JP2009001502A - Vesicle and external preparation for skin containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a technique for improving pharmaceutical compatibility and generality in an external preparation for skin, containing ursolic acid to its derivative. <P>SOLUTION: This external preparation for the skin, such as a cosmetic, comprises (1) an α,ε-bis(γ-N-(10-30C) acylglutamyl)lysine and/or its salt, (2) ceramide and/or its analogue, (3) one or more compounds selected from glyceryl fatty acid esters, polyglyceryl fatty acid esters, and pyroglutamic acid glyceryl fatty acids, and (4) one or more compounds selected from ursolic acid, ursolic acid derivatives, and their salts incorporated in a vesicle to be formulated in a cosmetic or the like. The acyl group in the α,ε-bis(γ-N-(10-30C) acylglutamyl)lysine is preferably lauroyl group, and the ceramide and/or its derivative is preferably ceramide type II or ceramide type III. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a vesicle suitable for inclusion in an external preparation for skin, and an external preparation for skin containing the vesicle.

  Ursolic acid is a kind of triterpenic acid, and it is known to have various actions suitable as cosmetics such as an antioxidant action, an anti-inflammatory action, and a melanin production inhibitory action (for example, Patent Document 1, Patent Document 2, (See Patent Document 3 and Patent Document 4). However, due to the problem of compatibility with cosmetic ingredients, depending on the type of dosage form, in some cases, an insoluble matter is precipitated during long-term storage. In view of such a situation, for the purpose of improving the compatibility with cosmetic raw materials, a technique leading to a derivative such as a phosphate ester has been studied, and the solubility has been improved by such derivatization (for example, patents) Unfortunately, the current situation is not enough.

  Among the means for improving the formulation of ursolic acid, as a preparation-side approach, for example, a technique using a specially-shaped liposome, particularly a liposome prepared with a ceramide having a pentadecerni group has been developed (for example, Since Patent Document 6 and Patent Document 7) are special liposomes using a special ceramide, there has been a problem with versatility. That is, it can be said that a technique for improving formulation blendability and versatility in a skin external preparation containing ursolic acid has been desired.

Japanese Patent Laid-Open No. 08-165231 Japanese Patent Laid-Open No. 08-201424 Table 01/072265 Japanese Patent Laid-Open No. 11-12122 WO06 / 132033 JP 2006-335651 A Special table 2003-508486 gazette

  The present invention has been made under such circumstances, and an object of the present invention is to provide a technique for improving formulation blendability and versatility in an external preparation for skin containing ursolic acid or a derivative thereof. To do.

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-C30) acylglutamyl) lysine and / or a salt thereof, 2) ceramide and / or an analog thereof, and 3) a glycerin fatty acid ester, 1 type or 2 or more types selected from polyglycerin fatty acid ester and pyroglutamic acid glycerin fatty acid ester, and 4) 1 type or 2 or more types selected from ursolic acid, ursolic acid derivatives and their salts The present invention has found that the formation stability of ursolic acid or its derivatives can be remarkably improved by forming a vesicle and incorporating it into an external preparation for skin. This has led to the completion. That is, the present invention is as follows.
<1> 1) α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine and / or a salt thereof, 2) ceramide and / or an analog thereof, and 3) a glycerin fatty acid ester, 1 type or 2 or more types selected from polyglycerol fatty acid ester and pyroglutamic acid glycerol fatty acid ester, and 4) 1 type or 2 or more types selected from ursolic acid, ursolic acid derivatives, and salts thereof Vesicle.
<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 a 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> 1) α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine and / or a salt thereof, 2) ceramide and / or an analog thereof, and 3) a glycerin fatty acid ester, 1 type or 2 or more types selected from polyglycerol fatty acid ester and pyroglutamic acid glycerol fatty acid ester, and 4) 1 type or 2 or more types selected from ursolic acid, ursolic acid derivatives, and salts thereof Skin external preparation.
<7> 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 Salt thereof, 2) ceramide and / or its analog, 3) one or more selected from glycerin fatty acid ester, polyglycerin fatty acid ester and pyroglutamic acid glycerin fatty acid ester, and 4) ursolic acid and ursol The skin external preparation according to <6>, comprising one or more selected from acid derivatives and salts thereof.

  ADVANTAGE OF THE INVENTION According to this invention, in the skin external preparation containing a ursolic acid or its derivative (s), the technique which improves formulation formulation and versatility can be provided.

(1) α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine, which is an essential component of the vesicle of the present invention, α, ε-bis (γ-N) -(C10-C30) acyl glutamyl) lysine is contained as an essential component. Such a component may contain a free form or may be contained in the form of a salt. These salts can be used without any 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. The acyl group has 10 to 30 carbon atoms. Such an acyl group may be linear, branched or cyclic, and may be saturated or unsaturated. good. Specific examples of the acyl group include, for example, a decanoyl group, a lauroyl group, a myristoyl group, a palmitoyl group, a stearoyl group, a behenoyl group, an isostearoyl group, an oleoyl group, a linoloyl group, and the like. Particularly preferred. Α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine has two acyl groups, and the two acyl groups may be the same or different. May be. α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine can be produced, for example, by the following procedure. That is, glutamic acid is reacted with acyl chloride in the presence of an alkali such as triethylamine to obtain N-acyl glutamic acid. Thereafter, it can be produced by condensing lysine at a molar ratio of 2: 1 in the presence of a peptide synthesis reagent such as DCC. The reaction product thus obtained can be purified by silica gel column chromatography or the like. Preferred examples of the elution solvent for silica gel column chromatography include a chloroform-methanol mixed solution system. The structure of such α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine is shown in Formula 1. In addition, as a salt of such a component, any salt used in an external preparation for skin can be used without any particular limitation. For example, alkali metal salts such as sodium salt and potassium salt, alkaline earth such as calcium salt and magnesium salt, etc. Preferred examples include organic metal salts such as metal salts, ammonium salts, triethylamine salts, triethanolamine salts and monoethanolamine salts, and basic amino acid salts such as lysine salts and alginates.

式１（但し、式中Ｒ１、Ｒ２はそれぞれ独立に炭素数１０〜３０のアシル基を表す。）

Formula 1 (wherein R 1 and R 2 each independently represents an acyl group having 10 to 30 carbon atoms)

  Α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine can be produced and used by the above method, but diα, ε-bis (γ-N- (carbon number). 10-30) Acylglutamyl) lysine already exists in the market, and such a commercial product can be purchased and used. As such a commercially available product, “Perisea L-30” (manufactured by Asahi Kasei Corporation; α, ε-bis (γ-N-lauroylglutamyl) lysine) can be preferably exemplified. The α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine thus obtained has the property of easily forming a bimolecular film, and this action makes other essential elements described below. Forms vesicles with excellent stability together with ingredients. Since such vesicles have physical properties similar to the membrane structure of epidermal cells, they are excellent in skin permeability. In addition, it is excellent in the action of retaining the active ingredient between the lipid bilayer membranes. This is because the lipid bilayer itself has amphipathic properties. In order to exert such an action, the vesicle is composed of one or more selected from α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine in a total amount. It is preferable to contain 1% by mass, more preferably 5% by mass, and 50% by mass as the upper limit, and more preferably 10% by mass with respect to the total amount. This is because there may be a case where a stable vesicle is not formed when there are too many or too few components.

(2) Ceramide as an essential component of the vesicle of the present invention The vesicle of the present invention is characterized by containing 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 a good example, "Ceramide I" (manufactured by Cosmo Farm Co., Ltd.), which is type 1, N- (27-octadecanoyloxy-heptacosanoyl-)-phytosphingosine ), “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-stearoyl phytosphingosine, which is type 3 (Cosmo) "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, “Cer Preferred examples include “amide VI” (manufactured by Cosmo Farm). These can contain only the seed | species, and can also be made to contain in combination of 2 or more type. These can contain only the seed | species, and can also contain it 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
（Ｒ１アルキル基乃至はアルケニル基を表し、Ｒ２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
（Ｒ１、Ｒ２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
(R1 represents an alkyl group or an alkenyl group, and R2 represents a linoleoyloxyalkyl group.)
Ceramide type 2
(R1 and R2 each independently represents an alkyl group or an alkenyl group.)

セラミドタイプ３
（Ｒ１、Ｒ２はそれぞれ独立に、アルキル基を表す。）

Ceramide type 3
(R1 and R2 each independently represents an alkyl group.)

セラミドタイプ４
（Ｒ１アルキル基を表し、Ｒ２はリノレオイルオキシアルキル基を表す。）

Ceramide type 4
(R1 represents an alkyl group, and R2 represents a linoleoyloxyalkyl group.)

セラミドタイプ５
（Ｒ１、Ｒ２はそれぞれ独立にアルキル基を表す。）

Ceramide type 5
(R1 and R2 each independently represents an alkyl group.)

セラミドタイプ６
（Ｒ１、Ｒ２はそれぞれ独立にアルキル基を表し、Ｒ３は水素原子乃至はアルキル基を表す。）

Ceramide type 6
(R1 and R2 each independently represents an alkyl group, and R3 represents a hydrogen atom or an alkyl group.)

セラミドタイプ７
（Ｒ１、Ｒ２はそれぞれ独立にアルキル基を表す。）

Ceramide type 7
(R1 and R2 each independently represents an alkyl group.)

  In the vesicle of the present invention, in addition to the ceramide, a component having a structure close to that of ceramide can be contained as a derivative of ceramide. Examples of such ceramide derivatives include sphingosine, sphingomyelin, sphingosylphosphorylcholine, JP-A-62-228048, JP-A-63-216812, JP-A-63-227513, JP-A-64-29347, Preferred examples include ceramide-like structural materials described in Japanese Utility Model Laid-Open No. 64-31752 and Japanese Patent Laid-Open No. 8-319263. Specific examples of the ceramide-like structural substance include the following components represented by Formula 2 and Formula 3.

式２
（但し、式中Ｒ１は炭素数１０〜２６の炭化水素基を表し、Ｒ２は炭素数９〜２５の炭化水素基を表し、Ｘは−（ＣＨ２）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 —, where n is 2 to 6 are represented.)

式３
（式中、Ｒ１’及びＲ２’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、Ｒ３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、Ｒ４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、Ｒ３が単結合のときはＲ４は水素原子である。）

Formula 3
(Wherein R1 ′ and R2 ′ are the same or different and each represent a hydrocarbon group having 1 to 40 carbon atoms which may be hydroxylated, and R3 represents a linear or branched alkylene group having 1 to 6 carbon atoms, or R4 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 R3 is a single bond, R4 is a hydrogen atom. is there.)

  Such a component represented by Formula 2 or Formula 3 can be produced in accordance with the contents of the patent document.

(3) Polyglycerin fatty acid ester or pyroglutamic acid glycerin fatty acid ester which is an essential component of the vesicle of the present invention The polyglycerin fatty acid ester or pyroglutamic acid glycerin fatty acid ester as an essential component. 2-20 are preferable and, as for the polymerization degree of glycerol in the polyglycerol of the said polyglycerol fatty acid ester, 2-10 are more preferable. The fatty acid residues include lauric acid residues, myristic acid residues, palmitic acid residues, stearic acid residues, behenic acid residues, isostearic acid residues, oleic acid residues, linoleic acid residues, linolenic acid Residues and the like can be suitably exemplified, and oleic acid residues, stearic acid residues or isostearic acid residues are particularly preferable. In such polyglycerin fatty acid ester, the number of fatty acid residues per molecule is preferably more than the number of free hydroxyl groups. Specific examples include diglycerin monooleate, diglycerin monolaurate, diglycerin. Monostearate, diglycerol monoisostearate, triglycerol dilaurate, triglycerol distearate, triglycerol dioleate, triglycerol diisostearate, pentaglycerol trilaurate, pentaglycerol tristearate Esters, pentaglycerin trioleate, pentaglycerin triisostearate, heptaglycerin tetralaurate, heptaglycerin ester Rastearic acid ester, heptaglycerin tetraoleate, heptaglycerin tetraisostearate, decaglycerin pentalaurate, decaglycerin pentastearate, decaglycerin pentaoleate, decaglycerin pentaisostearate Can be illustrated. Of course, those having a large number of hydroxyl groups such as decaglycerin monolaurate, decaglycerin monostearate, decaglycerin monoisostearate, decaglycerin monooleate can also be used because they are effective. Examples of the component that exhibits the same effect include pyroglutamic acid glycerin fatty acid esters such as pyroglutamic acid glycerin stearate ester and pyroglutamic acid glycerin oleate ester. Such components can also be used in the vesicles of the present invention.

  In the present invention, ceramides, α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine are stable for the first time in the presence of the polyglycerol fatty acid ester or pyroglutamic acid glycerol fatty acid ester. Form vesicles. In order to form such a stable vesicle, the total amount of polyglycerol fatty acid ester or pyroglutamic acid glycerin fatty acid ester is preferably 5 to 30% by mass, and preferably 10 to 25% by mass based on the total amount of vesicles. It is more preferable to contain. The ratio of the total mass of the polyglycerol fatty acid ester or pyroglutamic acid glycerin fatty acid ester to the mass of the α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine is as follows. 5: 1 to 1: 1 is preferable, and 4: 1 to 2: 1 is more preferable. The interaction between the two regulates the orientation of the lipid biphasic phase. In the bilayer membrane thus arranged, the active ingredient can be held between the bilayer membranes. Preferred examples of the active ingredient include those selected from ursolic acid, ursolic acid derivatives and salts thereof shown below. Of course, in addition to ursolic acid and its derivative, the active ingredient used with skin external preparations, such as cosmetics, can also be contained in addition to ursolic acid.

(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. Preferable examples of the ursolic acid derivative include ursolic acid hydrocarbon ester having 1 to 20 carbon atoms or ursolic acid phosphate ester. Examples of the hydrocarbon ester having 1 to 20 carbon atoms include fats such as methyl ester, ethyl ester, hexyl ester, cyclohexyl ester, octyl ester, isooctyl ester, lauryl ester, cetyl ester, stearyl ester, isostearyl ester, and oleyl ester. Preferred examples include hydrocarbon group esters having aromatic rings such as aromatic esters, benzyl esters, and phenethyl esters. Such components can be derived from ursolic acid according to conventional methods. In the case of a hydrocarbon ester, ursolic acid may be converted to a sodium salt with sodium hydride or the like, and a halogenated hydrocarbon obtained by reacting thalyl chloride or the like with alcohol may be added 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 components can be contained in the form of a salt by reacting with an alkali to form a salt. These salts can be used without any 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 a component is preferably contained in the vesicle in an amount of 0.1 to 30% by mass, and more preferably 1 to 10% by mass.

(5) Vesicle of the present invention The vesicle of the present invention contains the essential component. In addition to the above components, the vesicle of the present invention can contain an active ingredient having a preferable action on the skin together with ursolic acids. Specific examples of the active ingredient include, for example, an extract of a plant belonging to the genus Ranunculaceae, an extract of a mandarin family, an extract of a red algae, an extract of a plant of the genus Dokudami, a rose of the family Lamiaceae An extract of Marie, an extract of birch, an extract of a plant of the genus Achillea family such as Achillea millefolium, an extract of a plant of the genus Coleoptera, an extract of a plant of the genus Hypericaceae such as Hypericum perforatum, Natural protein hydrolysates, such as extracts from the genus Clevisaceae, extracts from the walnut family, citrus genus, soybean protein hydrolyzate, silk protein hydrolyzate, marine collagen hydrolyzate Decomposed product or acylated product, oleanolic acid or derivative thereof, betulin, betulinic acid or derivative thereof, pantetins Phosphonic acid or a derivative thereof, glycyrrhetinic acid or a derivative thereof, hydroquinone or a glycoside thereof, esculin, esculetin, glabrizine, methoxysalicylic acid, tranexamic acid or a derivative thereof, ascorbic acid or a derivative thereof, L-carnitine, etc. Can be mentioned. Such an active ingredient is, for example, an extract of a plant of the genus Ranunculaceae, an extract of a mandarin family, an extract of a red algae, an extract of a plant of the genus Dokudami, a calcium ion concentration gradient of the epidermis There is an action to adjust the skin barrier function. Rosemary extract is known to have an elastin degradation inhibitory effect. It is known that a birch extract has a Maillard reaction inhibitory effect, a heterogeneity improving effect, and the like. It is known that the action of suppressing the dendritic elongation of melanocytes is found in the extracts of Yarrow and Scarlet. It is known that an extract of clove or triterpenes such as eugenol, oleanolic acid, betulinic acid and betulin has a dermal collagen fiber bundle remodeling action. A protein hydrolyzate is known to have an elastase inhibitory action. Pantethine sulfonic acid or a derivative thereof, and glycyrrhetinic acid or a derivative thereof are known to suppress inflammatory factors. Hydroquinone or its glycoside, esculin, esculetin, glabrizine, methoxysalicylic acid, tranexamic acid or its derivative, ascorbic acid or its derivative erases active oxygen and places oxidative stress in the dermis It is known to have an action of suppressing the above. The content of these active ingredients in the vesicle of the present invention may be a sufficient amount to express the above-mentioned action. For example, each may preferably be 0.1 to 30% by mass with respect to the total amount of vesicle. 10 mass% is more preferable.

  The vesicle of the present invention may contain optional components that are usually used in vesicles and external preparations for skin, in addition to the essential and preferred components. Examples of such optional components include glycerin, diglycerin, dipropylene glycol, 1,3-butanediol, 1,2-pentanediol, isoprene glycol, 1,2-hexanediol, 1,2-octanediol, Polyhydric alcohols such as polyethylene glycol, cyclic alcohols such as cholesterol, campesterol, sitosterol and stigmasteranol, lecithin, hydrogenated lecithin, hydroxylated lecithin, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phos Phospholipids such as fatidylglycerol, fatty acids such as oleic acid, capric acid, caprylic acid, stearic acid, higher alcohols such as cetanol, stearyl alcohol, oleyl alcohol, methylparaben, Chiruparaben, etc. can be preferably exemplified. Among these, those particularly preferably contained are exemplified by cyclic alcohols, particularly plant sterols (phytosterols) such as campesterol, sitosterol, and stigmasterol, and polyhydric alcohols. The content of phytosterol is preferably 2: 1 to 1: 2 with respect to α, ε-bis (γ-N- (10 to 30 carbon atoms) acylglutamyl) lysine. The monohydric alcohol is preferably 5 to 15 times the content of α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine. The vesicle of the present invention can be produced as a vesicle dispersion composition by operating such essential components, preferred components, and optional components according to a conventional method.

(6) External preparation for skin of the present invention The external preparation for skin of the present invention is characterized by containing the vesicle. By containing such vesicles, the active ingredient is delivered to the dermis, and α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine, which is a constituent of vesicles, acts on the dermis, It can improve the properties of the dermis. In order to achieve such an effect, the vesicle is preferably contained in an amount of 0.1 to 10% by mass, more preferably 0.5 to 5% by mass, based on the total amount of the external preparation for skin. If the amount is too small, there may be cases where the active ingredient including α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine does not reach a delivery amount sufficient for effect expression. This is because there are cases where the effect reaches a peak and the degree of freedom of prescription is impaired.

  The skin external preparation of the present invention can be applied without particular limitation as long as it is usually administered externally to the skin, such as cosmetics including quasi-drugs, skin external medicines, skin external goods and the like. Preferred examples can be given. Among these, cosmetics are particularly preferable. This is because, in cosmetics, reachability to the dermis is desired, and there are many active ingredients that are difficult to reach the dermis. Preferred examples of such cosmetics include lotions such as lotions, emulsions, essences, creams, pack cosmetics, facial cleansing cosmetics, cleansing cosmetics and the like. Furthermore, the dosage form is not particularly limited as long as it is known in the cosmetics field, and can be preferably applied to lotion preparations, oil-in-water emulsion preparations, water-in-oil emulsion preparations, composite emulsion emulsion preparations and the like.

  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. Examples of such optional ingredients include 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, and hardened coconut oil. Oil, wax, oil such as beeswax, canola 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, the surface may be treated, inorganic pigments such as bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide; surface may be treated, mica Pearl agents such as titanium, fish phosphorus foil, bismuth oxychloride; red 202 which may be raked, red Color 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 No., green 201, purple 201, red 204, etc .; organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; para-aminobenzoic acid UV absorbers; anthranils Acid UV absorbers; salicylic acid UV absorbers; cinnamic acid UV absorbers; benzophenone UV absorbers; sugar UV absorbers; 2- (2′-hydroxy-5′-t-octylphenyl) benzo Ultraviolet absorbers such as triazole and 4-methoxy-4′-t-butyldibenzoylmethane; lower grades such as ethanol and isopropanol Alcohols; vitamin A or derivatives thereof, vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 or derivatives thereof, vitamin B such as vitamin B12, vitamin B15 or derivatives thereof; α-tocopherol, β- Preferred examples include vitamins such as tocopherol, γ-tocopherol and vitamin E acetate, vitamin D, vitamin D, vitamin H, pantothenic acid, panthetin, pyrroloquinoline quinone and the like; and antibacterial agents such as phenoxyethanol.

  The skin external preparation of this invention can be manufactured by processing the said essential component and arbitrary components in accordance with a conventional method.

  Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to only such examples.

  A vesicle dispersion 1 of the present invention was prepared according to the formulation shown below. That is, the components (a) and (b) were each heated to 70 ° C. and dissolved uniformly, and gradually added to the mixture under stirring to obtain a vesicle dispersion. A portion of this was taken out, weighed, centrifuged, the supernatant discarded, washed twice with water in the same manner, the water removed by drying, weighed, and the vesicle content in the vesicle dispersion was calculated. However, it was 9.3 mass%. Further, in the same procedure, Comparative Example 1 in which “Perisea L-30” was replaced with lecithin, Comparative Example 2 in which “Ceramide TIC-001” was replaced with “Pericea L-30”, and diglycerin monooleate was polyoxyethylene (2) The same procedure was applied to Comparative Example 3 in which oleate was substituted. As a result of observation with a polarizing microscope, it was found that none of Comparative Example 1, Comparative Example 2, and Comparative Example 3 showed the presence of polarized light and formed no vesicle dispersion.

  In accordance with the formulation shown below, a cosmetic, which is an external preparation for skin of the present invention, was produced. That is, the emulsion which is the skin external preparation of this invention was produced according to the prescription shown below. That is, the components (A) were mixed and heated to 80 ° C. On the other hand, each component of (B) was heated to 80 degreeC. The mixture of (B) was added to the mixture of (A) and stirred to emulsify, and further (C) was added to neutralize, and then the mixture was stirred and cooled to 35 ° C. to prepare emulsion 1. In the same manner, Comparative Example 4 in which the vesicle dispersion 1 was replaced with Comparative Example 1, Comparative Example 5 in which Comparative Example 2 was replaced, Comparative Example 6 in which Comparative Example 3 was replaced, and Same as emulsion 1 but not as a vesicle Milky lotion 2 (Table 3) which is an external preparation for skin containing ingredients was also prepared.

<Test Example 1>
Emulsion 1, emulsion 2, comparative example 4, comparative example 5 and comparative example 6 were aged at -10 ° C to 40 ° C (held at -10 ° C for 24 hours-> raised to 40 ° C over 24 hours-> 24 at 40 ° C Time retention → Stored for 6 months in a temperature-variable storage chamber having a temperature drop to -10 ° C over 24 hours), returned to 20 ° C, and examined precipitation of insoluble matter. Precipitation of insoluble matter took 20 mg of sample on a slide glass, and another slide glass was put on this, and the sample was pressed so that the sample spread over the entire slide glass, and the number of objects that could be recognized as a transparent mass or an opaque mass was counted. . Five samples were prepared for each specimen, and this average was taken. The results are shown in Table 4. From this, it was found that the form containing the vesicle of the present invention is excellent in the precipitation suppressing effect.

<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. From this, it can be seen that by using a vesicle dispersion system, a better TEWL suppressing effect is recognized. 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.

  In the same manner as in Example 1, the vesicle dispersion 2 of the present invention was prepared according to the following formulation, and an emulsion 3 containing the vesicle dispersion 2 was produced. In the vesicle dispersion 2, the presence of a lipid bilayer was observed with a polarizing microscope. In the evaluation of Test Example 1, the emulsion 3 showed no precipitate, and in the evaluation of Test Example 2, the TEWL was 13 with respect to the control TEWL 34.

<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 a 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 charged to the sum, and 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

  In the same manner as in Example 1, according to the following formulation, a vesicle dispersion 3 of the present invention was prepared, and an emulsion 4 containing this was produced. In the vesicle dispersion 3, the presence of a lipid bilayer was observed with a polarizing microscope. In the evaluation of Test Example 1, the emulsion 4 showed no precipitate, and in the evaluation of Test Example 2, the TEWL was 14 with respect to the control TEWL 34.

  The present invention can be applied to an external preparation for skin such as cosmetics.

Claims (7)

1) α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine and / or its salt, 2) ceramide and / or its analog, 3) glycerin fatty acid ester, polyglycerin fatty acid A vesicle containing one or more selected from esters and glyceryl fatty acid esters of pyroglutamic acid, and 4) one or more selected from ursolic acid, ursolic acid derivatives and salts thereof. 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 derivative thereof 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, which is one or more selected from a rate, decaglycerin pentaoleate and decaglycerin pentaisostearate. The vesicle according to any one of claims 1 to 4, wherein 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. 1) α, ε-bis (γ-N- (C10-30) acylglutamyl) lysine and / or its salt, 2) ceramide and / or its analog, 3) glycerin fatty acid ester, polyglycerin fatty acid A skin external preparation containing one or more selected from esters and glycerol fatty acid esters of pyroglutamic acid, and 4) one or more selected from ursolic acid, ursolic acid derivatives and salts thereof . 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 ) Ceramide and / or an analog thereof; 3) one or more selected from glycerin fatty acid ester, polyglycerin fatty acid ester and pyroglutamic acid glycerin fatty acid ester; and 4) ursolic acid, ursolic acid derivatives and these The skin external preparation according to claim 6, comprising one or more selected from salts.