated by utilizing such staining properties. Based on such findings, the present inventors are characterized in that CE in a skin-derived stratum corneum sample is stained with a dye capable of selectively staining a hydrophobic region, and the staining property of CE is used as an evaluation index. The CE property evaluation method and skin quality evaluation method have been proposed (Patent 3878787).

  On the other hand, as CE formation / maturation promoters, glycerin, erythritol, trimethylglycine (JP 2002-265347) and amidinosulfonic acid derivatives (JP 2006-96744) have been found. Improvement is necessary from the viewpoint of odor, and further effective means have been desired.

Patent 3878787 JP2002-265347 JP 2006-96744

J. Invest. Dermatol. 91: 11-15, 1988 Br. J. Dermatol. 122: 15-21, 1990

  As described above, the provision of further effective means for accelerating the formation and maturation of CE both quantitatively and qualitatively has been awaited.

  The present inventors have considered that immature CE retains the ability to be matured, and as a result, have found that immature CE can be converted to mature CE under certain conditions. Furthermore, it has been found that continuous use of a composition for external application containing a certain active ingredient that satisfies these conditions promotes the formation of CE in human skin. The present invention is based on such knowledge.

（一般式（１）中、Ｒは水素原子、０〜３個のヒドロキシル基を持つ炭素数１〜４の直鎖または分岐のアルキル基、または０〜５個のヒドロキシ基を持つ炭素数３〜７のシクロアルキル基を表す。） In order to solve the above-mentioned problems, the present inventors have conducted extensive studies, and as a result, found that certain pyrrolidone derivatives have the properties as described above and are very excellent, and have found the present invention. It came to be completed.
That is, the present invention provides a CE formation / maturation promoter comprising a pyrrolidone derivative represented by the following general formula (1) and / or a salt thereof for promoting the formation and / or maturation of CE.

(In the general formula (1), R is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms having 0 to 3 hydroxyl groups, or 3 to 3 carbon atoms having 0 to 5 hydroxy groups. 7 represents a cycloalkyl group.)

  The formation and / or maturation of CE can be promoted by applying the pyrrolidone derivative and / or salt thereof of the present invention to the skin.

  According to the present invention, it is possible to provide a CE formation / maturation promoter.

  The formation or maturation of CE referred to in the present invention means that a plurality of CE precursor proteins produced as epidermal keratinocytes differentiate and are cross-linked and insolubilized by the action of enzyme transglutaminase, etc. It means that ceramide and the like are covalently bonded to form a hydrophobic structure. Therefore, the formation or maturation of CE is caused by staining positive with a dye capable of selectively staining a hydrophobic region, for example, Nile red, or a decrease or disappearance of the antigenicity of a constituent protein of CE (specifically, an antibody against the protein) Decrease or disappearance).

  In addition, “having an effect of promoting the formation and / or maturation of CE” as used in the present invention means that the above-described formation and / or maturation of CE as described above can be achieved by applying the pyrrolidone derivative of the present invention to the skin. It means to show the action and effect that brings Accordingly, in the present invention, pyrrolidone derivatives are used in such a manner as to result in the formation and / or maturation of CE.

  The pyrrolidone derivative of the present invention is a known compound and can be easily synthesized. It can also be easily purchased from Tokyo Chemical Industry Co., Ltd. or ALDRICH. JP-A-60-36423 discloses use as an osmotic topical pharmaceutical composition. However, it is not known at all that the pyrrolidone derivative of the present invention has an effect of promoting the formation and / or maturation of CE.

  The chemical name of the pyrrolidone derivative of the present invention is 2-pyrrolidone, 1-methyl-2-pyrrolidone, 1- (2-hydroxyethyl) -2-pyrrolidone and the like.

  The pyrrolidone derivative of the present invention can be converted to an inorganic salt or an organic salt by a known method. Although it does not specifically limit as a salt used in this invention, For example, as an inorganic salt, hydrochloride, sulfate, phosphate, hydrobromide, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium Examples include salts. Organic salts include acetate, lactate, maleate, fumarate, tartrate, citrate, methanesulfonate, p-toluenesulfonate, triethanolamine salt, diethanolamine salt, amino acid salt, etc. Can be mentioned.

  The blending amount of the pyrrolidone derivative of the present invention in the preparation as a CE formation / maturation promoter is not particularly limited, but is usually 0.01 to 5% by mass in the total amount of the composition containing the pyrrolidone derivative, Preferably it is about 0.1-2 mass%.

In addition, in the CE formation / maturation promoter of the present invention, it is possible to use glycerol, erythritol, trimethylglycine, etc. in combination with a pyrrolidone derivative in order to enhance the effect of promoting the formation and / or maturation of the CE. is there.
The blending amount of glycerin, erythritol and trimethylglycine is usually 0.001 to 20% by mass, preferably 0.01 to 10% by mass in the composition.

  In addition to the above-mentioned essential components, the CE formation / maturation promoter of the present invention includes components that can be usually added to cosmetics and pharmaceuticals, such as liquid fats and oils, solid fats and oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters. , Silicones, anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, moisturizers, water-soluble polymer compounds, thickeners, coating agents, UV absorbers, sequestering agents , Lower alcohols, polyhydric alcohols, sugars, amino acids, organic amines, pH adjusters, skin nutrients, vitamins, antioxidants, fragrances, powders, coloring materials, water, etc., as appropriate Can do. Further, L-ascorbic acid and its salts, L-ascorbic acid phosphate ester, ester derivatives of L-ascorbic acid such as L-ascorbic acid sulfate, and salts thereof, and L-ascorbic acid such as L-ascorbic acid glucoside Glycosides and salts thereof, alkoxysalicylic acids such as 4-methoxysalicylic acid and salts thereof, hydroquinone glycosides such as hydroquinone β-D-glucose and hydroquinone α-D-glucose and salts thereof, tranexamic acid and tranexam Tranexamic acid derivatives such as acid methylamide hydrochloride, resorcin derivatives such as 4-n-butylresorcin, kojic acid, ellagic acid, linoleic acid, chamomile extract, retinoic acid, retinol, retinol acetic acid, retinol palmitic acid, glycyrrhizic acid and derivatives thereof Etc. may be blended as appropriate it can.

  The dosage form of the CE formation / maturation promoter of the present invention is not particularly limited, and examples thereof include a solution system, a solubilization system, a milk emulsion system, a powder dispersion system, a water-oil two-layer system, and a water-oil-powder. Arbitrary dosage forms such as a three-layer system, an ointment, a gel, and an aerosol can be taken. Also, the form of use is not particularly limited, and can take any form such as lotion, milky lotion, cream, essence, jelly, gel, ointment, pack, mask, foundation, and the like.

Example 1: CE maturation promotion test A stratum corneum rich in immature CE was collected by tape stripping, and the test solution was applied to the stratum corneum adhered to the tape and incubated for 4 days at a temperature of 37 ° C and a humidity of 70%. . After completion of the incubation, tris-HCl buffer containing dithiothreitol and sodium dodecyl sulfate was added and heated at 100 ° C. for 10 minutes. Insoluble material was collected by centrifugation at 4000 g for 10 minutes. Further, the eluate addition and heating were repeated to thoroughly remove soluble components. The insoluble material thus obtained was designated as CE.

  The properties of CE thus prepared were evaluated by the method of Japanese Patent No. 3878787. That is, CE was dropped on a slide glass, air-dried, and fixed in cold acetone. After hydration with Dulbecco's phosphate buffered saline, mouse anti-human involucrin antibody (NOVOCASTRA) was reacted as the primary antibody. After the excess antibody was removed by washing, a FITC-labeled rabbit anti-mouse immunoglobulin antibody was reacted as a secondary antibody. After removing the excess antibody by washing, the Nile red staining solution was reacted, sealed, and observed with a fluorescence microscope. The observed image was taken into a computer through a CCD camera, and the maturity of involcrine positive immature CE, Nile red positive mature CE, etc. was differentiated using image analysis software (Win Roof). The results are shown in Table 1.

表１ ＣＥ成熟促進効果

Table 1 CE maturation promotion effect

  From the results in Table 1, it was revealed that the pyrrolidone derivative according to the present invention can promote the maturation of CE.

  Formulation examples (formulation examples) of the pyrrolidone derivative according to the present invention as CE formation / maturation promoters are shown below. The present invention is not limited to these.

<Skin cream>
(Compounding ingredients) (mass%)
(1) 1,3-butylene glycol 5.0
(2) (Na-acrylate / acryloyldimethyltaurine) copolymer 1.0
(Product name: SIMULGEL EG, manufactured by SEPIC)
(3) CE formation / maturation promoter of the present invention (1- (2-hydroxyethyl) -2-pyrrolidone) 2.0
(4) Polyethylene glycol monostearate (40E.O.) 1.5
(Product name: NIKKOL MYS-40V, manufactured by Nikko Chemicals Co., Ltd.)
(5) Glyceryl monostearate (self-emulsifying type) 2.5
(Product name: NIKKOL MGS-ASE, manufactured by Nikko Chemicals Co., Ltd.)
(6) Hydrogenated polyisobutene 5.0
(7) Meadow foam oil 5.0
(8) Decamethylcyclopentasiloxane 3.0
(9) Stearyl alcohol 0.8
(10) Behenyl alcohol 1.5
(11) Cetanol 4.0
(12) Microcrystalline wax 2.0
(13) Acrylate / Beheneth-25 methacrylate copolymer 3.0
(Product name: ACULYN 28, manufactured by Rohm & Haas)
(14) Potassium hydroxide 0.1
(15) Appropriate amount of paraben (16) Appropriate amount of edetate salt (17) Appropriate amount of dibutylhydroxytoluene (18) Appropriate amount of perfume (19) Residual amount of purified water

(Manufacturing method)
(1) to (3), (13) to (17), (19) were mixed and dissolved uniformly and heated to 70 ° C., and (4) to (12) and (18) were added to 70 ° C. The oil phase, which is heated and uniformly dissolved, is gradually added and emulsified with a homomixer. Subsequently, it cooled with the heat exchanger and obtained the target skin care cream.

<Skincare emulsion>
(Compounding ingredients) (mass%)
(1) 1,3-butylene glycol 4.0
(2) Dynamite glycerin 7.0
(3) Polyethylene glycol 1500 1.5
(4) Polyethylene glycol 20000 1.0
(5) Xylitol 1.0
(6) Acetylated hyaluronic acid 0.01
(7) Carboxyvinyl polymer 0.14
(8) Xanthan gum 0.05
(9) Sodium hydroxide 0.2
(10) Acrylate / Stearless-20 Methacrylate Copolymer 1.0
(Product name: ACULYN 22 (30%), manufactured by Rohm & Haas)
(11) Crosslinked poly-γ-glutamic acid (Production Example 1) 1.0
(12) PEG-60 glyceryl isostearate 1.2
(Product name: EMALEX GWIS-160, manufactured by Nippon Emulsion Co., Ltd.)
(13) PEG-5 glyceryl stearate 0.5
(Product name: EMALEX GM-5, manufactured by Nippon Emulsion Co., Ltd.)
(14) Stearic acid 0.45
(15) Myristic acid 0.15
(16) Hydrogenated palm oil 2.0
(17) Squalane 1.0
(18) Tetra-2-ethylhexanoic acid pentaerythrit 4.5
(19) Dimethylpolysiloxane (6 mPa · s) 2.0
(20) Izayoi Rose Fruit Extract 0.02
(21) L-serine 0.01
(22) Trimethylglycine 1.0
(23) Tranexamic acid 2.0
(24) Vitamin-E acetate 0.05
(25) Sodium hexametaphosphate (first grade reagent) 0.01
(26) CE formation / maturation promoter of the present invention
(1- (2-hydroxyethyl) -2-pyrrolidone) 0.2
(27) Butylparaben 0.1
(28) Iron oxide appropriate amount (29) Paraben appropriate amount (30) Fragrance appropriate amount (31) Purified water remainder

(Manufacturing method)
(1) to (11), (20) to (30), (31) were mixed and dissolved uniformly and heated to 70 ° C., and (12) to (19) and (30) were added to 70 ° C. The oil phase, which is heated and uniformly dissolved, is gradually added and emulsified with a homomixer. Subsequently, it cooled with the heat exchanger and the target skin care emulsion was obtained.

Claims (2)

CE formation / maturation that promotes the formation and / or maturation of a cornified envelope (corneal thickening membrane; hereinafter abbreviated as CE) comprising a pyrrolidone derivative represented by the following general formula (1) and / or a salt thereof: Accelerating agent.

(In the general formula (1), R is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms having 0 to 3 hydroxyl groups, or 3 to 3 carbon atoms having 0 to 5 hydroxy groups. 7 represents a cycloalkyl group.)   The CE formation / maturation promoter for promoting the formation and / or maturation of CE according to claim 1, wherein R is 2-hydroxyethyl group in the general formula (1) according to claim 1.