FR2847467A1 - Cosmetic compositions, e.g. for combating skin barrier function deficiency, dryness or aging symptoms, contain modulator of oxysterol 7 alpha-hydroxylase activity, e.g. dexamethasone - Google Patents

Abstract

The use of oxysterol 7alpha-hydroxylase activity modulator(s) (I) is claimed in cosmetic compositions (A) for preventing and/or treating cutaneous and/or mucous membrane disorders affecting proper cutaneous barrier function.

Description

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 The present invention relates to the use of an agent modulating the activity of oxysterol 7a-hydroxylase for the treatment, in particular cosmetic of epidermal disorders.

 Oxysterol 7a-hydroxylase is an enzyme known to be involved in particular in the metabolism of the steroid hormone DHEA or dehydroepiandrosterone, and of certain molecules belonging to the family of oxysterols.

 Oxysterols are natural metabolites of cholesterol. They are known in particular for being able to block the proteolytic process of the proteins known as SREBP (Sterol Regulatory Element Binding Proteins), necessary for the transcriptional expression of a certain number of enzymes involved in the synthesis of cholesterol (Brown and Goldstein Cell 89: 331-340,1997). They are therefore likely to act as inhibitors of cholesterol synthesis.

 In addition, it is known that oxysterols act at the level of terminal differentiation and of the formation of the cornified envelope in keratinocytes (K. Hanley et al. J. Invest. Dermatol.114: 545 553,2000). More specifically, it has been found that they stimulate the differentiation of keratinocytes and inhibit their proliferation. It is thus known that the stresses undergone by the epidermis, caused in particular by UV radiation or ambient pollution, as well as aging, increase the oxidation state of the keratinocytes and, therefore, induce an increased formation of oxysterols. Finally, it has recently been found that the application, on reconstituted skin, of specific oxysterols, namely 22- and 25-hydroxysterols, makes it possible to increase the thickness of the epidermis. Oxysterols therefore also constitute an attractive therapeutic target for the treatment of skin disorders associated with a decrease in the differentiation of keratinocytes and / or an increase in their proliferation such as, for example, psoriasis.

 For its part, DHEA is a natural steroid produced essentially by the adrenal cortex. In recent years, a great deal of research, both on the DHEA molecule and on its chemical or biological precursors and metabolites, has made it possible to highlight interesting anti-aging properties for these molecules.

 Among the metabolites of DHEA, mention may more particularly be made of 7ahydroxy DHEA which is a major metabolite thereof, obtained precisely by the action of

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 oxysterol 7a-hydroxylase.

 It has thus been shown that this metabolite makes it possible to increase the proliferation of fibroblasts and the viability of human keratinocytes, and exhibits anti-free radical effects (WO 98/40074). It has also been demonstrated in rats (WO 00/28996) that this same metabolite increases the thickness of the dermis and the elastin and collagen content of the skin. Consequently, it has already been suggested to use this metabolite of DHEA to prevent and / or treat the harmful effects of UV on the skin, fight against wrinkles and increase the firmness and tone of the skin.

 Insofar as these oxysterols and DHEA have the particularity of being metabolized by the same enzyme, namely oxysterol 7a-hydroxylase, the latter could constitute an advantageous alternative for the modulation of their expression.

 However, to the knowledge of the Applicant, the direct use of this specific enzyme as a cosmetic target for in particular treating skin disorders linked in particular to a poor functioning of the skin barrier and / or to chronobiological aging, has never been considered.

 Unexpectedly, the inventors very recently characterized the presence of oxysterol 7a-hydroxylase in the skin. More particularly, they detected the presence of messenger RNA corresponding to the CYP7B1coding gene for said protein in extracts of human skin.

 This observation is particularly interesting insofar as it makes it possible precisely to envisage the selective activation or inactivation of this enzyme, at the level of the epidermis and therefore by a topical route. Such a mode of administration is, for obvious reasons, more comfortable and associated with fewer secondary risks than a systemic action.

 Consequently, the present invention relates, according to one of its aspects, to the use of at least one agent modulating the activity of oxysterol 7a-hydroxylase for the preparation of a cosmetic composition intended to prevent and / or treat skin and / or mucous membrane membranes disorders that affect the proper functioning of the skin barrier.

 The present invention also relates, according to another of its aspects,

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 the use of at least one agent for modulating the activity of oxysterol 7a-hydroxylase for the preparation of a cosmetic composition intended to increase the firmness and tone of the skin.

 Another subject of the present invention, according to another of its aspects, is the use of at least one agent which modulates the activity of oxysterol 7a-hydroxylase, for the preparation of a cosmetic composition intended to hydrate the skin. , prevent and / or treat dry skin.

 Another object of the present invention, according to another of its aspects, is the use of at least one agent which modulates the activity of 7a-hydroxylase for the preparation of a cosmetic composition intended to prevent and / or treat signs of chronobiological skin aging.

 By signs of skin aging, we mean all modifications of the external appearance of the skin due to chronobiological aging, such as for example wrinkles and fine lines, or even the lack of elasticity and / or tone of the skin.

 The modulating agent used in the context of the present invention may be either an oxysterol 7a-hydroxylase inhibiting agent or an activating agent thereof.

 In this case, it is advantageous to use an activator of this protein when it is desired to increase the production of 7a-hydroxy DHEA in the skin and / or to decrease the concentration of oxysterols. Regarding the concentration of oxysterol, we know that by reducing it, we induce an increase in cholesterol synthesis. However, this increased concentration of cholesterol is precisely advantageous for treating skin disorders resulting from a dysfunction of the skin barrier linked in particular to an insufficient presence of cholesterol.

 Consequently, the use of an activator is preferred when it is more particularly desired to prevent and / or treat epidermal dysfunctions linked to the natural aging of the skin, an epidermal deficiency in cholesterol (eg aged skin, barrier function attacked by stress, repetitive exposure to chemical agents, excessive washing, etc.) or to increase the firmness and tone of the skin.

 By way of illustration of these activating agents, mention may in particular be made of dexamethasone.

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 With regard to inhibiting agents, their use is preferred when, on the contrary, it is sought to significantly increase, the endogenous levels of certain oxysterols such as 25- and 27-hydroxysterols in the epidermis. It also acts on other functional disorders of the skin barrier. This type of compound is more particularly advantageous when it is sought to prevent and more particularly to treat dry skin associated, if necessary, with scaling. The compositions according to the present invention are in this case particularly advantageous for treating skins thus weakened with a view to effectively reducing their permeability vis-à-vis external aggressive chemical and / or thermal agents.

 As a representative of the inhibitors which can be used according to the invention, mention may in particular be made of ketoconazole, miconazole, clotrimazole, metyrapone, anaphtoflavone, antipyrine, nafimidone, denzimol, 3p-hydroysteroids and their mixtures.

 Among these agents, more particularly suitable are metyrapone, a-naphthoflavone, antipyrine, nafimidone, denzymol, 3-ss-hydroxysteroids and their mixtures.

 The concentration of modulating agent (s) of oxysterol 7a-hydroxylase can vary from 0.0001% to 10% by weight, in particular from 0.001% to 5% by weight, and in particular from 0.005 to 1% by weight. weight relative to the total weight of the composition.

 In general, the composition of the invention can be ingested, injected or applied to the skin (on any cutaneous zone of the body) or on the mucous membranes (buccal, jugale, gingival, genital, conjunctival ...).

 Depending on the mode of administration considered, it can be in all the dosage forms normally used. Preferably, it is applied directly to the skin or the mucous membranes, that is to say topically.

 Thus, a composition intended for topical application of the skin may have the form in particular of aqueous or oily solutions or of dispersions of the lotion or serum type, of 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 vice versa (W / O), of suspensions or emulsions of soft consistency of the aqueous or anhydrous cream or gel type, of microcapsules or microparticles, of vesicular dispersions of the ionic type and / or not ionic or foam. These compositions are prepared according to the usual methods.

 For injection, the composition may be in the form of lotions

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 aqueous, oily or in the form of serums.

 For the eyes, it can be in the form of drops.

 For ingestion, it can be in the form of capsules, granules, syrups or tablets.

 The compositions according to the invention may also consist of solid preparations constituting soaps or cleaning bars.

 The compositions can also be packaged in the form of aerosol compositions also comprising a propellant under pressure.

 A composition according to the invention may also be a composition for caring for the scalp, and in particular a shampoo, a treatment lotion, a cream or a styling gel.

 Of course, the composition may contain adjuvants and additives customary for compositions for body use and in particular surfactants, thickening agents, and / or humectants.

 When the composition is an emulsion, the proportion of the fatty phase can vary from approximately 5% to 80% by weight, and in particular from approximately 5% to 50% by weight relative to the total weight of the composition. The oils, waxes, emulsifiers and co-emulsifiers used in the composition in the form of an emulsion are chosen from those conventionally used in the cosmetic field. The emulsifier and the co-emulsifier may be present in the composition in a proportion ranging from 0.3% to 30% by weight, and in particular from 0.5% to 20% by weight relative to the total weight of the composition.

 The emulsion can, in addition, contain lipid vesicles.

 When the composition is an oily solution or gel, the fatty phase can represent more than 90% of the total weight of the composition.

 In a known manner, the cosmetic composition may also contain adjuvants customary in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, perfumes, fillers, filters, odor absorbers and coloring matters. The amounts of these various adjuvants are those conventionally used in the cosmetic field, and for example can vary from approximately 0.01% to 10% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced into

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 the fatty phase, in the aqueous phase and / or in the lipid spherules.

 The composition may contain other hydrophilic active agents such as proteins or protein hydrosylates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, water-soluble vitamins, plant extracts and hydroxy acids.

 As lipophilic active agents, retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides, essential oils, salicylic acid and its derivatives can be used.

 For use with a view to preventing or combating the signs of skin aging, the composition according to the invention may comprise other anti-aging active agents, in particular anti-wrinkle active agents acting by tightening effect, anti-free radical agents or even compounds which act on the firmness of the skin by inhibiting elastase or increasing the synthesis of collagen.

 The examples which follow are presented by way of nonlimiting illustration of the invention.

 The quantities indicated in these examples are given in percentage by weight, unless otherwise indicated.

 FIGURE 1: Photograph of the electrophoresis gel obtained according to Example 1.

EXAMPLE 1:
Characterization of the expression of the mRNA corresponding to the CYP7B1 gene in an extract of human skin.

 The human skin cDNA was obtained from the company Invitrogen. A cDNA isolated from the liver, available from Stratagene was used as a positive control.

 In parallel, the messenger RNA is isolated from EPISKIN samples using the Quiagen Rneasy mRNA # preparation kit. The cDNAs are obtained using the Superscript single-strand synthesis system. The PCR reactions are then carried out using the cDNAs obtained and two sets of primers corresponding to the specific sequences identified in the published gene sequence CYP7B registered under the reference 4406533 in the Gene Bank. The two sets of primers used are the

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 following: 5 '-GAC CCG GTG AGC CTC CAT TGA TAA- 3', (SEQ Id N 1) - 5 '-CAG TTC TGC CGT GTC CCA ACT TGT- 5', (SEQ Id N 2) and - 5 '- GGG ACA CGG CAG AAC TGT ATC CAT-3 ', (SEQ Id N 3) - 5' -CTA CCA AGT CTC CCT TTC GCA CA? - 3 '(SEQ Id N 4).

 The use of the first set of primers makes it possible to amplify a fragment of 416 base pairs corresponding to nucleotides 124 to 540, while the use of the second set of primers makes it possible to amplify the fragment of 656 base pairs corresponding at nucleotides 523 to 1179.

 Following the PCR reaction, the PCR products are analyzed on Agarose electophoresis gel. The PCR products, of expected sizes, are obtained from the two sets of primers 1 and 2 for the liver, the positive control, the samples of human skin and the Episkin samples.

 As expected, no product was amplified in the negative control in which all the reaction components, except the cDNAs, had been included.

 In Figure 1 is shown a photograph of the electrophoresis gel.

EXAMPLE 2:
Composition for tonic application.

 A care cream having the following composition was prepared: Dexamethasone sold by the company SIGMA 0.01% Glycerol stearate 2% Polysorbate 60 (Tween 60 # sold by the company ICI) 1% Stearic acid 1.4% Triethanolamine 0, 7% Carbomer 0.4% Liquid fraction of shea butter 12% Perhydrosqualene 12% Perfume 0.5% Preservative QS Water QSP 100%

Claims (12)

1. Use of at least one agent which modulates the activity of oxysterol 7ahydroxylase for the preparation of a cosmetic composition intended to prevent and / / treat skin disorders and / or membranes of mucous type affecting the proper functioning of the skin barrier.  2. Use of at least one agent which modulates the activity of oxysterol 7a-hydroxylase for the preparation of a cosmetic composition intended to hydrate the skin and prevent and / or treat dry skin.  3. Use of at least one agent modulating the activity of 7ahydroxylase in a cosmetic composition intended to prevent and / or treat the signs of chronobiological skin aging.  4. Use of at least one agent modulating the activity of 7ahydroxylase in a cosmetic composition intended to increase the firmness and tone of the skin.  5. Use according to any one of the preceding claims, characterized in that the modulating agent is at least one agent which activates the oxysterol 7a-hydroxylase.  6. Use according to claim 5, characterized in that the activating agent is at least dexamethasone.  7. Use according to any one of claims 1 to 4, characterized in that the modulating agent is at least one agent inhibiting the oxysterol 7a-hydroxylase.  8. Use according to claim 7, characterized in that the inhibiting agent is chosen from ketoconazole, miconazole, clotrimazole, metyrapone, a-naphtoflavone, antipyrine, nafimidone, denzymol and 3-p-hydroxysteroids and their mixtures.  9. Use according to claim 7 or 8, characterized in that the inhibiting agent is chosen from metyrapone, a-naphtoflavone, antipyrine, nafimidone, denzymol and 3-p-hydroxysteroids and their mixtures.  10. Use according to any one of the preceding claims, characterized in that the modulating agent is used in the proportion of 0.0001 to 10% and in particular from 0.001 to 5% by weight, relative to the total weight of the composition.  11. Use according to any one of the preceding claims, <Desc / Clms Page number 9>  characterized in that said composition is administered topically.  12. Use according to claim 11, characterized in that said composition is in the form of an aqueous or oily solution, a dispersion of lotion or serum type, of emulsion of fatty phase type in an aqueous phase or vice versa, suspension or emulsion of the cream, aqueous or anhydrous gel type, of micro capsules or microparticles or of vesicular dispersion of ionic and / or nonionic type or of foam.