WO2003011245A1

WO2003011245A1 - Composition based on lipid lamellar vesicles incorporating at least a dhea compound

Info

Publication number: WO2003011245A1
Application number: PCT/FR2002/002571
Authority: WO
Inventors: Jean-Thierry Simonnet
Original assignee: L'oreal
Priority date: 2001-07-27
Filing date: 2002-07-18
Publication date: 2003-02-13
Also published as: FR2827765B1; FR2827765A1

Abstract

The invention concerns a composition comprising: a dispersion, in an external aqueous phase, of vesicles consisting of lipid lamellar phases separated from one another by hydrophilic layers and encapsulating a hydrophilic core, said lamellar phases comprising at least an amphiphilic lipid; and at least a DHEA compound contained, in solubilized form in free molecular state, in particular non-complexed, in the hydrophilic layers and/or in the hydrophilic core; and at least a solubilizer of said DHEA compound (preferably a glycol optionally combined with water and/or glycerine). The incorporation of the DHEA compound in the hydrophilic core of the vesicles enable to prevent its recrystallization in the external aqueous phase and to improve its bioavailability.

Description

Composition based on lipid lamellar vesicles incorporating at least one compound based on DHEA

The invention relates to a composition comprising vesicles formed from lipid lamellar phases containing at least one DHEA-based compound. It also relates to a process for the preparation of this composition. By compound based on DHEA is meant within the meaning of the invention, DHEA itself, the precursors of DHEA or the derivatives of DHEA.

There are many patents describing cosmetic or dermatological compositions for topical application comprising compounds based on DHEA. For example, US patent US-5989568 describes the use of dehydroepi- androsterone sulfate in a topical composition for treating wrinkles, fine lines and / or combating sagging skin and / or subcutaneous and / or reviving the radiance of the skin.

Administered topically or orally, DHEA or dehydroepi-androsterone is known for its ability to promote keratinization of the epidermis (JP-07 196 467) and to treat dry skin by increasing the endogenous production and the secretion of sebum and thereby strengthening the barrier effect of the skin (US-4,496,556). The use of DHEA to remedy atrophy of the dermis by inhibiting the loss of collagen and connective tissue has also been described in patent US Pat. No. 5,843,932. It has also been described in US Pat. No. 5,736,537 the oral use of DHEA esters, in particular DHEA salicylate, for regulating the atrophy of the skin due to thinning or general degradation of the dermis. Finally, the Applicant has demonstrated the ability of DHEA to combat the papery appearance of the skin (FR 00/00349), and to modulate the pigmentation of the skin and hair (FR 99/12773). These properties of DHEA make it a candidate of choice as an anti-aging active.

Among the metabolites of DHEA, particular attention has been paid in recent years to 7α-hydroxy DHEA. It has indeed been shown that this metabolite, which does not have the hormonal activity of DHEA, makes it possible to increase the proliferation of fibroblasts and the viability of human keratinocytes and has anti-radical effects (WO 98/40074). It has also been demonstrated in rats (WO 00/28996) that 7α-hydroxy DHEA increases the thickness of the dermis and the elastin and collagen content of the skin. It has thus been suggested to use this metabolite of DHEA to prevent and / or treat the harmful effects of UV rays on the skin, fight wrinkles and increase the firmness and tone of the skin.

However, DHEA-based compounds have the disadvantage of being very poorly soluble in cosmetic solvents, and of crystallizing in the presence of an aqueous phase. This results in a more or less significant loss of effectiveness of these compositions depending on the degree of crystallization, which goes against the objective sought.

In addition, DHEA-based compounds have better bioavailability in the skin when they are in solubilized form in cosmetic carriers, and moreover at high rates, than if they are in crystallized form with a bad crystal size. controlled.

By bioavailability is meant, within the meaning of the invention, the penetration of an active ingredient into the skin so that it is biologically available for the living elements of the skin, and in particular the epidermis. Thus, the increase in the bioavailability of an active ingredient has the effect of increasing the active ingredient level which will reach the living epidermis.

It is of course possible to dissolve the DHEA-based compounds, at a temperature of 25 ° C., in certain solvents such as in particular ethanol, pisopropanol, octyldodecanol, capric-caprylic triglycerides, tocopheryl acetate but it it is necessary, for this, to have very high concentrations of solvents to solubilize high levels of compounds based on DHEA. However, these solvents being preferably oily, we will rather seek to limit their level in the final composition to have the most acceptable cosmetic feel possible.

By dissolved form is meant, within the meaning of the invention, a dispersion in a liquid, in the free molecular state, in particular not complexed. No crystallization of the active agent being visible to the naked eye or under cross-polarization optical microscopy.

There therefore remains the need to dissolve the DHEA-based compounds in a physiologically acceptable vehicle.

Now, the Applicant has now discovered that DHEA-based compounds can be introduced in a solubilized form and at high rates, into the internal hydrophilic phase of vesicles formed by lipid layers (whose structure is of the lamellar liquid crystal type) , ie in the hydrophilic heart and / or between the lipid layers of the vesicles. These vesicles can be either niosomes of the type described in application EP-0 582 503, or liposomes of conventional type.

Those skilled in the art are aware of the use of liposomes to encapsulate lipophilic substances in their aqueous core. Thus, international application WO-95/15746 describes liposomes comprising in their aqueous heart at least one complex formed of at least one lipophilic molecule and at least one receptor linked noncovalently to this molecule. The receptors described in this application are all substances capable of forming a complex with the lipophilic molecule, to modify its solubility. The lipophilic molecules described in this application can in particular be chosen from retinoic acid, DHEA, retinol, vitamins D and E, D-tocopherol, chlorambucil, dexamethasone and indomethacin. This application describes in particular liposomes encapsulating in their aqueous core cyclodextrin (or cyclodextrin derivative) / DHEA complexes. These complexes have the disadvantage of being labile and difficult to control.

The subject of the present invention is therefore a composition comprising:

a dispersion, in an external aqueous phase, of vesicles formed by lipidic lamellar phases separated from each other by hydrophilic layers and encapsulating a hydrophilic core, said lamellar phases comprising at least one amphiphilic lipid, and

at least one DHEA-based compound contained, in solubilized form in the free molecular state, in particular not complexed, in the hydrophilic layers and / or in the hydrophilic core, and

- At least one solubilizer of said DHEA-based compound. The incorporation in a solubilized form of said DHEA-based compound in the hydrophilic layers and / or in the hydrophilic core makes it possible to effectively avoid its crystallization in the aqueous phase. In addition, the solubilized form is the most suitable form for obtaining good bioavailability in the living elements of the skin of said DHEA-based compound. A particular aspect of the invention relates to compositions for which the weight ratio between the hydrophilic phase containing said DHEA-based compound and the lipids constituting the vesicles is between 1/100 and 500/100 and preferably between 10/100 and 250/100.

This is thus in the presence of an aqueous dispersion of compound based on DHEA which does not recrystallize over time (at least three days at 25 ° C.), because it is perfectly encapsulated in the heart and between the lamellar layers of the vesicles .

The solubilizers of DHEA-based compounds which can be used according to the invention are generally chosen from glycols, and water-glycol, glycerin-glycol and water-glycerin-glycol mixtures, because they have good solubilization properties of compounds based on DHEA, and help promote the penetration of the active ingredient into the living epidermis while limiting any possible safety problem.

Advantageously, the glycols which can be used according to the invention are chosen from dipropylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol and polyethylene glycol from 4 to 50 ethoxy units.

When glycol is combined with water and / or glycerin to form water-glycol (hydroglycolic solution), glycerin-glycol (glycolic solution) and water-glycerin-glycol mixtures, care must be taken that the ^(or) compound (s) of DHEA, does not crystallize (s) not at room temperature after 24 hours.

Generally, the water activity a _w of the hydrophilic phase encapsulated in the vesicles is preferably less than 0.90 and more preferably less than 0.85.

The water activity a _w of a medium containing water is the ratio of the water vapor pressure of the product "P _H2 o product" and the vapor pressure of pure water "P _H2O pure At the same temperature. It can also be expressed as the ratio of the number of water molecules "N _H20 " to the number of total molecules "N _H20 + N _{dissolved body} ", which takes into account those of the dissolved bodies "N _{dissolved body} ".

It is given by the following formulas:

P _H20 product N _H20 a - * _u w P _H20 pure N _H20 + N _{corpS dlssous}

Different methods can be used to measure water activity a. Most common is the manometric method by which the vapor pressure is directly measured.

Conventionally, a cosmetic or dermatological composition has a water activity of around 0.95 to 0.99. A water activity of less than 0.90 represents a significant decrease.

The DHEA-based compounds which can be used according to the invention are chosen from DHEA itself, DHEA precursors and DHEA derivatives.

As DHEA precursors which can be used according to the invention, mention may be made of its biological precursors which are capable of transforming into DHEA during metabolism, as well as its chemical precursors which can transform into DHEA by exogenous chemical reaction. Examples of biological precursors are Δ5-pregnenolone, 17α-hydroxy pregnenolone and 17α-hydroxy pregnenolone sulfate, without this list being limiting. Examples of chemical precursors are sapogenins and their derivatives, such as diosgenin (or spirost-5-en-3-beta-ol), hecogenin, hecogenin acetate, smilagenin and sarsapogenin, tigogenin , yamogenin, and yuccagenin, as well as the natural extracts containing it, in particular fenugreek and extracts of Dioscorea such as the root of wild yam or Wild Yam, without this list being exhaustive.

As a derivative of DHEA which can be used according to the invention, mention may be made of its metabolic derivatives as well as its chemical derivatives. As metabolic derivatives, there may be mentioned in particular Δ5-androstene-3,17-diol and Δ4-androstene-3,17-dione, as well as 7α-OH DHEA, 7β-OH DHEA, 11α-OH DHEA, and 7-keto-DHEA, without this list being exhaustive. 7α-OH DHEA is preferred for use in the present invention. A process for the preparation of this compound is described in particular in patent applications FR-2 771 105 and WO 94/08588.

As chemical derivatives, mention may in particular be made of DHEA salts, in particular water-soluble salts, such as DHEA sulfate. Mention may also be made of esters, such as the esters of hydroxycarboxylic acids and of DHEA described in particular in US Pat. No. 5,736,537 or the other esters such as salicylate, acetate, valerate (or n-heptanoate) and enanthate of DHEA. Mention may also be made of the DHEA derivatives (DHEA carbamates, DHEA 2-hydroxy malonate esters and DHEA amino acid esters) described in application FR 00/03846 in the name of Applicant. Finally, mention may be made of the 3-alkylesters of 7-keto-DHEA, for example 3-acetoxy-7-keto-DHEA, in particular 3β-acetoxy-7-keto-DHEA. This list is obviously not exhaustive.

Other chemical derivatives of DHEA suitable for carrying out the present invention are the derivatives of formula (1):

(D

in which :

R., and R ₂ are independently chosen from:

• a C 1 -C 4 alkyl group, saturated or unsaturated, linear, branched or cyclic which may optionally contain one or more heteroatoms, and optionally substituted by one or more groups chosen from -OR 'and / or -SR' and / or - COOR 'and / or -NR'R' and / or halogen and / or sulfate and / or phosphate and / or aryl and / or heterocycle, said heterocycle possibly advantageously being chosen from an indole, a pyrimidine, a piperidine, a morpholine, pyran, furan, piperazine, pyridine;

an alkylcarbonyl group, the C _r C ₂₄ alkyl part of which is saturated or unsaturated, linear, branched or cyclic, and optionally substituted by one or more groups chosen from -OR 'and / or -SR' and / or -COOR 'and / or -NR'R 'and / or halogen and / or sulfate and / or phosphate and / or aryl and / or heterocycle, said heterocycle can advantageously be chosen from an indole, a pyrimidine, a piperidine, a morpholine, a pyran, furan, piperazine, pyridine;

an arylcarbonyl group, preferably a phenylcarbonyl, or an arylalkylcarbonyl group, preferably a benzylcarbonyl, optionally substituted by one or more groups -OR 'and / or -SR' and / or -COOR 'and / or -NR'R' and / or halogen and / or aryl and / or heterocycle;

• a group O = P (OH) OR '; a group (O) ₂ SOR ';

a trialkylsilyl group (SiR ' ₃ ) in which the 3 R' groups can be identical or different;

a carbonyloxyalkyl group (R'OCO);

• a carbonylaminealkyle group (R'NHCO);

in which R ′ is chosen from a hydrogen atom, a C 1 -C 4, preferably C 4 -C 6 alkyl group, saturated or unsaturated, linear, branched or cyclic which may optionally contain one or more heteroatoms, optionally functionalized with a or more groups -OR ", -COOR", halogen, -NR "R"; or by an aryl group, preferably a phenyl, optionally functionalized by one or more groups -OR ", -COOR", halogen or -NR "R"; R "representing a hydrogen atom, an alkyl chain, preferably C., - C ₆ , saturated or unsaturated, linear, branched or cyclic, it being understood that in each of the groups -NR'R 'and -NR" R ", the substituents R ', respectively R", are identical or different.

Among the derivatives of formula (1), there may be mentioned in particular the diesters of 7-OH-DHEA and more preferably 3-O-acetyl-7-benzoyloxy-dehydroepiandrosterone which is in particular available from the company GATTEFOSSE under the trade name 3-acetoxy-7-benzoate DHEA.

The compound or compounds based on DHEA can represent from 0.001 to 10% by weight relative to the total weight of the composition. The vesicles according to the invention are formed by, or comprise, from one to twenty five sheets of substantially concentric lamellar phases of bimolecular type. These sheets are obtained from lipids which have both the property of forming mesomorphic phases, the state of organization of which is intermediate between the crystalline state and the liquid state, and of swelling in the presence of a solution aqueous to form said lamellar phases which will give, with stirring, the vesicles dispersed in the aqueous phase.

The vesicles according to the invention are lipid lamellar vesicles with an aqueous core, that is to say encapsulating a hydrophilic phase, which is the internal hydrophilic phase. These vesicles can be either niosomes of the type described in application EP 0 582 503, the teaching of which is incorporated here by reference, or the like, or liposomes of conventional type.

In the case of niosomes, the lamellar phases comprise at least one nonionic amphiphilic lipid, chosen from alkyl- or polyalkylesters of polyol, optionally oxyethylenated, and alkyl- or polyalkylethers of polyol, optionally oxyethylenated, having a melting point of at least 40 ° C. Non-ionic amphiphilic lipids suitable for use in the present invention are in particular glycolipids of natural or synthetic origin (for example cerebrosides), or mixtures of polyol esters and at least one acid with a hydrocarbon chain saturated comprising at least 14 carbon atoms, as well as polyol ethers and at least one alcohol with a saturated hydrocarbon chain comprising at least 14 carbon atoms.

By "mixture of esters" is meant not only mixtures of pure esters of different chemical families, but also any product containing several chemically pure polyol esters of the same family in variable proportions, such as polyglycerol esters comprising a statistical number of glycerol units. The nonionic amphiphilic lipid can thus consist of a mixture of esters or ethers of at least one polyol chosen from the group formed by polyethylene glycol comprising from 1 to 60 ethylene oxide units, sorbitan, sorbitan bearing 2 to 60 ethylene oxide units, glycerol carrying 2 to 30 ethylene oxide units, polyglycerols comprising 2 to 15 glycerol units, sucroses, glucoses carrying 2 to 30 ethylene oxide units, and d '' at least one fatty acid comprising a C ₁₄ -C ₂₀ hydrocarbon chain, saturated or unsaturated, linear or branched.

As polyol ethers which can be used according to the invention, there may be mentioned: - linear or branched polyglycerol ethers of respective formulas R- [OCH ₂ -CH (OH) -CH ₂ ] _n -OH

(Ie

R- [O-CH ₂ -CH (CH ₂ OH)] _n -OH

(II)

where n is an integer between 1 and 6, preferably equal to 2, and R is a radical chosen from:

(a) a linear or branched, saturated or unsaturated aliphatic chain comprising from 14 to 30 carbon atoms, such as a tetradecyl, hexadecyl radical or the alkyl radical of oleic alcohol or isostearyl alcohol; (b) a lanolin alcohol hydrocarbon radical;

(c) a hydroxy-2-alkyl residue of an α-diol whose hydrocarbon chain comprises at least 14 carbon atoms; and - polyoxyethylenated fatty alcohols, such as 10 mole oxyethylenated oleic alcohol (product "Brij 96" sold by the company ICI Atlas). Furthermore, in order to improve the stability of the niosomes, the lamellar phases can also comprise an ionic amphiphilic lipid. The latter can be chosen from anionic lipids and cationic lipids.

The anionic amphiphilic lipids suitable for the implementation of the invention can be:

• neutralized anionic lipids, preferably chosen from the alkaline salts of diketylphosphate, and of dimyristylphosphate, in particular the sodium and potassium salts, the alkaline salts of phosphatidic acid, in particular the sodium salt, the alkali salts of cholesterol sulfate, in particular the sodium salt, the alkaline salts of cholesterol phosphate, in particular the sodium salt, the lipoamino acid salts such as the mono- and disodium acylglutamates, more particularly the disodium salt N-stearoyl L-glutamic acid sold under the name Acylglutamate HS21 by the company AJINOMOTO;

• amphoteric lipids, preferably phospholipids, in particular pure soy phosphatidylethanolamine;

"alkylsulfonic derivatives, in particular the compounds of formula:

in which R represents a C ₁₂ to C ₂₂ hydrocarbon radical, in particular the C ₁₆ H ₃₃ and C ₁₈ H ₃₇ radicals, and M is an alkali metal, preferably sodium.

The cationic amphiphilic lipids which can be used in the vesicles of the invention as ionic amphiphilic lipids can be more particularly chosen from the group formed by quaternary ammonium salts, fatty amines and their salts.

Among the ammonium salts which are particularly suitable for implementing the invention, mention will be made of:

those represented by the following formula (II):

in which the radicals R., to R ₄ , which may be identical or different, represent an aliphatic radical, linear or branched, comprising from 1 to 30 carbon atoms, or an aromatic radical such as aryl or alkylaryl. The aliphatic radicals can comprise heteroatoms such as in particular oxygen, nitrogen, sulfur, halogens. The aliphatic radicals are for example chosen from the alkyl, alkoxy, polyoxyalkylene (C ₂ -C ₆ ), alkylamide, alkyl (C ₁₂ -C ₂₂ ) amidoalkyl (C ₂ -C ₆ ), alkyl (C ₁₂ - C ₂₂ ) radicals acetate, hydroxyalkyl having about 1 to 30 carbon atoms; X is an anion chosen from the group of halides, phosphates, acetates, lactates, (C ₂ -C ₆ ) alkyl sulfates, alkyl-or-alkylarylsulfonates. As quaternary ammonium salts of formula (II), preference is given, on the one hand, to chlorides of tetraikylammonium such as, for example, dialkyldimethylammonium or alkyltrimethylammonium chlorides, in which the alkyl radical contains from approximately 12 to 22 atoms. carbon, in particular the chlorides of behenyltrimethylammonium, distearyldimethylammonium, cetyltrimethylammonium, benzyl dimethyl stearylammonium or alternatively, stearamidopropyldimethyl chloride (myristyl acetate) ammonium sold under the name "CERAPHYL 70" by the company VAN DY .

• the quaternary ammonium salts of imidazolinium, for example represented by the following formula (III):

wherein R ₅ represents an alkenyl or alkyl radical comprising from 8 to 30 carbon ^'atoms, for example derived from tallow fatty acids; R ₆ represents a hydrogen atom, an alkyl radical containing from 1 to 4 carbon atoms or an alkenyl or alkyl radical comprising from 8 to 30 carbon atoms; R ₇ represents an alkyl radical containing from 1 to 4 carbon atoms; R ₈ represents a hydrogen atom, an alkyl radical containing from 1 to 4 carbon atoms; X is an anion chosen from the group of halides, phosphates, acetates, lactates, alkyl sulfates, alkyl-or- alkylarylsulfonates. Preferably, R ₅ and R ₆ denote a mixture of alkenyl or alkyl radicals comprising from 12 to 21 carbon atoms, for example derived from tallow fatty acids, R ₇ denotes a methyl radical, R ₈ denotes hydrogen. Such a product is for example sold under the name "REWOQUAT W 75" by the company REWO.

the quaternary diammonium salts represented by the following formula (IV):

++

R 10 R I,.

I ι ¹²

R. - N- (CH ₂ ) ₃ -N- R 14 2X (IV)

R 11 R 13

in which R6 denotes an aliphatic radical containing approximately from 16 to 30 carbon atoms; R7, R8, R9, R10, and R11, identical or different, are chosen from hydrogen or an alkyl radical containing from 1 to 4 carbon atoms; and X is an anion selected from the group of halides, acetates, phosphates, nitrates and methylsulfates. Such quaternary diammonium salts include in particular propane diammonium dichloride.

Besides the nonionic and ionic amphiphilic lipids, the lamellar phases of the vesicles of the niosome type can also contain at least one additive chosen from sterols, fatty chain alcohols and diols, amines with a fatty chain and their quaternary ammonium derivatives.

It is preferred to use cholesterol which, in addition to its cosmetic and / or dermopharmaceutical activity linked to its capacity to reconstitute the lipids of the skin, makes it possible to improve the stability of the vesicles by avoiding the crystallization of the surfactants with which it is associated. By improving the impermeability of the lamellar phases of the vesicles, cholesterol also makes it possible to increase the retention power of the water-soluble active agents possibly contained in the hydrophilic phase encapsulated by the niosomes.

The lamellar phases of niosome-type vesicles can for example contain 35 to 90% by weight of nonionic amphiphilic lipid, 2 to 20% by weight of ionic amphiphilic lipid, 5 to 50% by weight cholesterol relative to the total weight of the lipids constituting the lamellar phase.

As indicated above, the lipid lamellar vesicles according to the invention can comprise not only vesicles of nonionic type such as niosomes, but also conventional liposomes, comprising at least one amphiphilic lipid such as a phospholipid, natural or synthetic, in in particular lecithin, preferably hydrogenated, associated either with cholesterol and optionally with an ionic surfactant, or with an oxyethylenated phytosterol comprising from 2 to 50 ethylene oxide units.

In this variant embodiment of the invention, the vesicles can comprise: from 50 to 100% by weight of lecithin from 0 to 40% by weight of cholesterol, and from 0 to 20% by weight of ionic surfactant relative to the weight total of the constituent lipids of the lamellar phase. As a variant, they may comprise from 40 to 100% by weight of lecithin, and from 0 to 60% by weight of mixture of oxyethylenated phytosterols relative to the total weight of the lipids constituting the lamellar phase.

The methods of manufacturing the vesicles according to the invention are known to those skilled in the art, but the preferred methods are the following:

Bangham method

The vesicular lipids are dissolved in a mixture of organic solvents. This mixture is then placed in a flask and the solvents are evaporated in a rotary evaporator under reduced pressure. A lipid film then forms. After complete evaporation of the solvents, the film is hydrated with the hydrophilic, glycolic or hydro-glycolic solution in which the DHEA and / or its derivatives and / or its precursors is dissolved, with vigorous stirring. The temperature is adapted to the melting temperature of the lipids. A suspension of liposomes is then obtained. It is then possible to homogenize it using Ultra Sounds.

Method by direct hydration of lipids The lipids may or may not have been preassociated (by fusion or by solvent). The lipid mixture is then introduced with vigorous stirring (rotor stator for example) in a hydrophilic, glycolic or hydro-glycolic solution, in which the compound (s) based on DHEA usable according to the invention is (or are ) solubilized at an appropriate temperature. After a few minutes (generally 5 to 90 minutes), a suspension of liposomes is obtained.

In the composition according to the invention, the vesicles with a hydrophilic core described above (niosomes or liposomes) are dispersed in an aqueous dispersion phase, or external aqueous phase, comprising a physiologically acceptable medium, that is to say compatible with the skin or its appendages, and possibly with the mucous membranes and / or semi-mucous membranes.

The aqueous dispersion phase can be gelled. Gelling agents which can be used according to the invention are, for example, carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate / alkylacrylate copolymers, polyacrylamides such as partially neutralized and highly crosslinked polyacrylamidomethyl propane acid, polysaccharides, natural gums and clays

Alternatively, the aqueous dispersion phase can comprise an oily phase dispersed in said aqueous phase (oil-in-water emulsion).

As oils which can be used according to the invention, there may be mentioned animal or vegetable oils, natural or synthetic essential oils, hydrocarbons such as isohexadecane and paraffin oil, halogenated carbides and silicone oils. As animal or vegetable oils which can be used according to the invention, mention may in particular be made of animal or vegetable oils formed by fatty acid esters of polyols, in particular liquid triglycerides, for example sunflower, corn, soybean oils , squash, grapeseed, jojoba, sesame, hazelnut, fish oils, glycerol tricaprocaprylate, or vegetable or animal oils of formula R ₁ COOR ₂ , formula in which R. represents the rest of a higher fatty acid comprising from 7 to 19 carbon atoms and R ₂ represents a branched hydrocarbon chain containing from 3 to 20 carbon atoms, for example Purcellin oil. As essential oils which can be used according to the invention, mention may be made of natural or synthetic essential oils such as, for example, the oils of eucalyptus, lavandin, lavender, vetiver, litsea cubeba, lemon, sandalwood, rosemary, chamomile, savory nutmeg, hyssop cinnamon, caraway, orange, geraniol, cade and bergamot.

As halogenated carbides which can be used according to the invention, mention may be made of fluorocarbons such as fluoroamines, for example perfluorotributylamine, fluorinated hydrocarbons, for example perfluorodecahydronaphthalene, fluoroesters and fluoroethers. In the case where the vesicles according to the invention are dispersed in the aqueous phase of an oil-in-water emulsion, said emulsion may comprise surfactants other than those constituting the vesicles, provided that these surfactants do not dissolve the vesicles in forming micelles.

According to another possibility, however, the composition according to the invention, when it is in the form of an oil-in-water emulsion, may not contain any surfactant other than those forming the lipid lamellar vesicles. The vesicles according to the invention may indeed be able to stabilize a dispersion of oil droplets in the aqueous dispersion phase, without the need to add a surfactant to said aqueous phase. The vesicles of the compositions according to the invention may contain, in a known manner, one or more active compound (s) having cosmetic and / or dermopharmaceutical activity, which, depending on their solubility characteristics, may have different locations.

If the active agents are water-soluble, they are introduced into the encapsulated hydrophilic phase of the vesicles.

If the active agents are liposoluble, they are introduced into the lipid phase constituting the membrane.

If the active agents are amphiphilic, they are distributed between the lipid phase and the encapsulated hydrophilic phase with a partition coefficient, which varies according to the nature of the amphiphilic active agent and the respective compositions of the lipid phase and of the encapsulated hydrophilic phase. As active,. it is possible in particular to use depigmentants, emollients, moisturizers,. anti-seborrheic, anti-acne, agents promoting hair regrowth, keratolytic and / or desquamating agents, anti-wrinkle and tensioning agents, anti-irritant agents, soothing agents, vitamins and their mixtures. In known manner, the composition according to the invention may also contain adjuvants customary in the cosmetic field, such as preservatives, antioxidants, active agents, solvents, perfumes, odor absorbers, neutralizers, sun filters , polymers, emulsifiers and coemulsifiers, and coloring matters. The compositions according to the invention can thus contain at least one UV filter.

(or sun filter) which can be a chemical filter or a physical filter or a mixture of such filters.

The amounts of the various constituents of the composition according to the invention are those conventionally used in cosmetics. Of course, those skilled in the art will take care to choose any additional additives and / or their quantity in such a way that the advantageous properties of the composition according to the invention are not or substantially not affected by the addition envisaged. In particular, these compounds should not harm the advantageous properties of the compound or compounds based on DHEA, nor promote their recrystallization. The composition according to the invention can in particular constitute protection / care / makeup products for the face / body.

The invention also relates to the cosmetic use of the composition according to the invention mentioned above, for preventing or treating the signs of intrinsic or photo-induced skin aging. Finally, it relates to the use of the composition described above for manufacturing a preparation intended to prevent or treat atrophy of the skin or mucous membranes.

The invention will now be illustrated with the aid of the following nonlimiting examples.

EXAMPLES

EXAMPLE 1: DHEA-based Niosomes Phase a

Hexadecyl triglyceryl ether 4.5%

Cholesterol 4.5% Vit E acetate 0.5%

Dicetyl phosphate 0.5%

Phase b

DHEA 0.5% Dipropylene Glycol 10%

Phase c

100% QSP Distilled Water.

Procedure

Phase a is brought to 90 ° C, homogenized, then brought back to 60 ° C. It is hydrated, with vigorous stirring by phase b, itself at 60 ° C. A concentrated vesicular phase is obtained, easily detectable by a person skilled in the art, by optical microscopy in polarized light. The vesicles then have a multi-leaf structure of onion type. This vesicular phase is then brought to room temperature and is dispersed in phase c. Finally, an aqueous suspension of liposomes is obtained, encapsulating in their aqueous globule DHEA, and also in the hydrophilic layers between the lipid sheets. EXAMPLE 2: Niosomes based on DHEA

Phase a

Sorbitan palmitate 4.5%

Cholesterol 4.5% Sodium mono acylglutamate 1%

Phase b DHEA 0.5%

7.5% distilled water

Glycerol 12.5%

Dipropylene glycol 17%

Phase c

Carbomer 0.3%

Preservatives 1%

Distilled water QSP 100 Triethanolamine 0.3%

The procedure is the same as for Example 1, except that the vesicular suspension is introduced into a carbomer gel. A composition for topical use containing 0.5% of dissolved DHEA is then obtained.

Claims

1. Composition including:

- a dispersion, in an external aqueous phase, of vesicles formed by. lipid lamellar phases separated from each other by hydrophilic layers and encapsulating a hydrophilic core, said lamellar phases comprising at least one amphiphilic lipid, and

- At least one solubilizer of said DHEA-based compound.

2. Composition according to claim 1, characterized in that the solubilizer of said DHEA-based compound is a glycol, a water-glycol mixture, a glycerin-glycol mixture, or a water-glycerin-glycol mixture.

3. Composition according to claim 2, characterized in that the solubilizer of DHEA and / or of the precursor of DHEA, and / or of the derivative of DHEA is chosen from dipropylene glycol, propylene glycol, butylene glycol, pentylene glycol , hexylene glycol, and polyethylene glycol from 4 to 50 ethoxy units.

4. Composition according to claim 2 or 3, characterized in that the water activity a _w of the hydrophilic phase encapsulated in the vesicles is less than 0.90 and preferably less than 0.85.

5. Composition according to any one of the preceding claims, characterized in that said DHEA-based compound is chosen from DHEA, DHEA precursors, and DHEA derivatives.

6. Composition according to claim 5, characterized in that the precursor of

DHEA is a biological precursor chosen from Δ5-pregnenolone, 17 α-hydroxy pregnenolone and 17 α-hydroxy pregnenolone sulfate.

7. Composition according to claim 5, characterized in that the precursor of

DHEA is a chemical precursor chosen from sapogenins, and preferably from diosgenin, hecogenin, smilagenin, sarsapogenin, tigogenin, yamogenin and yuccagenin, natural fenugreek extracts and extracts of

Dioscorea.

8. Composition according to claim 5, characterized in that the DHEA derivative is chosen from Δ5-androstene-3,17-diol and Δ4-androstene-3,17-dione, 7α- OH DHEA, 7β- OH DHEA, 11α-OH DHEA, there 7-keto-DHEA, 3-acetoxy-7-keto-DHEA, DHEA sulfate, esters of hydroxycarboxylic acids and DHEA, DHEA salicylate, acetate of DHEA, DHEA valerate, DHEA enanthate, DHEA carbamates, DHEA 2-hydroxy malonate esters and DHEA amino acid esters.

9. Composition according to claim 5, characterized in that the DHEA derivative is represented by the formula (1):

d)

in which :

R., and R ₂ are independently chosen from:

• alkyl, C -, - 0, _2, saturated or unsaturated, linear, branched or cyclic optionally may contain one or more heteroatoms, and optionally substituted by one or more groups chosen from -OR 'and / or -SR' and / or -COOR 'and / or -NR'R' and / or halogen and / or sulfate and / or phosphate and / or aryl and / or heterocycle, said heterocycle possibly advantageously being chosen from an indole, a pyrimidine, piperidine, morpholine, pyran, furan, piperazine, pyridine;

An alkylcarbonyl group, the C 1 -C ₂₄ alkyl part of which is saturated or unsaturated, linear, branched or cyclic, and optionally substituted by one or more groups chosen from -OR 'and / or -SR' and / or - COOR 'and / or -NR'R' and / or halogen and / or sulfate and / or phosphate and / or aryl and / or heterocycle, said heterocycle possibly advantageously being chosen from an indole, a pyrimidine, a piperidine, a morpholine, pyran, furan, piperazine, pyridine;

"An arylcarbonyl group, preferably a phenylcarbonyl, or an arylalkylcarbonyl group, preferably a benzylcarbonyl, optionally substituted by one or more groups -OR 'and / or -SR' and / or -COOR 'and / or -NR'R' and / or halogen and / or aryl and / or heterocycle;

• a group O = P (OH) OR ';

• a group (0) ₂ SOR ';

• a trialkylsilyl group (SiR ' ₃ ) in which the 3 R' groups can be identical or different;

• a carbonyloxyalkyl group (R'OCO);

• a carbonylaminealkyle group (R'NHCO);

wherein R 'is selected from hydrogen, alkyl GpC ^, preferably C _r C _6, saturated or unsaturated, linear, branched or cyclic optionally ^to' contain one or more heteroatoms, optionally functionalized with one or more groups -OR ", -COOR", halogen, -NR "R"; or with an aryl group, preferably a phenyl, optionally functionalized with one or more groups -OR ", -COOR", halogen or -NR "R"; R "representing a hydrogen atom, an alkyl chain, preferably C ^ Ce, saturated or unsaturated, linear, branched or cyclic, it being understood that in each of the groups -NR'R 'and -NR" R ", the substituents R ', respectively R ", are the same or different.

10. Composition according to claim 9 characterized in that the DHEA derivative is 3-0-acetyl-7-benzoyloxy-dehydroepiandrosterone.

11. Composition according to any one of claims 1 to 10, characterized in that the DHEA-based compound represents from 0.001 to 10% by weight of the total weight of the composition.

12. Composition according to any one of the preceding claims, characterized in that the weight ratio between the hydrophilic phase containing the DHEA-based compound and the lipids constituting the vesicles is between 1/100 and 500/100, and preferably between 10/100 and 250/100.

13. Composition according to any one of the preceding claims, characterized in that the lamellar phases comprise at least one non-ionic amphiphilic lipid, chosen from mixtures of alkyl- or polyalkylesters of polyol, optionally oxyethylenated, and alkyl- or polyalkylethers polyol, optionally oxyethylenated, having a melting point of at least 40 ° C.

14. Composition according to claim 13, characterized in that said nonionic amphiphilic lipid is a mixture of polyol esters and at least one acid with a saturated hydrocarbon chain comprising at least 14 carbon atoms.

15. Composition according to Claim 13, characterized in that the said nonionic amphiphilic lipid is a polyol ether and at least one alcohol with a saturated hydrocarbon chain comprising at least 14 carbon atoms.

16. Composition according to any one of claims 13 to 15, characterized in that said nonionic amphiphilic lipid consists of a mixture of esters or ethers of at least one polyol chosen from the group formed by polyethylene glycol comprising from 1 to 60 ethylene oxide units, sorbitan, sorbitan comprising 2 to 60 ethylene oxide units, glycerol comprising 2 to 30 ethylene oxide units, polyglycerols comprising 2 to 15 glycerol units, sucroses, glucoses comprising 2 to 30 units of ethylene oxide, and at least one fatty acid comprising a C ₁₄ -C ₂₀ hydrocarbon chain, saturated or unsaturated, linear or branched.

17. Composition according to any one of claims 13 to 16, characterized in that the lamellar phases further comprise at least one ionic amphiphilic lipid.

18. Composition according to claim 17, characterized in that the ionic amphiphilic lipid is chosen from the group formed by the alkaline salts of diketyl and of dimyristylphosphate; alkali salts of cholesterol sulfate; alkaline salts of cholesterol phosphate; mono- and disodium acylglutamates; the sodium salt of phosphatidic acid; phospholipids; and alkylsulfonic derivatives; the ammonium salts represented by the following formula (II):

in which the radicals R., to R ₄ , which may be identical or different, represent an aliphatic radical, linear or branched, containing from 1 to 30 carbon atoms, or an aromatic radical such as aryl or alkylaryl .; X is an anion chosen from the group of halides, phosphates, acetates, lactates, (C ₂ -C ₆ ) alkyl sulfates, alkyl-or-alkylarylsulfonates, quaternary ammonium salts of imidazolinium, for example represented by the formula (III) following:

in which R ₅ represents an alkenyl or alkyl radical comprising from 8 to 30 carbon atoms, R ₆ represents a hydrogen atom, an alkyl radical comprising from 1 to 4 carbon atoms or an alkenyl or alkyl radical comprising from 8 to 30 carbon atoms; R ₇ represents an alkyl radical containing from 1 to 4 carbon atoms; R ₈ represents a hydrogen atom, an alkyl radical containing from 1 to 4 carbon atoms; X is an anion chosen from the group of halides, phosphates, acetates, lactates, alkyl sulfates, alkyl-or-alkylarylsulfonates, and the quaternary diammonium salts represented by the following formula (IV):

in which R6 denotes an aliphatic radical containing approximately from 16 to 30 carbon atoms; R7, R8, R9, R10, and R11, identical or different, are chosen from hydrogen or an alkyl radical containing from 1 to 4 carbon atoms; and X is an anion selected from the group of halides, acetates, phosphates, nitrates and methylsulfates.

19. Composition according to any one of claims 13 to 18, characterized in that said lamellar phases contain at least one additive chosen from sterols, fatty chain alcohols and diols, amines with a fatty chain and their quaternary ammonium derivatives.

20. Composition according to Claim 19, characterized in that the said additive is cholesterol.

21. Composition according to claim 20, characterized in that said lamellar phases comprise from 35 to 90% by weight of nonionic amphiphilic lipid, from 2 to 20% by weight of ionic amphiphilic lipid, and from 5 to 50% by weight of cholesterol relative to the total weight of the lipids constituting the lamellar phase.

22. Composition according to any one of claims 1 to 12, characterized in that the ^" lamellar phases comprise at least one amphiphilic lipid chosen from phospholipids, natural or synthetic, associated either with cholesterol and optionally with an ionic surfactant, either to an oxyethylenated phytosterol comprising from 2 to 50 ethylene oxide units.

23. Composition according to claim 22, characterized in that the ionic lipid is lecithin, preferably hydrogenated.

24. Composition according to one of claims 22 or 23, characterized in that the lipid vesicles comprise from 50 to 100% by weight of lecithin, from 40 to 0% by weight of cholesterol, and from 0 to 20% by weight of ionic surfactant relative to the total weight of the lipids constituting the lamellar phase.

25. Composition according to one of claims 22 or 23, characterized in that the lipid vesicles comprise from 40 to 100% by weight of lecithin and from 0 to 60% by weight of mixture of oxyethylenated phytosterol relative to the total weight of lipids constitutive of the lamellar phase.

26. Composition according to any one of the preceding claims, characterized in that it is in the form of a gel.

27. Composition according to any one of claims 1 to 25, characterized in that it further comprises an oily phase dispersed in the external aqueous phase.

28. Composition according to any one of the preceding claims, characterized in that it comprises at least one water-soluble, liposoluble or amphiphilic active ingredient.

5

29. Cosmetic use of a composition as defined according to any one of claims 1 to 28, for preventing or treating the signs of intrinsic or photo-induced skin aging.

Q 30. Use of the composition according to any one of claims 1 to 28 for manufacturing a preparation intended to prevent or treat atrophy of the skin or mucous membranes.