JP2009001502A5 - - Google Patents

Description

Japanese Patent Laid-Open No. 08-165231 Japanese Patent Laid-Open No. 08-208424 Table 01/072265 Japanese Patent Laid-Open No. 11-12122 WO06 / 132033 JP 2006-335651 A Special table 2003-508486 gazette

In view of such a situation, the present inventors have made intensive research efforts in search of a technique for improving formulation blendability and versatility in an external preparation for skin containing ursolic acid or a derivative thereof. As a result, 1) α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine and / or a salt thereof, and 2) ceramide and / or an analog thereof are selected. 2 or more , 3) one or more selected from glycerin fatty acid ester, polyglycerin fatty acid ester and pyroglutamic acid glycerin fatty acid ester, and 4) selected from ursolic acid, ursolic acid derivatives and salts thereof Forming vesicles using one or two or more of them, and adding them to the external preparation for skin remarkably improves the formulation stability of ursolic acid or its derivatives. It found that the allowed to above, has led to the completion of the invention. That is, the present invention is as follows.
<1> 1) alpha, .epsilon.-bis (γ-N- (10~30 carbon atoms) acyl Guru Tamil) lysine and / or a salt thereof, 2) one to be selected from ceramides and / or its analogs 2 or more , 3) one or more selected from glycerin fatty acid ester, polyglycerin fatty acid ester and pyroglutamic acid glycerin fatty acid ester, and 4) selected from ursolic acid, ursolic acid derivatives and salts thereof A vesicle containing one or more kinds.
<2> The vesicle according to <1>, wherein the acyl group in the α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine is a lauroyl group.
<3> The vesicle according to <1> or <2>, wherein the ceramide and / or derivative thereof is ceramide type II or ceramide type III.
<4> One or more selected from the above glycerin fatty acid ester, polyglycerin fatty acid ester and pyroglutamic acid glycerin fatty acid ester are diglycerin monooleate, diglycerin monoisostearate, decaglycerin monooleate, decaglycerin. <1>-<3> The vesicle according to any one of <1> to <3>, which is one or more selected from monoisostearate, decaglycerin pentaoleate and decaglycerin pentaisostearate.
<5> The ursolic acid derivative is a hydrocarbon ester having 1 to 20 carbon atoms of ursolic acid or a phosphoric acid ester of ursolic acid, according to any one of <1> to <4>. Vesicles.
< 6 > In a form containing the vesicle according to any one of <1> to <5>, 1) α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine and / or 1 ) or 2 or more kinds selected from the salt thereof, 2) ceramide and / or an analog thereof, and 3) one or more kinds selected from glycerin fatty acid ester, polyglycerin fatty acid ester and pyroglutamic acid glycerin fatty acid ester and two or more, 4) ursolic acid, intradermal Hadagaiyo agent you characterized by containing one or is a more selected from ursolic acid derivatives and salts thereof.

式１（但し、式中Ｒ ₁ 、Ｒ ₂ はそれぞれ独立に炭素数１０〜３０のアシル基を表す。）

Formula 1 (However, R < ₁ >, R < ₂ > represents a C10-C30 acyl group each independently.)

(2) vesicle ceramide present invention is an essential component of the vesicle of the present invention is characterized by containing a ceramide as an essential component. As ceramide, it is known that there are usually seven types of type 1 to type 7, and any of them can be used. Among them, type 2 is particularly preferable, and N-stearoyl dihydroxysphingosine is particularly preferable. Such ceramides have commercial products, and such commercial products can be purchased and used. Among such commercial products, as the good better castings of the type 1, N-(27- octadecanoyloxy - Heputakosanoiru -) - phytosphingosine as a component, "Ceramide I" (Cosmo Pharm Ltd. ), “Ceramide TIC-001” (manufactured by Takasago Kagaku Kogyo Co., Ltd.), which is composed of N-stearoyl dihydroxysphingosine, which is type 2, and “Ceramide III,” which is composed of N-stearoylphytosphingosine, which is type 3 "Ceramide IIIA" (manufactured by Farm), type 3 N-linoleoyl phytosphingosine (Cosmo Farm), type 3 "Ceramide IIIB" (component) N-oleoyl phytosphingosine Cosmo Farm), type 6 N-2-hydroxystearoylphytosphingosine, "Cerami De VI "(manufactured by Cosmo Farm) and the like can be preferably exemplified. These can contain only the seed | species, and can also be made to contain in combination of 2 or more type . In the vesicle of the present invention, such a component has an action of reinforcing the vesicle structure produced by the α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine. In order to exhibit such an effect, it is preferable to contain 1% by mass, more preferably 5% by mass, and 50% by mass as an upper limit, and more preferably 10% by mass with respect to the total amount of vesicles. Even if there are too many such components, there may be cases where the above-mentioned effect is not achieved.

セラミドタイプ１
（Ｒ ₁ アルキル基乃至はアルケニル基を表し、Ｒ ₂ はリノレオイルオキシアルキル基を表す。）
セラミドタイプ２
（Ｒ ₁ 、Ｒ ₂ はそれぞれ独立に、アルキル基乃至はアルケニル基を表す。）

Ceramide type 1
(R ₁ represents an alkyl group or an alkenyl group, and R ₂ represents a linoleoyloxyalkyl group.)
Ceramide type 2
(R ₁ and R ₂ each independently represents an alkyl group or an alkenyl group.)

セラミドタイプ３
（Ｒ ₁ 、Ｒ ₂ はそれぞれ独立に、アルキル基を表す。）

Ceramide type 3
(R ₁ and R ₂ each independently represents an alkyl group.)

セラミドタイプ４
（Ｒ ₁ アルキル基を表し、Ｒ ₂ はリノレオイルオキシアルキル基を表す。）

Ceramide type 4
(R ₁ represents an alkyl group, and R ₂ represents a linoleoyloxyalkyl group.)

セラミドタイプ５
（Ｒ ₁ 、Ｒ ₂ はそれぞれ独立にアルキル基を表す。）

Ceramide type 5
(R ₁ and R ₂ each independently represents an alkyl group.)

セラミドタイプ６
（Ｒ ₁ 、Ｒ ₂ はそれぞれ独立にアルキル基を表し、Ｒ ₃ は水素原子乃至はアルキル基を表す。）

Ceramide type 6
(R ₁ and R ₂ each independently represents an alkyl group, and R ₃ represents a hydrogen atom or an alkyl group.)

セラミドタイプ７
（Ｒ ₁ 、Ｒ ₂ はそれぞれ独立にアルキル基を表す。）

Ceramide type 7
(R ₁ and R ₂ each independently represents an alkyl group.)

式２
（但し、式中Ｒ ₁ は炭素数１０〜２６の炭化水素基を表し、Ｒ ₂ は炭素数９〜２５の炭化水素基を表し、Ｘは−（ＣＨ ₂ ）ｎ−で表される基において、ｎが２〜６のものを表す。）

Formula 2
(In the formula, R ₁ represents a hydrocarbon group having 10 to 26 carbon atoms, R ₂ represents a hydrocarbon group having 9 to 25 carbon atoms, and X represents a group represented by — (CH ₂ ) n—). , N represents 2-6.)

式３
（式中、Ｒ ₁ ’及びＲ ₂ ’は同一又は異なって炭素数１〜４０のヒドロキシル化されていてもよい炭化水素基を示し、Ｒ ₃ は炭素数１〜６の直鎖若しくは分岐鎖のアルキレン基又は単結合を示し、Ｒ ₄ は水素原子、炭素数１〜１２の直鎖若しくは分岐鎖のアルコキシ基又は２，３−ジヒドロキシプロピルオキシ基を示す。ただし、Ｒ ₃ が単結合のときはＲ ₄ は水素原子である。）

Formula 3
(In the formula, R ₁ ′ and R ₂ ′ are the same or different and each represent a hydrocarbon group having 1 to 40 carbon atoms which may be hydroxylated, and R ₃ is a linear or branched chain having 1 to 6 carbon atoms. Represents an alkylene group or a single bond, and R ₄ represents a hydrogen atom, a linear or branched alkoxy group having 1 to 12 carbon atoms or a 2,3-dihydroxypropyloxy group, provided that when R ₃ is a single bond, R ₄ is a hydrogen atom.)

(4) Ursolic acids as essential components of the vesicle of the present invention The vesicle of the present invention is characterized by containing one or more selected from ursolic acid, ursolic acid derivatives and salts thereof. Preferred examples of the ursolic acid derivative include ursolic acid hydrocarbon group ester having 1 to 20 carbon atoms, ursolic acid phosphate ester, and the like. As the hydrocarbon group ester having 1 to 20 carbon atoms,
Aromatic rings such as methyl esters, ethyl esters, hexyl esters, cyclohexyl esters, octyl esters, isooctyl esters, lauryl esters, cetyl esters, stearyl esters, isostearyl esters, oleyl esters, benzyl esters, phenethyl esters, etc. Preferred examples include hydrocarbon group esters. Such components can be derived from ursolic acid according to conventional methods. In the case of a hydrocarbon group ester, ursolic acid is converted to a sodium salt with sodium hydride or the like, and a halogenated hydrocarbon obtained by reacting thalyl chloride with alcohol is added thereto to react. The reaction may be performed at room temperature or under reflux conditions for 1 to 12 hours. The phosphate ester can be obtained by reacting dimethyl-N, N-diethyl phosphoramidate with ursolic acid to form ursolic acid methyl phosphate, which is demethylated with bromotrimethylsilane or the like. Such a component can be reacted with an alkali to form a salt and contained in the form of a salt. These salts can be used without particular limitation as long as they are used in skin external preparations, for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts. Preferred examples include organic amine salts such as ammonium salt, triethylamine salt, triethanolamine salt, and monoethanolamine salt, and basic amino acid salts such as lysine salt and alginate. Such component is preferably contained in the vesicle in an amount of 0.1 to 30% by mass, more preferably 1 to 10% by mass.

The external preparation for skin of the present invention can contain, in addition to such components, optional components that are usually used in external preparations for skin. Such optional ingredients include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, hydrogenated coconut oil Oil, wax, oils such as beeswax, owl, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax; liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, petrolatum , Hydrocarbons such as microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol, isostearyl Higher alcohols such as alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebacate, cetyl lactate, malic acid Diisostearyl, di-2-ethylhexanoic acid ethylene glycol, dicaprate neopentyl glycol, di-2-heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane, tri Synthetic ester oils such as trimethylolpropane isostearate and pentane erythritol tetra-2-ethylhexanoate; dimethylpolysiloxane, methylphenylpoly Linear polysiloxanes such as oxane and diphenylpolysiloxane; cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecamethylcyclohexanesiloxane; amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane, Oil agents such as silicone oils such as modified polysiloxanes such as fluorine-modified polysiloxanes; Anionic surfactants such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine ether of alkyl sulfates; Cationic surfactants such as stearyltrimethylammonium, benzalkonium chloride, laurylamine oxide; imidazoline-based amphoteric surfactants (2-cocoyl-2-imida Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), and amphoteric surfactants such as acylmethyltaurine; sorbitan fatty acid esters (sorbitan) Monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (eg, glyceryl monostearate), propylene glycol fatty acid esters (eg, propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ethers, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid ester Tells (POE-glycerol monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl) Ethers, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), Nonionic surfactants such as sucrose fatty acid ester and alkyl glucoside; polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene Polyhydric alcohols such as recall, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, 1,2-octanediol; sodium pyrrolidonecarboxylate Moisturizing ingredients such as lactic acid and sodium lactate; powders such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, barium sulfate, etc. whose surface may be treated Body , surface may be treated, bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide inorganic pigments , surface may be treated, mica titanium , Sakanarinhaku, pearl agent such as bismuth oxychloride, good red No. 202 be laked red 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1 Organic dyes such as green 201, purple 201 and red 204 , polyethylene powder, polymethyl methacrylate, nylon powder, organic powders such as organopolysiloxane elastomer , paraaminobenzoic acid UV absorber , anthranilic acid UV absorbers , salicylic acid UV absorbers , cinnamic acid UV absorbers , benzophenone UV absorbers , sugar UV absorbers , 2- (2'-hydroxy-5'-t-octylphenyl) benzotriazole, 4 - methoxy-4'-t-butyl dibenzoyl-UV absorbing agents such as methane, ethanol, lower alcohol such as isopropanol S, vitamin A or its derivatives, vitamin B ₆ hydrochloride, vitamin B ₆ tripalmitate, vitamin B ₆ dioctanoate, vitamin B ₂ or derivatives thereof, vitamin B _12, vitamin B such as vitamin B ₁₅ or a derivative thereof, alpha - tocopherol, beta-tocopherol, .gamma.-tocopherol, vitamin E such as vitamin E acetate, vitamin D, vitamin H, pantothenic acid, pantethine, vitamins pyrroloquinoline quinone such like, such as antibacterial agents such as phenoxyethanol is preferably exemplified it can.

<Test Example 2>
Using emulsion 1, emulsion 2, comparative example 4, comparative example 5 and comparative example 6 as specimens, 1% sodium lauryl sulfate aqueous solution was previously occluded for 24 hours to increase transepidermal water loss (TEWL), The specimen was occluded for 6 hours, and 30 minutes after removal of the adhesive bandage, TEWL was measured using “Tevameter” (manufactured by Integral). As a control, water was attached. The results are shown in Table 5. Than this, by making the vesicle dispersion, it can be seen that more excellent TEWL-suppressing effect is observed. Even if vesicles are not formed, these components improve the dermis reachability of ursolic acid in a system containing “Perisea L-30”, “Ceramide TIC-001”, and “Diglycerin monooleate”. It has also been found that TEWL improves. In addition, it was confirmed that “Perisea L-30” itself has an action of suppressing TEWL.

<Reference example>
A mixture of ursolic acid (48.1 g, 0.105 mol), dimethyl-N, N-diethyl phosphoramidate (Dimethyl N, N-diethylphosphoramidate; 34.82 g, 0.211 mol), dry tetrahydrofuran (1250 ml) was added at 35 ° C. After heating to a clear solution, 1-H tetrazole (44.25 g, 0.632 mol) was added at once at an internal temperature of 27 ° C., and the mixture was stirred at room temperature (22 ° C.) for 1 hour. After confirming the formation of dimethyl phosphite by TLC, the reaction solution was cooled with acetone / dry ice, and 70% t-butyl hydroperoxide aqueous solution (84 mL, 0.607 mol) was added dropwise at −20 ° C. The temperature was gradually returned to room temperature except for the cooling bath, and disappearance of dimethyl phosphite and formation of dimethyl phosphate were confirmed by TLC, and then the reaction was stopped at 0 ° C. with 10% aqueous sodium bisulfite solution (300 ml). Ethyl acetate (1250 mL) was added to the reaction solution, and the organic layer was separated. The organic layer was washed successively with 10% aqueous sodium hydrogen sulfite solution (100 ml × 3), 5% aqueous sodium hydrogen carbonate solution (200 ml × 3) and saturated brine, and then dried over anhydrous magnesium sulfate. Silica gel (400 mL) was added to the organic layer and concentrated to dryness under reduced pressure. Silica gel (400 mL) was filled with hexane , the adsorbed silica gel was charged with hexane, and then developed with hexane / ethyl acetate (2: 1). The fraction with a single composition was concentrated to obtain 35 g of the title compound as a gel powder. As for this thing, absorption of the dichloromethane used for washing with ethyl acetate by NMR was recognized. Moreover, 6 g was obtained as a fraction containing impurities slightly. Ursolic acid 3-methyl phosphate (35 g 62 mmol) synthesized in this way was dissolved in dry dichloromethane (350 ml), and bromotrimethylsilane (25 mL, 186 mmol) was added under an argon stream at room temperature. The reaction was carried out for 1 hour. After confirming TLC, the solution was concentrated under reduced pressure, and the residue was dissolved and concentrated in again dried toluene (200 ml × 2) to completely remove excess bromotrimethylsilane. The concentrate 95% methanol (300 mL) was added and dissolved, and the mixture was stirred at room temperature for 1 hour to precipitate crystals. After concentrating under reduced pressure as it was, it was dried overnight under reduced pressure over anhydrous phosphoric acid at 50 ° C. to obtain 23.5 g of ursolic acid phosphate.
¹ H-NMR (ppm): 5.23 (m, 1H), 3.87 (m, 1H), 2.20 (d, 1H), 2.05-1.25 (m, 25H), 12 (s, 3H), 1.02 (s, 3H), 0.99 (s, 3H), 0.97 (d, 3H), 0.87 (d, 3H), 0.85 (s, 3H) )
Mass: 535 (M ⁺ )
IR (cm ⁻¹ ): 2948, 1694, 1456, 1378, 1028, 661, 566

Claims (6)

1) One or more selected from α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine and / or a salt thereof, and 2) ceramide and / or an analog thereof And 3) one or more selected from glycerin fatty acid esters, polyglycerin fatty acid esters and pyroglutamic acid glycerin fatty acid esters, and 4) one or more selected from ursolic acid, ursolic acid derivatives and salts thereof. Is a vesicle containing two or more. The vesicle according to claim 1, wherein an acyl group in the α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine is a lauroyl group. The vesicle according to claim 1 or 2, wherein the ceramide and / or its derivative is ceramide type II or ceramide type III. One or more selected from the glycerin fatty acid ester, polyglycerin fatty acid ester, and pyroglutamic acid glycerin fatty acid ester are diglycerin monooleate, diglycerin monoisostearate, decaglycerin monooleate, decaglycerin monoisostearate. The vesicle according to any one of claims 1 to 3, wherein the vesicle is one or more selected from rate, decaglycerin pentaoleate and decaglycerin pentaisostearate. The vesicle according to any one of claims 1 to 4, wherein the derivative of ursolic acid is a C1-C20 hydrocarbon group ester of ursolic acid or a phosphoric acid ester of ursolic acid. A form containing the vesicle according to any one of claims 1 to 5, 1) α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine and / or a salt thereof, and 2 1) one or more selected from ceramide and / or its analogs, and 3) one or more selected from glycerin fatty acid ester, polyglycerin fatty acid ester and pyroglutamic acid glycerin fatty acid ester, 4) ursolic acid, intradermal Hadagaiyo agent you characterized by containing one or is a more selected from ursolic acid derivatives and salts thereof.