FR2855049A1 - Cosmetic or dermatological active agent combination for reinforcing skin barrier function, e.g. in combating dry skin, containing 6-hydroxy-sphingenin based ceramide precursor and 6-hydroxylase activator - Google Patents

Abstract

New combinations (A) comprise (a) at least one precursor for 6-hydroxy-sphingenin based ceramide or 6-hydroxy-sphingenin based ceramide derivative, which is a substrate for 6-hydroxylase enzymes and (b) activator(s) for the 6-hydroxylase pathway. An independent claim is included for compositions comprising (A) in a physiologically acceptable medium. ACTIVITY : Dermatological. MECHANISM OF ACTION : 6-Hydroxylase pathway activator; stimulant of epidermal synthesis of ceramides based on 6-hydroxy-sphingenin. Addition of vitamin C at 50 Microg/ml to a culture medium for reconstructed epidermis increased the 6-hydroxy-sphingenin content after 6 days from ca. 1000 ng to ca. 5000 ng and reduced the sphingenin content after 6 days from ca. 14000 ng to ca. 4000 ng (all per mg of total lipids).

Description

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The present invention relates to a combination containing at least one 6-hydroxy-sphingenine-based ceramide precursor, a substrate for 6-hydroxylase enzymes, and at least one activating substance of the 6-hydroxylase pathway and its use for enhancing the function barrier of the skin.

Human skin consists of two compartments namely a deep compartment, the dermis, and a superficial compartment, the epidermis.

The epidermis is in contact with the external environment. Its role is to protect the body from dehydration and external aggressions, be they chemical, mechanical, physical or infectious.

The natural human epidermis is composed mainly of three types of cells, which are the keratinocytes, a very large majority, melanocytes and Langerhans cells.

Each of these cell types contributes by its own functions to the essential role played in the body by the skin.

 The cells constituting the epidermis are delimited by a lipid domain. During differentiation, the phospholipids whose role is to develop the fluid structure of the cell membranes of the living layers of the epidermis, are gradually replaced by a mixture composed mainly of fatty acids, cholesterol and sphingolipids .

 These lipids are organized in specific lamellar liquid crystal phase whose integrity depends not only on the quality of the fractions present but also on their respective proportions. This lamellar lipid structure of the lipid domain of the epidermis is responsible for the epidermal barrier function.

 Epidermal lipids are synthesized mainly in the living epidermis. They consist mainly of phospholipids, ceramides (or sphingolipids), cholesterol, free fatty acids, triglycerides, cholesterol esters and alkanes.

 Ceramides are one of the essential constituents of epidermal lipids, partially ensuring the lamellar liquid crystal structure of these, but also the barrier function of the epidermis and the maintenance of the integrity of the stratum corneum.

 Ceramides are composed of a sphingoid base which can be of four types, sphinganine (also called dihydrosphingosine), 4-sphingenine (also called

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 sphingosine), phytosphingosine (also called 4-hydroxy-sphinganine) and 6-hydroxy-4sphingenin (also called 6-hydroxy-sphingenine), and a saturable, hydroxylated or esterified fatty acid. The various possible combinations between bases and fatty acids lead to about ten ceramides listed by Robson, K.J .; Stewart M.E .; Michelsen, S .; Lazo N.D .; Downing, D.T., 6-hydroxy-4-sphingenin in human epidermal ceramides, in J. Lipid Res. 1994 35: 2060-2068; and Chopart M., Castiel Higounenc I., Arbey E., Guey C., Gaetani Q., Schmidt R., The Normal Human Stratum Corneum: a new ceramide profile, Perspectives in Percutaneous Penetration, 8th International Conference, Antibes Juan-Les Pins - France, April 2-6,2002. This latter document further discloses that ceramides of type 2 or 5 may be sphinganine-based or 4-sphingenine-based.

 The importance of lipids and more specifically ceramides in maintaining the integrity of the stratum corneum and its barrier function has been demonstrated in the case of dry, rough, damaged, aged, sensitive, and / or atopic skin in which has been shown to disrupt the synthesis of said lipids. These skin disorders are characterized by an alteration of the physical properties of the skin and more precisely of its barrier function. The destruction of the integrity of the cutaneous barrier is accompanied by an increase in the insensible water loss (PIE).

 For example, the following documents may be mentioned: Imokawa et al. in Invest Dermatol, 96 (4): 523-6, 1991 discloses that ceramides are involved in the barrier function and that their synthesis, particularly that of ceramide 1, is decreased in the case of atopic and xerotic skin.

 - Di Nardo et al. in Acta Derm Venereol, 78 (1): 27-30,1998) describe atopic dermatitis as an easily irritable and dry skin, in which the barrier function is impaired. The authors have shown that a decrease in the synthesis of ceramides 1 and 3 may be the cause of dry skin and the alteration of the barrier function in atopic dermatitis; - Rogers et al. in Arch. Dermatol. Res. 288: 765-770, 1996 discloses a decrease in the synthesis of ceramides, in particular ceramide 1, which contributes, in the aged skins, to a disturbance of the barrier function and to xerosis, particularly during the winter months .

 - Rogers et al. in J. Invest. Dermatol. 100: 510, 1993 describe that the multilayer lipid structure of dry skin is disturbed, and that this disturbance is accompanied by an increase in free fatty acids and a decrease in ceramides.

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In order to improve the aged skin, dry skin and cutaneous sensitivity, compositions containing a precursor for the synthesis of ceramides chosen from: sphinganine bases, sphingosine, fatty acid amides and vitamin B3 as stimulator are already known. of the synthesis of ceramides (WO99 / 47114) and compositions containing an intermediate of the synthesis routes or precursor of ceramides chosen from: fatty acids, sphinganine and sphingosine bases, and vitamin A as a stimulator of ceramide synthesis ( W094 / 23694).

These known compositions do not always make it possible to meet the specific needs of consumers, which stimulates the search for new compositions so as to be able to give an even more adapted response to the disorders or skin disturbances mentioned above.

After carrying out clinical studies, the Applicant has been able to show that skin disorders such as dry, rough, damaged or even elderly, sensitive skin, are linked to a specific deficiency of ceramides containing a 6-hydroxy-base.
4-sphingosine.

 The Applicant then found that it was possible to overcome this specific deficiency of 6-hydroxy-4-sphingosine-based ceramides by using a composition comprising a substance capable of specifically activating the in vivo synthesis of this class of ceramide containing a 6-hydroxy-4-sphingosine base, that is to say an activating substance of the 6-hydroxylase pathway, in combination with a sphingosine-based precursor ceramide (also called 4-sphingenine) or a sphingosine-based precursor ceramide derivative .

 The combinations according to the invention containing an activating substance for the 6-hydroxylase pathway and a sphingosine-based precursor ceramide or a sphingosine-based precursor ceramide derivative now make it possible to respond to the abovementioned cutaneous disorders by specifically filling the deficiency of 6-hydroxy-4-sphingosine-based ceramides.

 Ceramides or ceramide derivatives based on 6-hydroxy-sphingenine are called "target ceramides".

 Ceramides or ceramide derivatives based on sphingosine are called "precursor ceramides".

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The 6-hydroxylases are enzymes of the epidermis which provide the in vivo synthesis of ceramides or 6-hydroxy-4-sphingenine-based derivatives by hydroxylation at the 6-position of the sphingosine base of ceramides or precursor derivatives.

Brought topically into contact with the epidermis, the activating substance of the 6-hydroxylase pathway will make it possible to specifically transform the ceramides or sphingosine-based derivatives, both those naturally present in the epidermis, and both those provided by the composition topically, ceramide or 6-hydroxy-sphingenine-based derivatives.

The precursor ceramide according to the invention is a ceramide which will give the target ceramide after hydroxylation in position 6.

By providing topically the contact with the epidermis, the activating substance of the 6-hydroxylase pathway and the precursor ceramide, is thus directly available to the epidermis all the components necessary to obtain the target ceramides. Thus, the increase in target ceramides will not be to the detriment of ceramides or derivatives of ceramide-based sphingosine naturally present in the epidermis although it is not excluded that they are also mobilized by the enzymes 6 hydroxylases. The provision of precursor ceramides thus makes it possible to obtain faster and greater access to an increase in the content of the epidermis in target ceramides without the natural biosynthesis upstream of the precursor ceramides being a limiting factor.

 An object of the present invention relates to a combination containing at least one ceramide precursor or 6-hydroxy-4-sphingenine-based ceramide derivative, a substrate for 6-hydroxylase enzymes, and at least one activating substance of the 6-hydroxylase.

 Preferably, the 6-hydroxy-4-sphingenine-based ceramide or ceramide derivative precursor is a ceramide or a sphingosine-based ceramide derivative.

 Advantageously, said sphingosine base (or 4-sphingenine) is of erythro conformation (2S, 3R).

 The term "ceramide derivatives" is intended to mean glycosylceramides or cerebrosides (the combination of a ceramide with a sugar) or sphingomyelins (mainly ceramide phosphoryl choline or ceramide phosphoryl etahanolamine) see the hydrolysed form of ceramide, that is to say the sphingoid base alone or phosphorylated.

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dans laquelle: # R1 est une chaîne hydrocarbonée saturée ou insaturée, linéaire ou ramifiée, comprenant entre 11 et 21 carbones, de préférence R1 est linéaire et saturé et comporte entre 13 à 17 carbones, avantageusement 13, 14, 15 ou 17 carbones; # X est une chaîne hydrocarbonée comprenant entre 2 et 33 carbones saturée ou insaturée, linéaire ou ramifiée, substitué ou non par un ou plusieurs groupements OH, de préférence un groupement OH; # R2 est un atome d'hydrogène, un groupement glycosylé, avantageusement glucosylé ou galactosylé, un groupement phosphorylé, avantageusement phosphoryl choline ou phosphoryl ethanolamine, de préférence R2 est un atome d'hydrogène; # Y représente un atome d'hydrogène, un groupement OH ou un groupement OCOR3; # R3 est une chaîne linéaire hydrocarbonée saturée ou insaturée comprenant entre 7 et
25 carbones; ses isomères optiques, ou ses sels physiologiquement acceptables. Advantageously, the precursor of ceramide or 6-hydroxy-sphingenine-based ceramide derivative is a compound of formula (I) below:

wherein: # R1 is a saturated or unsaturated hydrocarbon chain, linear or branched, comprising between 11 and 21 carbons, preferably R1 is linear and saturated and has between 13 to 17 carbons, preferably 13, 14, 15 or 17 carbons; # X is a hydrocarbon chain comprising between 2 and 33 saturated or unsaturated carbons, linear or branched, substituted or not by one or more OH groups, preferably an OH group; # R2 is a hydrogen atom, a glycosylated group, advantageously glucosylated or galactosylated, a phosphorylated group, advantageously phosphoryl choline or phosphoryl ethanolamine, preferably R2 is a hydrogen atom; # Y represents a hydrogen atom, an OH group or an OCOR3 group; # R3 is a saturated or unsaturated hydrocarbon linear chain comprising between 7 and
25 carbons; its optical isomers, or its physiologically acceptable salts.

When X is substituted with an OH group, the compound of formula (I) is a ceramide 5 or a ceramide derivative 5.

When X is not substituted with an OH group and Y represents a hydrogen atom, the compound of formula (I) is a ceramide 2 or a ceramide derivative 2.

When X is not substituted by an OH group and Y represents a grouping
OCOR3, the compound of formula (I) is a ceramide 1 or a ceramide derivative 1
When X is not substituted with an OH group and Y represents a hydrogen atom, X is a saturated or unsaturated hydrocarbon chain, linear or branched, comprising between 3 and 31 carbons and saturated R1 comprises 13,14 or 15 carbons.

Advantageously, X comprises between 5 and 29 carbons, preferably 5.7, 11, 15, 17,
21, 23, 24, 25, 26 or 27.

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According to this embodiment, the particularly preferred compounds of the invention are chosen from the following list: 2-hexanoylamino-4-octadecene-1,3-diol; D, L-Erythro-2-hexanoylamino-4-octadecene-1,3-diol; 2-octanoylamino-4-octadecene-1,3-diol; D, L-Erythro-2-octanoylamino-4-octadecene-1,3-diol; 2-Lauroylamino-4-octadecene-1,3-diol; Erythro 2-hexadecanoylamino-4-octadecene-1,3-diol; 2-Hexadecanoylamino-4-octadecene-1,3-diol; N-Stearoyl-DL-sphingenine or 2-Stearoylamino-DL-4-octadecene-1,3-diol; - 2-Behenoylamino-4-octadecene-1,3-diol; Erythro 2-docosanoylamino-4-octadecene-1,3-diol; 2-Tetracosanoylamino-4-octadecene-1,3-diol; Erythro 2-tetracosanoylamino-4-octadecene-1,3-diol; 2- (3'E) -Hexenoylamino-4-octadecene-1,3-diol; N-Oleyl-dihydrosphingosine or 2-Oleoylamino-4-octadecene-1,3-diol; - D, L, Erythro 2-oleoylamino-4-octadecene-1,3-diol; - 2-Linoleoylamino-octadecene-1,3-diol or 2-linoleoylamino-3-ol-4-octadecenoic acid; 2-Undecenoylamino-4-octadecene-1,3-diol; N- (2-butyloctanoyl) -2-amino-4-octadecene-1,3-diol; N- (2-Decyl-tetradecanoyl) -2-amino-4-octadecene-1,3-diol; N- (2-hexyl-decanoyl) -2-amino-4-octadecene-1,3-diol.

When X is substituted by an OH group and Y represents a hydrogen atom, the OH group is in position a, ss, y or #, advantageously at a, of the grouping.
CONH, X is a saturated or unsaturated hydrocarbon chain, linear or branched, comprising between 2 and 29 carbons, preferably X is saturated and advantageously comprises 2,3, 4,5, 7,9, 10, 15,23, 24, 25, 26, 27 or 29 carbons, and saturated R1 comprises 13, 14 or 15 carbons.

 According to this embodiment, the particularly preferred compounds of the invention are chosen from the following list: - N- [alpha] -hydroxypalmitoyl-sphingosine or N- (2-hydroxyhexadecanoyl) -sphingenine or N- (2-Hydroxy-hexadecanoyl) 2-amino-4-octadecene-1,3-diol; Erythro n- (2-hydroxy-hexadecanoyl) -2-amino-4-octadecene-1,3-diol; 2- (2-hydroxy-docosanoyl) amino-4-octadecene-1,3-diol;

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 N- (2-hydroxy-propanoyl) -2-amino-4-octadecene-1,3-diol; 2- (16-Hydroxy-hexadecanoyl) -amino-4-octadecene-1,3-diol; Erythro N- (16-hydroxy-hexadecanoyl) -2-amino-4-octadecene-1,3-diol.

4-Hydroxy-N-[2-hydroxy-1 -(hydroxymethyl)heptadecyl-3-enelpentanam ide
4-Hydroxy-N-[2-hydroxy-1-(hydroxymethyl)heptadecyl-3-ene]octanamide ;
4-Hydroxy-N-[2-hydroxy-1-(hydroxymethyl)heptadecyl-3-ene]decanamide ;
4-Hydroxy-N-[2-hydroxy-1-(hydroxymethyl)heptadecyl-3-ene]undecanamide ;
6-Hydroxy-N-[2-hydroxy-1-(hydroxymethyl)heptadecyl-3-ene]hexanamide. 3-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] butanamide;

4-Hydroxy-N- [2-hydroxy-1 - (hydroxymethyl) heptadecyl-3-enelpentanam ide
4-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] octanamide;
4-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] decanamide;
4-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] undecanamide;
6-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] hexanamide.

When X is not substituted with an OH group and Y represents an OCOR3 group, X is preferably saturated and comprises either (i) between 27 and 33 carbons, advantageously 29 carbons, or (ii) between 13 and 19 carbons, advantageously 15 carbons, the group R 3 is saturated or unsaturated and comprises between 9 and 25 carbons, preferably 9, 11, 13, 15, 17, 19 or 21 carbons, advantageously at least one monounsaturated, particularly preferably 17 unsaturated carbons, and saturated R1 comprises 13, 14 or 15 carbons.

According to this embodiment, the particularly preferred compounds of the invention are chosen from the following list: N- (16- [linoleoyloxy] hexadecanoyl) -2-amino-4-octadecene-1,3-diol; 2- (16-Hexadecanoyloxy-hexadecanoyl) -amino-4-octadecene-1,3-diol; 2- (16-Oleoyloxy-hexadecanoyl) -amino-4-octadecene-1,3-diol; DL Erythro 2- (16-oleoyloxy-hexadecanoyl) -amino-4-octadecene-1,3-diol.

As salts of the compound of formula (1), mention may be made of the salts obtained by adding the derivative of formula (1) with an inorganic acid, chosen in particular from hydrochloric, sulfuric, nitric, carbonic and phosphoric acids, or with a organic acid, chosen in particular from succinic acid, fumaric acid, lactic acid, glycolic acid, citric acid, gluconic acid, salicylic acid and tartaric acid.

Advantageously, the sphingosine base (or 4-sphingenine) of the compounds of formula (1) is erythro (2S, 3R) conformation.

These compounds can be prepared according to extraction methods made from the skin or by conventional chemical synthetic methods of man described in particular in JP2000 / 143598, EP0647617, EP0500437.

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By activating substance of the 6-hydroxylase pathway is meant a substance capable of increasing the content of the epidermis in at least one ceramide or a 6-hydroxy-sphingenine-based ceramide derivative by activating hydroxylation in the 6-position. of the sphingosine base constitutive of at least one precursor of said ceramide or of said derivative.

The activating substance of the 6-hydroxylase pathway is therefore a substance which makes it possible to increase the conversion rate of sphingosine-based ceramides into 6-hydroxy-sphingenine-based ceramides.

 In order to determine whether a substance is an activator of the 6-hydroxylase pathway according to the invention, it is possible to use any analytical method making it possible to quantify the epidermal content in sphingolipids, advantageously ceramides or ceramide derivatives, based on 6-hydroxy- sphingenine and measure whether this content is increased following the dermal application of the said substance.

This method can be carried out for example on reconstructed epidermis or on human skin by following for example the following protocol: ~ 1) Application
After correct formulation of the combination according to the invention (see the examples of composition below), the composition comprising the combination is applied topically to the epidermis for the time necessary for the demonstration of the activity.
For example in the case of an application on human skin 1 to 2 times a day for one to 6 weeks and in the case of an application on reconstructed epidermis one application every two days for one week.

2) Extraction
When the test is carried out on human skin, the lipids can be taken: by direct extraction by turbine with organic solvents, for example with a chloroform-methanol or hexane-ethanol mixture, through the epidermis to drive the lipids.

 - by extraction from varnished stripping. This technique includes the application of an adhesive tape -vernis + nylon- on the skin, then tearing of the assembly resulting in the same part of the stratum corneum. The strips obtained are then brought into contact with organic solvents of the chloroform ethanol type.

 When the test is performed on a reconstructed epidermis, the reconstructed epidermis is removed, and the lipids extracted by various solvents or solvent mixtures selected from chloroform, methanol and water.

 From the lipidic extract obtained, the ceramides and derivatives can be separated and isolated after migration by thin layer chromatography.

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3) Analysis The ceramides or derivatives are quantified via the quantification of their sphingoid bases obtained by hydrolysis of the ceramide (cleavage of the amide bond of the ceramide). For example, the method for analyzing the ceramides or derivatives may consist in hydrolysing either the whole of the lipid extract or the ceramides or separated and isolated derivatives obtained at the end of step 2) by an alkaline hydrolysis, followed methanol extraction of the sphingoid bases thus liberated by hydrolysis. After specific derivation with orthophthalaldehyde (fluoroaldehyde) the bases are then analyzed by HPLC in fluorescence detection.

This analytical method therefore consists in using techniques conventionally used and well known to those skilled in the art, for example those described in the following documents: - C. Faller et al., Toxicology in Vitro, 10 (2002) 557 -572 ("Predictive ability of reconstructed human epidermis equivalents for the assessment of skin irritation of cosmetics"); - Mr. Ponec, Adv. Lipid Res., 24 (1991) 83-117 ("Lipid metabolism in cultured keratinocytes"); - H. -S. Yoo et al., Toxicology in Vitro, (1996) 77-84 ("A rapid method for quantifying free sphingoid bases and complex sphingolipids in micrograms of cells following exposure to fumonisin B1"); J. Bodennec et al., Journal of Lipid Research, 41 (2000), 1524-1531 ("A procedure for fractionation of sphingolipid classes by solid-phase extraction on aminopropyl cartridges").

 Advantageously, an activating substance of the 6-hydroxylase pathway is chosen from ascorbic acid (vitamin C) or its analogues. Preferably, the ascorbic acid may be in D or L form, advantageously in L form, and its analogues chosen from its salts, preferably sodium ascorbate, magnesium or sodium ascorbylphosphate, and its esters, preferably its acetic, propionic or palmitic esters, or its sugars, preferably glycosylated ascorbic acid, and the derivatives of formula (II):

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dans laquelle : R6 représente un atome d'hydrogène, un reste de sucre, un groupe carbonyle, un groupe alkyloxycarbonyle ou un groupe carbamoyle, ou bien R60 représente une fonction sulfate ou une fonction phosphate, R7 représente un reste de sucre ou un groupe -COR10 où Rio est choisi parmi : (a) un radical hydrocarboné en CrC2o, saturé ou insaturé, linéaire, cyclique ou ramifié, éventuellement hydroxylé, (b) un radical aryle éventuellement hydroxylé, (c) un radical aralkyle de formule (III) :

où R, R' et R", identiques ou différents, représentent un atome d'hydrogène, un radical hydroxy, alkoxy, fluoroalkoxy ou alkylcarbonyloxy, et R8, R9, identiques ou différents, représentent un atome d'hydrogène ou un groupe -COR10 tel que défini précédemment ou encore, pris ensemble, forment un radical isopropylidène, ou un sel de ce dérivé.

in which: R6 represents a hydrogen atom, a sugar residue, a carbonyl group, an alkyloxycarbonyl group or a carbamoyl group, or R60 represents a sulfate function or a phosphate function, R7 represents a sugar residue or a group - COR10 wherein R10 is chosen from: (a) a saturated or unsaturated, linear, cyclic or branched, optionally hydroxylated, CrC20 hydrocarbon radical, (b) an optionally hydroxylated aryl radical, (c) an aralkyl radical of formula (III):

where R, R 'and R ", which may be identical or different, represent a hydrogen atom, a hydroxy, alkoxy, fluoroalkoxy or alkylcarbonyloxy radical, and R8, R9, which may be identical or different, represent a hydrogen atom or a -COR10 group as defined above or taken together form an isopropylidene radical, or a salt thereof.

The R6 group is chosen such that the R60 bond is readily hydrolyzable on contact with the skin.

By "sugar residue" is preferably meant a residue of glucose, galactose, mannose, fructose or N-acetylglucosamine.

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By "saturated hydrocarbon radical, linear or branched, having from 1 to 20 carbon atoms", is meant for example a radical chosen from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl and iso-butyl radicals, tert-butyl, hexyl, heptyl, 2-ethylhexyl, octyl, nonyl, iso-nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl and octadecyl, and preferably the undecyl radical.

In addition, the term "unsaturated hydrocarbon radical, linear or branched, having from 1 to 20 carbon atoms" more particularly means a radical selected from the group consisting of radicals containing from 2 to 5 carbon atoms and having one or more ethylenic unsaturations, in particular the allyl radical.

The preferred or unsubstituted aryl radical is benzyl. Examples of aralkyl radicals of formula (III) above are those in which the aryl group is substituted with: one or more hydroxy radicals; alkoxy such as a radical selected from the group consisting of methoxy, ethoxy and butoxy, and preferably the methoxy radical; fluoroalkoxy such as the trifluoromethoxy radical; and alkylcarbonyloxy such as a radical selected from the group consisting of acetoxy, propionyloxy and butyryloxy, and preferably acetoxy.

 Preferred ascorbic acid derivatives for use according to the present invention are selected from the group consisting of: (a) (5,6-Isopropylidene) ascorbyl 2-hexadecanoate (b) 2-benzoate (5,6-isopropylidene) ascorbyl isopropylidene) ascorbyl (c) 2-0-αD glucopyranosyl of (5,6-isopropylidene) ascorbic acid (d) ascorbyl 2-cinnamate, (e) ascorbyl 2-ferulate, (f) ) (5,6-isopropylidene) ascorbyl 2-ferulate, and (g) (5,6-isopropylidene) ascorbyl 2- (4-acetoxyferulate).

 Compounds (a) and (b), above, as well as their process of preparation, are respectively described in the applications JP-46 024 699 and JP-44 000 220. The compound (c) above is available in the trade with HAYASHIBARA, under the trade name Ascorbic Acid 2-glucoside. Compounds (d), (e), (f) and (g) can be prepared as described in EP-0 664 290.

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Particularly preferred combinations according to the invention are the following: - ascorbic acid and N-oleyl-sphingosine and / or - ascorbic acid and Na-hydroxypalmitoyl-sphingosine and / or - ascorbic acid and Na hydroxybhenoyl-sphingosine and / or phosphorylated ascorbic acid and N-oleyl sphingosine and / or phosphorylated ascorbic acid and Na-hydroxypalmitoyl-sphingosine and / or phosphorylated ascorbic acid and Na-hydroxybhenoyl sphingosine and / or glycosylated ascorbic acid and N-oleyl-sphingosine and / or - glycosylated ascorbic acid and Na-hydroxypalmitoyl-sphingosine and / or - glycosylated ascorbic acid and Na-hydroxybhenoyl-sphingosine and / or - ascorbic acid and N- (16- [Linoleoyloxy] -hexadecanoyl) -2-amino-4-octadecene
1,3-diol and / or - phosphorylated ascorbic acid and N- (16- [Linoleoyloxy] -hexadecanoyl) -2-amino-4-octadecene-1,3-diol and / or - glycosylated ascorbic acid and N- (16- [Linoleoyloxy] hexadecanoyl) -2-amino-4-octadecene-1,3-diol.

By a physiologically acceptable medium is meant a medium compatible with the skin and optionally with its integuments (eyelashes, nails, hair) and / or mucous membranes.

The present invention also relates to compositions for cosmetic or dermatological use comprising at least the combination according to the invention.

The composition according to the invention contains, in a physiologically acceptable medium, at least one precursor of 6-hydroxysphingenine-based ceramide or ceramide derivative as previously described in an amount representing from 0.0001% to 30% by weight, of preferably from 0.0001 to 1% by weight, advantageously from 0.005 to 0.1% by weight, relative to the total weight of the composition and, at least one activating substance of the 6-hydroxylase pathway as previously described in a quantity representing from 0.001% to 10% by weight, preferably from 0.01% to 5%, advantageously from 0.1% to 1%.

The physiologically acceptable medium in which the compounds according to the invention may be employed, as well as its constituents, their quantity, the galenic form of the composition and its method of preparation, may be chosen by those skilled in the art on the basis of their general knowledge according to the type of composition sought.

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The compositions according to the invention may be in the form of emulsions, hydroalcoholic, oily or oleo-alcoholic lotions, gels, dispersions or solid rods, sprays or aerosol foams.

The compositions are, for example, lotions, milks or emollient creams, milks or creams for the care of the skin or hair, creams, lotions or make-up removers, foundation bases, lotions, sun protection milks or creams, lotions, artificial tanning milks or creams, shaving creams or foams, aftershave lotions, shampoos or mascaras.

The composition may therefore comprise an aqueous phase which may comprise water, a floral water such as cornflower water, mineral water such as VITTEL water, LUCAS water or LA ROCHE water. POSAY and / or thermal water.

Said aqueous phase may also comprise alcohols such as C 1 -C 8 monohydric alcohols, among which mention may be made of ethanol, propanol, butanol, isopropanol or isobutanol; and / or polyols such as glycerol, butylene glycol, isoprene glycol, propylene glycol, polyethylene glycol.

 The composition according to the invention may also comprise a fatty phase, especially consisting of liquid fats at 25 ° C., such as oils of animal, vegetable, mineral or synthetic origin, volatile or otherwise; solid fats at 25 ° C., such as waxes of animal, vegetable, mineral or synthetic origin; pasty fatty substance; gums; their mixtures.

 The volatile oils are generally oils having, at 25 ° C., a saturating vapor pressure of at least 0.5 millibar (ie 50 Pa).

 Amongst the constituents of the fatty phase, mention may be made of: cyclic volatile silicones having from 3 to 8 silicon atoms and preferably from 4 to 6. It is, for example, cyclotetradimethylsiloxane, cyclopentadimethylsiloxane or cyclohexadimethylsiloxane; cyclocopolymers of the dimethylsiloxane / methylalkylsiloxane type, linear volatile silicones having from 2 to 9 silicon atoms. This is for example hexamethyldisiloxane or a low viscosity PDMS (1 cSt). Mention may also be made of hexamethyldisiloxane and alkyltrisiloxanes, such as hexylheptamethyltrisiloxane or octylheptamethyltrisiloxane.

 volatile hydrocarbon oils, such as isoparaffins and in particular

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 isododecane; polyalkyl (C 1 -C 20) siloxanes and especially those with trimethylsilyl end groups, among which mention may be made of linear polydimethylsiloxanes and alkylmethylpolysiloxanes such as cetyldimethicone (CTFA name), silicones modified with aliphatic and / or aromatic groups, optionally fluorinated, or with functional groups such as hydroxyl groups, thiols and / or amines.

phenyl silicone oils, oils of animal, vegetable or mineral origin, and in particular animal or vegetable oils formed by esters of fatty acids and of polyols, in particular liquid triglycerides, for example sunflower oils. corn, soya, squash, grape seed, sesame, hazelnut, apricot, almond or avocado; fish oils, tricaprocaprylate of glycerol, or vegetable or animal oils of formula R, COOR2 in which R1 represents the residue of a higher fatty acid having from 7 to 19 carbon atoms and R2 represents a branched hydrocarbon chain containing From 3 to 20 carbon atoms, for example, Purcellin oil; paraffin oil, petrolatum, perhydrosqualene, wheat germ oil, calophyllum, sesame, macadamia, grape seed, rapeseed, coconut, peanut, palm, castor oil, jojoba, olive or cereal sprouts; fatty acid esters; alcohols; acetylglycerides; octanoates, decanoates or ricinoleates of alcohols or polyalcohols; triglycerides of fatty acids; desglycérides; - Fluorinated and perfluorinated oils.

silicone gums; waxes of animal, vegetable, mineral or synthetic origin, such as microcrystalline waxes, paraffin wax, petrolatum, petrolatum, ozokerite, montan wax; beeswax, lanolin and its derivatives; Candelilla, Ouricury, Carnauba, Japan waxes, cocoa butter, cork fiber waxes or sugar cane waxes; 25 C solid hydrogenated oils, ozokerites, fatty esters and glycerides at 25 ° C; polyethylene waxes and waxes obtained by Fischer-Tropsch synthesis; hydrogenated oils that are solid at 25 ° C .; lanolins; concrete fatty esters to
25 C; silicone waxes; fluorinated waxes.

 When the composition according to the invention is in the form of an emulsion, it may optionally further comprise a surfactant, preferably in an amount representing from 0.01 to 30% by weight relative to the total weight of the composition. The composition according to the invention may also comprise at least one co-emulsifier which may be chosen from oxyethylenated sorbitan monostearate, fatty alcohols such as

<Desc / Clms Page number 15>

 stearyl alcohol or cetyl alcohol, or esters of fatty acids and polyols such as glyceryl stearate.

The composition according to the invention may further comprise a particulate phase which may comprise pigments and / or nacres and / or fillers usually used in cosmetic compositions.

 In known manner, the composition according to the invention may comprise the usual adjuvants in the field in question, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, active agents in particular cosmetic or pharmaceutical hydrophilic or lipophilic, preservatives, antioxidants, solvents, perfumes, fillers, pigments, nacres, UV filters, odor absorbers and dyes. The nature and amount of these adjuvants may be chosen by those skilled in the art, on the basis of their general knowledge, so as to obtain the desired form of presentation for the composition. In any case, those skilled in the art will take care to choose any possible additional compounds and / or their amount, so that the advantageous properties of the composition according to the invention are not, or not substantially impaired by the envisaged addition.

 For an application on the skin, the composition may have the form in particular of aqueous or oily solution; dispersion of the lotion or serum type; emulsions of liquid or semi-liquid consistency of the milk type obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O); suspensions or emulsions of soft consistency of the cream or gel type aqueous or anhydrous; microcapsules or microparticles; vesicular dispersions of ionic and / or nonionic type.

 Advantageously, the combination according to the invention is formulated in the form of liposomes, of niosomes or more generally in the form of vesicles or vesicular dispersions.

 By vesicle or vesicular dispersion is meant a dispersion of amphiphilic lipids forming in contact with water or a hydrophilic medium, particles whose core is hydrophilic (water or hydrophilic mixture) and whose wall consists of bilayers. lamellar liquid crystal type. These vesicles are commonly called liposomes. They consist mainly of phospholipids, natural or synthetic, hydrogenated or not. Niosomes, in turn, consist of nonionic surfactants, optionally combined with cholesterol and / or an ionic surfactant.

 These vesicular dispersions are particularly preferred because they make it possible to improve the bioavailability and the penetration of the combination according to the invention within

<Desc / Clms Page number 16>

 layers of the epidermis. Said bioavailability is improved because the lamellar-type formula of said vesicular dispersion represents a formula close to the multilayer lipid structures of the epidermis, in particular the stratum corneum.

The vesicles according to the invention are formed by, or comprise, from one to twenty five layers of essentially concentric lamellar phases of the bimolecular type.

 The vesicles according to the invention can be either niosomes of the type of those described in applications EP 0 958 856, EP 0 582 503, EP 0 455 528, EP 0 043 327, or liposomes of conventional type. The ratio by weight between the amount of lipid phase and the amount of aqueous phase of the dispersion is between 1/1000 and 300/1000.

 A preferred composition according to the invention comprises a dispersion, in an external aqueous phase, of vesicles formed by lipidic lamellar phases separated from each other by hydrophilic layers, said lamellar phases comprising at least one precursor of ceramide or of a derivative of 6-hydroxy-sphingenine-based ceramide, 6-hydroxylase enzyme substrate, and at least one 6-hydroxylase pathway promoting substance.

 For an application on the hair, the composition may be in the form of aqueous, alcoholic or aqueous-alcoholic solutions; in the form of creams, gels, emulsions, foams; form of aerosol compositions also comprising a propellant under pressure.

 The compositions according to the invention may especially be in the form of: a skincare, treatment or protection product, keratin materials, and in particular the skin of the face or of the body including the scalp, such as a care composition (day, night, moisturizing) of the face or body; anti-wrinkle or anti-aging composition for the face; a mattifying composition for the face; a composition for irritated skin; cleansing composition; a body milk, in particular moisturizer, possibly after-sun; - a composition of sun protection, artificial tanning (self-tanning) or after-sun care; a hair composition, and in particular a cream or a sun-protecting gel; scalp care composition, especially anti-hair loss or regrowth; a pest control shampoo; a makeup product for keratin materials such as a foundation, a tinted cream, a blush or an eyeshadow, a loose or compact powder, a concealer stick, a camouflaging stick, a lipstick , a care of the lips; a nail polish, a

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 nail care, a mascara, a treatment mascara, an eyeliner.

The compositions according to the invention find a preferred application as a skin care composition for the face, a moisturizing type, and as a sunscreen or after-sun composition. The composition according to the invention may also contain in particular at least one other active product chosen moisturizers, softeners, products for the treatment of skin conditions, sunscreens, germicides, dyes, preservatives, perfumes and thrusters.

The active product may be chosen for example from humectants such as glycerine, sorbitol, pentaerythritol, pyrrolidone carboxylic acid and its salts; artificial browning agents such as dihydroxyacetone, erythrulose, glyceraldehyde, gamma-dialdehydes such as tartaric aldehyde, these compounds optionally being associated with dyes; water soluble sunscreens; antiperspirants, deodorants, astringents, refreshing, tonic, healing, keratolytic, depilatory, scented water products; plant tissue extracts, such as polysaccharides; water-soluble dyes; antidandruff agents; antiseborrhoeic agents, oxidants such as bleaching agents such as hydrogen peroxide; reducing agents such as thioglycolic acid and its salts.

 The active product may also be chosen for example from fat-soluble sunscreens, substances intended to improve the condition of dry or senile skin, tocopherols, vitamins E, F or A and their esters, retinioic acid, antioxidants , glycyrrhetinic acid, keratolytics and carotenoids.

 The composition of the invention may furthermore contain active agents which may help to improve the surface appearance of keratin materials, in particular the skin, and even more preferably dry, rough, damaged and / or aged skin, such as sphingenine, sphinganine or 4-OH-sphinganine or 6-OH-sphingenine, other ceramides different ceramides precursors ceramides bases 6-hydroxy-4-sphingenines, triglycerides, sterols such as cholesterol, fats usually used in cosmetics.

 Another subject of the invention relates to the use of the combination as defined above, as a cosmetic agent.

 The subject of the present invention is also the use of the combination as defined above or of a composition containing it to reinforce the barrier function of the

<Desc / Clms Page number 18>

 skin. More specifically, the subject of the invention is the use of the combination as defined above or of a composition containing it: to strengthen the lipid barrier of the epidermis, in particular dry and / or sensitive skin and / or or rough and / or damaged and / or aged and / or - to restore or maintain the integrity of the stratum corneum, and / or - to improve the surface appearance and / or flexibility and / or hydration of the skin and / or - to protect the skin, especially dry and rough skin, and / or - as an essential nutrition agent for keratinous substances (skin, hair, eyelash, nail), and / or - to reinforce the lipid barrier of reconstructed skin, or skin equivalent and / or - to improve and / or maintain the lipid profile of the human epidermis, in vivo and in vitro, and / or - to improve the quality and properties such as lipid content and / or barrier function, reconstructed epidermis and / or cultures of cel epidermal lules and / or - to decrease the insensitive loss in water of dry and / or sensitive and / or rough and / or damaged and / or aged skin.

 Another subject of the invention relates to the use of an association as described above for the manufacture of a composition intended for the treatment of dermatological conditions resulting in an imbalance of the barrier function or epidermal homeostasis, advantageously the xerotic skins.

 Another subject of the invention relates to the use of at least one activating substance of the 6-hydroxylase pathway or of an association as defined above to stimulate the synthesis of epidermal ceramides containing a 6-hydroxy-base. sphingenine.

In one embodiment of the invention, the combination according to the invention is used in the form of a composition comprising at least one ceramide precursor based on
6-hydroxy-sphingenine or 6-hydroxy-sphingenine-based ceramide derivative, substrate of the 6-hydroxylase enzymes, and at least one activating substance of the 6-hydroxylase pathway.

 Another embodiment of the invention consists in keeping in separate devices at least one 6-hydroxy-sphingenine-based ceramide precursor or derivative

<Desc / Clms Page number 19>

 of 6-hydroxy-sphingenine-based ceramide, a substrate for 6-hydroxylase enzymes, and at least one activating substance for the 6-hydroxylase pathway and for preparing the composition comprising the combination according to the invention extemporaneously just prior to application.

Another embodiment finally consists of applying the components of the association according to the invention separately, either simultaneously or successively or staggered in time.

The combination according to the invention may be packaged in these cases, in particular in a multi-compartment device also called "Kit" or necessary, the first compartment contains at least the precursor ceramide 6-hydroxysphingenin base or derivative of 6-hydroxy-sphingenine-based ceramide, 6-hydroxylase enzyme substrate and the second compartment contains the 6-hydroxylase pathway promoting substance. This device can be equipped with a mixture of compositions just at the time of application.

 Another subject of the invention relates to a cosmetic process for protecting the skin, characterized in that a sufficient quantity of at least one combination as defined above is applied by means of a single composition. or separately, either simultaneously or sequentially or staggered over time on the skin. Improving the surface appearance and / or the suppleness and / or the hydration of the skin makes it possible to obtain an embellished skin.

 The invention is illustrated in more detail in the following examples. These examples can not in any way limit the scope of the invention.

EXAMPLE 1 Effect of Vitamin C on the Activation of 6-Hydroxylases
Reconstructed epidermis of the EPISKINTM model are treated with Vitamin C introduced directly into the culture medium (at approximately 50 g / ml) 7 days after seeding the keratinocytes on their dermal equivalent (ie on day 7) and this during
6 days (the culture medium and therefore the treatment is repeated twice)
Figure 1 (Fig. 1) is a histogram showing the effect of vitamin C on certain sphingoid bases of the ceramides of the EPISKINTM reconstructed epidermis model.

<Desc / Clms Page number 20>

The results presented in FIG. 1 show that Vitamin C increases the synthesis of ceramides based on 6-hydroxy-sphingenine from their precursor, which are 4-sphingenine-based ceramides.

EXAMPLE 2: Demonstration of 6-hydroxysphingenin ceramide-based deficiency observed in dry skin (score 2) A study was conducted to compare the lipid profiles of samples of normal skin (score 0 of dryness) and dry skin ( drought score 2). The samples (lipids extracted from stratum varnish stripping) are carried out on 22 subjects of score 0 and 19 subjects of score 2. The samples were then pooled by score for reasons of sensitivity to the analysis.

The ceramides were therefore quantified by HPLC / mass spectrometry detection after separation of the different classes by thin layer chromatography. A quantification of the ceramides contained in each migration band was then carried out by HPLC / fluorimetric detection after hydrolysis of the ceramides in bases and fatty acids and specific derivation of the bases (very precise quantitative approach). The results presented in Figure 2.

Figure 2 (Figure 2) is a histogram showing the profile of sphingoid bases by class between dry skin of score 2 and normal skin.

 The results of this study presented in Figure 2 show that the average amount of 6-hydroxy-sphingenine-based ceramides (CER 5. 5, 7 and 4) is lower in dry skin of score 2 than normal skin.

EXAMPLE 3 Compositions

<Tb>
<tb> Formula <SEP> with <SEP> Niosomes <SEP> containing <SEP> the association <SEP> ceramide <SEP> 2 <SEP> + <SEP> vitamin <SEP> C <SEP> glycosylated
<tb> Palmitate <SEP> of <SEP> sorbitan <SEP>(<SEP> Span <SEP> 40 <SEP> marketed <SEP> by <SEP> Uniqema) <SEP> 0. <SEP> 225%
<tb> Cholesterol <SEP> 0. <SEP> 125%
<tb> N <SEP> Stearoyl <SEP> L <SEP> Glutamic <SEP> acid <SEP> disodium <SEP> 0. <SEP> 050%
<tb> Propylene <SEP> Glycol <SEP> 3. <SEP> 000%
<tb> Glucoside <SEP> Ascorbyl <SEP> 0.100%
<tb> N-Oleyl-sphingosine <SEP> 0. <SEP> 050%
<tb> Water <SEP> qsp <SEP> 100. <SEP> 000%
<Tb>
Niosome formula containing the combination ceramide 5+ vitamin C glycosylated Sorbitan palmitate (Span 40 marketed by Uniqema) 0. 225%

<Desc / Clms Page number 21>

Cholesterol 0. 125% N Stearoyl L Glutamic acid disodium 0.050% Propylene glycol 3.000% Ascorbyl glucoside 0.100% N- (2-hydroxyhexadecanoyl) -sphingosine 0. 050% Water qs 100.000% Niosome formula containing the ceramide combination 1 + glycosylated vitamin C Sorbitan palmitate (Span 40 marketed by Uniqema) 0. 225% Cholesterol 0.125% N Stearoyl L Glutamic acid disodium 0.050% Propylene glycol 3.000% Ascorbyl glucoside 0.100% N- (16- [Linoleoyloxy] -hexadecanoyl) -2-amino-4-octadecene-1,3-diol 0. 050% Water qs 100. 000%
Formula. Liposomes containing the combination ceramide 2+ glycosylated vitamin C
Soy lecithin (enriched to 75% of PC) Lipoid S75 0. 5000%
Propylene glycol 3. 0000%
Ascorbyl glucoside 0.100%
N-Oleyl-sphingosine 0. 050%
Water qs 100. 000%
Liposome Formula Containing Ceramide 5+ Vitamin C Glycosylated
Soy lecithin (enriched to 75% of PC) Lipoid S75 0. 5000%
Propylene glycol 3. 0000%
Ascorbyl glucoside 0.100%
N- (2-hydroxyhexadecanoyl) -sphingosine 0. 050%
Water qs 100. 000%
Liposome formula containing the combination ceramide 1+ vitamin C glycosylated
Soy lecithin (enriched to 75% of PC) Lipoid S75 0. 5000%
Propylene glycol 3. 0000%
Ascorbyl glucoside 0.100%
N- (16- [Linoleoyloxy] -hexadecanoyl) -2-amino-4-octadecene-1,3-diol 0. 050%
Water qs 100. 000%

<Desc / Clms Page number 22>

Formula of lamellar type containing the combination ceramide 2 and 5 and + vitamin C alucosylated - stearic acid (triple pressure) (C6-18: 50/50) 1.32
2-Phenoxyethanol 0.5 - Demineralized sterilized water 51.19 - di-sodium salt of ethylene di-amine tetracetic acid, 2 H2O 0. 1 - Iso-paraffin (6-8 moles of iso-butylene) hydrogen 2.5 ( viscosite: 34 CST at 25 degrees Celsius) - Butyl p-hydroxybenzoate 0.3 - Sorbitan monostearate oxyethylene (4 EO) 1.76 - Cyclopenta dimethylsiloxane (viscosity: 4 CST) 3 - Vaseline 2 - White beeswax, pure 1.5 - Liquid fraction of unrefined refined shea butter 5 (palmitic-stearic-oleic-linoleic triglycerides 5/25/60/10) - Glycerine 8 - Natural tocopherols mixture in soya oil (50/50) 0.2 - Oil refined unstabilized deodorized apricot kernel 5 (oleic-linoleic acid triglycerides 66/28) - Syntheticized carboxyvinyl polymer in methylene chloride 0.2 - Perfume 0.25 - methyl p-hydroxybenzoate 0.25 - Stabilized cholesterol (BHT 0. 02 to 0. 04%) 0.05 - 99% tri-ethanolamine 0.53 - n-Oleyl sphin technical gosine 0.03 - Iso-cetyl stearate 5 - Tri-palmito / sucrose stearate (mono / di / tri and poly: 15-25 / 30-40 / 40-50) 2.64 - Vichy water (Lucas source) 5 - N- (2-hydroxyhexadecanoyl) -sphingosine O. 02 - Octane-1,2 diol 0.15 - Arginine pyrrolidone carboxylate 0. 2 to 60% in unstabilized water - Mixture of coriander, macadamia, jojoba, passionflower, apricot kernel (10/10/10/20/50) refined unstabilized 2 - stearyl alcohol (95% cl8) 1.21 - Glucoside ascorbide 0.1

Claims (28)

 1. A combination formed by at least one 6-hydroxysphingenin-based ceramide precursor or 6-hydroxy-sphingenine-based ceramide derivative, a substrate for 6-hydroxylase enzymes, and at least one activating substance for the 6-hydroxylase pathway. 2. Association according to the preceding claim, characterized in that the ceramide precursor or ceramide derivative 6-hydroxy-sphingenine base is a ceramide or a sphingosine-based ceramide derivative. 3. Association according to one of the preceding claims, characterized in that the precursor ceramide or 6-hydroxy-4-sphingenine-based ceramide derivative is a compound of formula (I) below:

 wherein: # R1 is a saturated or unsaturated hydrocarbon chain, linear or branched, comprising between 11 and 21 carbons; # X is a hydrocarbon chain comprising between 2 and 33 saturated or unsaturated carbons, linear or branched, substituted or not by one or more OH groups; # R2 is a hydrogen atom, a glycosyl group, advantageously glucosylated or galactosylated, a phosphorylated group; # Y represents a hydrogen atom, an OH group or an OCOR3 group; # R3 is a saturated or unsaturated hydrocarbon linear chain comprising between 7 and 25 carbons; its optical isomers, or its physiologically acceptable salts. 4. Association according to the preceding claim, characterized in that in the compound of formula (I) X is not substituted with an OH group and Y represents a hydrogen atom, X is a saturated or unsaturated hydrocarbon chain, linear or branched, comprising between 3 and 31 carbons, and saturated R1 comprises 13,14 or 15 <Desc / Clms Page number 24>  carbons. 5. Association according to the preceding claim, characterized in that in the compound of formula (I) X comprises between 5 and 29 carbons, preferably 5.7, 11, 15, 17, 21, 23, 24, 25, 26 or 27. 6. Association according to the preceding claim, characterized in that the compound of formula (I) is selected from the following list: - 2-hexanoylamino-4-octadecene-1,3-diol; D, L-Erythro-2-hexanoylamino-4-octadecene-1,3-diol; 2-octanoylamino-4-octadecene-1,3-diol; D, L-Erythro-2-octanoylamino-4-octadecene-1,3-diol; 2-Lauroylamino-4-octadecene-1,3-diol; Erythro 2-hexadecanoylamino-4-octadecene-1,3-diol; 2-Hexadecanoylamino-4-octadecene-1,3-diol; N-Stearoyl-DL-sphingenine or 2-Stearoylamino-DL-4-octadecene-1,3-diol; - 2-Behenoylamono'-4-octadecene-1,3-diol; Erythro 2-docosanoylamino-4-octadecene-1,3-diol; 2-Tetracosanoylamino-4-octadecene-1,3-diol; Erythro 2-tetracosanoylamino-4-octadecene-1,3-diol; 2- (3'E) -Hexenoylamino-4-octadecene-1,3-diol; N-Oleyl-dihydrosphingosine or 2-Oleoylamino-4-octadecene-1,3-diol; - D, L, Erythro 2-oleoylamino-4-octadecene-1,3-diol; 2-Linoleoylamino-octadecene-1,3-diol or 2-linoleoylamino-3-ol-4-octadecenoic acid; 2-Undecenoylamino-4-octadecene-1,3-diol; N- (2-butyloctanoyl) -2-amino-4-octadecene-1,3-diol; N- (2-Decyl-tetradecanoyl) -2-amino-4-octadecene-1,3-diol; N- (2-hexyl-decanoyl) -2-amino-4-octadecene-1,3-diol. 7. Association according to any one of claims 1 to 3, characterized in that in the compound of formula (I) X is substituted by an OH group and Y represents a hydrogen atom, the OH group is in position a, ss, y or # of the CONH group, X is a saturated or unsaturated hydrocarbon chain, linear or branched, comprising between 2 and 29 carbons and saturated R1 comprises 13,14 or 15 carbons. <Desc / Clms Page number 25> 8. Association according to the preceding claim, characterized in that in the compound of formula (I) X is saturated and comprises 2, 3, 4, 5, 7, 9, 10, 15, 23, 24, 25, 26, 27 or 29 carbons. 9. Association according to the preceding claim, characterized in that the compound of formula (I) is chosen from the following list: - Na-hydroxypalmitoyl-sphingosine or N- (2-hydroxyhexadecanoyl) -sphingenine or N- (2-Hydroxy- hexadecanoyl) -2-amino-4-octadecene-1,3-diol; Erythro n- (2-hydroxy-hexadecanoyl) -2-amino-4-octadecene-1,3-diol; 2- (2-Hydroxy-docosanoyl) -amino-4-octadecene-1,3-diol; N- (2-hydroxy-propanoyl) -2-amino-4-octadecene-1,3-diol; 2- (16-Hydroxy-hexadecanoyl) -amino-4-octadecene-1,3-diol; Erythro N- (16-hydroxy-hexadecanoyl) -2-amino-4-octadecene-1,3-diol.  4-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] octanamide; 4-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] decanamide; 4-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] undecanamide; 6-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] hexanamide.

3-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] butanamide; 4-Hydroxy-N- [2-hydroxy-1- (hydroxymethyl) heptadecyl-3-ene] pentanamide; 10. Association according to any one of claims 1 to 3, characterized in that in the compound of formula (I) X is not substituted by an OH group and Y represents a group OCOR3, X is saturated and comprises either ( i) between 27 and 33 carbons, advantageously 29 carbons, ie (ii) between 13 and 19 carbons, advantageously 15 carbons, the R 3 group is saturated or unsaturated and comprises between 9 and 25 carbons and saturated R 1 comprises 13, 14 or 15 carbons . 11. Association according to the preceding claim, characterized in that in the compound of formula (I) R3 comprises 9,11, 13, 15, 17, 19 or 21 carbons. 12. Association according to the preceding claim, characterized in that the compound of formula (I) is chosen from the following list: - N- (16- [Linoleoyloxy] hexadecanoyl) -2-amino-4-octadecene-1,3 -diol; 2- (16-Hexadecanoyloxy-hexadecanoyl) -amino-4-octadecene-1,3-diol; 2- (16-Oleoyloxy-hexadecanoyl) -amino-4-octadecene-1,3-diol; <Desc / Clms Page number 26> DL Erythro 2- (16-oleoyloxy-hexadecanoyl) -amino-4-octadecene-1,3-diol. 13. Association according to any one of the preceding claims, characterized in that the activating substance of the 6-hydroxylase pathway is a substance capable of increasing the content of the epidermis in at least one ceramide or a ceramide derivative to 6-hydroxy-sphingenine base by activating the hydroxylation in the 6-position of the sphingosine base constitutive of at least one precursor of said ceramide or of said derivative. 14. Association according to the preceding claim, characterized in that the activating substance of the 6-hydroxylase pathway makes it possible to increase the conversion rate of sphingosine-based ceramides into ceramides based on 6-hydroxy-sphingenine. 15. Association according to one of claims 13 and 14, characterized in that the activating substance of the 6-hydroxylase pathway is selected from ascorbic acid or its analogues. 16. Association according to the preceding claim, characterized in that the analogs of ascorbic acid are chosen from its salts, its esters, its sugars, and the derivatives of formula (II):

 wherein: R6 represents a hydrogen atom, a sugar residue, a carbonyl group, an alkyloxycarbonyl group or a carbamoyl group, or R6O represents a sulfate function or a phosphate function, R7 represents a sugar residue or a group - COR10 wherein R10 is chosen from: (a) a saturated or unsaturated, linear, cyclic or branched, optionally hydroxylated, C1-C20 hydrocarbon radical, (b) an optionally hydroxylated aryl radical, (c) an aralkyl radical of formula (III) ): <Desc / Clms Page number 27>  where R, R 'and R ", which may be identical or different, represent a hydrogen atom, a hydroxy, alkoxy, fluoroalkoxy or alkylcarbonyloxy radical, and R8, R9, which may be identical or different, represent a hydrogen atom or a -CORO group; as defined above or taken together form an isopropylidene radical, or a salt thereof.

17. Association according to the preceding claim, characterized in that the analogs of ascorbic acid are selected from sodium ascorbate, magnesium or sodium ascorbyl phosphate, acetic, propionic or palmitic esters of vitamin C, l. glycosylated ascorbic acid. The combination according to any one of the preceding claims formed by: - ascorbic acid and N-Oleyl-sphingosine and / or - ascorbic acid and Na-hydroxypalmitoyl-sphingosine and / or - ascorbic acid and Na-hydroxybhenoyl-sphingosine and / or phosphorylated ascorbic acid and N-oleyl sphingosine and / or phosphorylated ascorbic acid and Na-hydroxypalmitoyl sphingosine and / or phosphorylated ascorbic acid and Na hydroxybhenoyl-sphingosine and / or - glycosylated ascorbic acid and N-oleyl-sphingosine and / or - glycosylated ascorbic acid and Na-hydroxypalmitoyl-sphingosine and / or - glycosylated ascorbic acid and Na-hydroxybehenoyl -sphingosine and / or - ascorbic acid and N- (16- [Linoleoyloxy] hexadecanoyl) -2-amino-4-octadecene 1,3-diol and / or - phosphorylated ascorbic acid and N- (16- [Linoleoyloxy] hexadecanoyl) -2-amino-4-octadecene-1,3-diol and / or - glycosylated ascorbic acid and N- (16- [Linoleoyloxy] hexadecanoyl) -2-amino-4-octadecene-1,3-diol.  19. Composition comprising in a physiologically acceptable medium at least one combination as defined in one of the preceding claims. <Desc / Clms Page number 28> 20. Composition according to the preceding claim, characterized in that the precursor of ceramide or 6-hydroxy-4-sphingenine-based ceramide derivative is present in an amount representing from 0.0001% to 30% by weight, and the substance activator of the 6-hydroxylase pathway is present in an amount of 0.001% to 10% by weight, based on the total weight of the composition. 21. Use of the combination according to any one of claims 1 to 18, as a cosmetic agent. 22. Cosmetic use of the combination according to any one of claims 1 to 18 or a composition according to any one of claims 19 and 20 for reinforcing the barrier function of the skin. 23. Cosmetic use of the combination or a composition containing it according to the preceding claim: to strengthen the lipid barrier of the epidermis, in particular of dry and / or sensitive and / or rough and / or damaged skin and / or or aged, and / or - to restore or maintain the integrity of the stratum corneum, and / or - to improve the surface appearance and / or suppleness and / or hydration of the skin, - to protect the skin, in particular dry and rough skins, and / or - as an essential nutrition agent for keratinous substances (skin, hair, eyelash, nail), and / or - to reinforce the lipid barrier of the reconstructed skin, or skin equivalent and / or or - to improve and / or maintain the lipid content of the human epidermis, in vivo and in vitro, and / or - to improve the quality and properties such as the lipid content and / or the barrier function, reconstructed epidermis and / or epidermal cell cultures and / or - r reduce the insensitive loss of water in dry and / or sensitive and / or rough and / or damaged and / or aged skin.  24. Use of a combination as described in any one of claims 1 to 18 for the manufacture of a composition for the treatment of dermatological conditions resulting in an imbalance of barrier function or epidermal homeostasis. <Desc / Clms Page number 29> 25. Use according to the preceding claim, characterized in that the condition is the xerotic skin. 26. Cosmetic use of at least one activating substance of the 6 hydroxylase pathway as described in any one of Claims 13 to 17 or of an association as defined in any one of Claims 1 to 18 for stimulating the synthesis of epidermal ceramides containing a 6-hydroxysphingenin base. 27. A cosmetic process for beautifying the skin, characterized in that a sufficient quantity of at least one combination as defined in any one of Claims 1 to 18 is applied by means of a single composition. or separately, either simultaneously or sequentially or staggered over time on the skin. 28. Multi-compartment device or "kit", characterized in that it comprises in a first compartment at least one 6-hydroxy-sphingenine-based ceramide precursor or 6-hydroxy-sphingenine-based ceramide derivative, substrate enzymes 6 hydroxylases, as defined in one of claims 1 to 12 and in a second compartment at least one activating substance of the 6-hydroxylase pathway as defined in one of claims 13 to 17.