WO2002047655A1

WO2002047655A1 - Composition, in particular cosmetic, comprising 7-hydroxy dhea or 7-keto dhea and at least a no-synthase inhibitor

Info

Publication number: WO2002047655A1
Application number: PCT/FR2001/003946
Authority: WO
Inventors: Marie-Madeleine Cals-Grierson; Roland Roguet; Guy Courchay
Original assignee: L'oreal
Priority date: 2000-12-15
Filing date: 2001-12-11
Publication date: 2002-06-20
Also published as: FR2818136A1; FR2818136B1; AU2002219286A1

Abstract

The invention concerns a composition comprising, in a physiologically acceptable medium: (a) at least a DHEA derivative selected among 7-hydroxy DHEA and 7-keto DHEA, and (b) at least a NO-synthase inhibitor. The inventive composition is for oral or topical administration. It can be used for cosmetic purposes, to prevent or treat skin irritation and/or sensitive skins and/or for skin ageing symptoms. The NO-synthase inhibitor can be selected among lipochroman-6, a grape, olive tree or gingko biloba or epicatechin extract.

Description

Composition, especially cosmetic, comprising 7-hydroxy DHEA and / or 7-keto DHEA and at least one NO-synthase inhibitor

The invention relates to a composition comprising, in a physiologically acceptable medium: (a) at least one DHEA derivative chosen from 7-hydroxy DHEA and 7-keto DHEA, and (b) at least one NO- inhibitor synthase, as well as its cosmetic and dermatological uses.

The term NO-synthase covers a family of enzymes which ensure the enzymatic catalysis of L-arginine into citrulline, during which catalysis is produced a gaseous mediator with multiple functions, nitrogen monoxide or NO. Due to its electronic hyperreactivity linked to the presence of an additional electron in its structure, NO can cause degradation or even destruction of cells, and is therefore particularly involved in intrinsic and / or extrinsic aging of the skin.

More generally, NO is a multifunctional signal molecule active in a wide variety of body systems and tissues. It is notably well accepted that NO plays a preponderant role in the skin.

NO can indeed be synthesized by all varieties of cells constituting the skin and as such it intervenes in multiple and complex regulatory processes such as the regulation of cell differentiation and / or proliferation, vasodilation, melanogenesis, of the response to environmental variations (homeostasis).

It also intervenes in the skin's immunological and inflammatory processes. It is indeed commonly accepted that NO plays a role in contact hypersensitivity reactions, in allergic skin manifestations, in the skin's immune response. Similarly, in addition to its direct pro-inflammatory role, it is the mediator between neuropeptides such as substance P and / or the peptide associated with the calcitonin gene (calcitonin gene related peptide or CGRP) in cutaneous neurogenic inflammatory processes, of where its involvement in so-called sensitive skin phenomena.

The involvement of NO in vasodilation makes it associated with skin erythemas, particularly erythemas induced by ultraviolet radiation. NO is also recognized as an intermediary in melanogenesis induced by type B ultraviolet radiation (UVB). Finally, NO seems to be involved in the control of sweating as well as in that of lipolysis (inhibitory effect) or even in hair loss.

We therefore understand the interest that exists in having inhibitors of NO-synthases. In this regard, numerous inhibitors have already been proposed in the prior art. Mention may more particularly be made of N ^G- monomethyl-L-arginine (NM A), the methyl ester of N ⁶ -nitro-L-arginine (NAME), N ^G -nitro-L-arginine (NNA), N ^G -amino-L-arginine (NAA), N ^Θ .N ^G - dimethyl-arginine (asymmetric dimethylarginine, called ADMA), diphenyleneiodonium chloride, 2- (4-carboxyphenyl) -4,4, 5,5-tetramethylimidazoline-1 -oxy-3-oxide, 7-nitroindazole, N (5) - (1-iminoethyl) -L-ornithine, aminoguanidine, canavanine and ebselen.

More recently, other NO-synthase inhibitors more suitable for cosmetic application have been described. These are in particular lipochroman-6 (FR 00/05520), grape extract (FR 00/05521), olive tree (FR 00/05522) or gingko biloba (FR 00/05523) or epicatechin (FR 00/05524).

However, there remains the need to reinforce the effectiveness of these compounds in the prevention and / or treatment of certain disorders, notably cutaneous.

However, it appeared to the Applicant that certain derivatives of DHEA could make it possible to improve the effectiveness of the compositions comprising inhibitors of NO-synthase.

DHEA, or dehydroepiandrosterone, is a natural steroid produced primarily by the adrenal cortex. Exogenous DHEA, administered topically or orally, is known for its ability to promote keratinization of the epidermis (JP-07 196 467) and to treat dry skin by increasing endogenous production and sebum secretion and by strengthening thus the barrier effect of the skin (US Pat. No. 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. Finally, the Applicant has demonstrated the ability of DHEA 'to fight against the papery appearance of the skin (FR 00/00349), to modulate the pigmentation of the skin and hair (FR 99/12773) and to fight against atrophy of the epidermis (FR 00/06154). 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 on the skin, fight against wrinkles and increase the firmness and tone of the skin.

7α-hydroxy DHEA is, with 5-androstene 3β, 17β-diol, a major metabolite of DHEA, obtained by the action of 7α-hydroxylase on DHEA. Among the minor metabolites of DHEA, there may be mentioned 7β-hydroxy DHEA, obtained by the action of 7β-hydroxylase on DHEA and 7-keto DHEA, which is itself a metabolite of 7β-hydroxy DHEA.

In the remainder of this description, the expression "7-hydroxy DHEA" will be used to denote either 7α-hydroxy DHEA and 7β-hydroxy DHEA.

To the knowledge of the Applicant, it has never been suggested to combine 7-hydroxy DHEA and / or 7-keto DHEA with an inhibitor of NO-synthase.

The subject of the invention is therefore a composition comprising, in a physiologically acceptable medium: (a) at least one DHEA derivative chosen from 7-hydroxy DHEA and 7-keto DHEA, and (b) at least one NO inhibitor synthase.

7-hydroxy DHEA is preferably 7α-OH DHEA. A process for the preparation of this compound is described in particular in patent applications FR-2 771 105 and WO 94/08588. However, 7β-OH DHEA is also suitable for use in the present invention. The concentration of DHEA derivative in the composition according to the invention is advantageously between 0.0001% and 10% by weight, preferably between 0.001% and 5% by weight, relative to the total weight of the composition.

For its part, the NO-synthase inhibitor is chosen from the compounds inhibiting the synthesis and / or accelerating the catabolism of NO-synthase, the compounds neutralizing NO-synthase or the compounds intervening by modulating the signal transduced by NO synthase. Thus, according to the invention, NO-synthase inhibitors are products which make it possible, in situ on humans, to partially or even completely inhibit the synthesis of nitrogen monoxide (NO).

NO-synthases exist in three forms, namely two constitutive forms grouping together neuronal NO-synthase (or NOS 1) and endothelial NO-synthase (or NOS 3), and an inducible form (or NOS 2) (Medicine / Sciences , 1992, 8, pp. 843-845). In the present application, the term NO-synthase covers all of the isoforms of the enzyme.

The NO synthase inhibitor can be chosen from: N-monomethyl-L-arginine (NMMA), N ^G -nitro-L-arginine; the methyl ester of N ^G -nitro-L-arginine; diphenyleneiodonium chloride; 7-nitroindazole; N (5) - (1-iminoethyl) -L-ornithine, NG, NG-dimethyl-L-arginine; NG.NG-dimethyl-arginine; 2- (4-carboxyphenyl) -4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide; aminoguanidine; canavanine and ebselen.

Alternatively, and according to a preferred embodiment, the NO-synthase inhibitor according to the invention can be chosen from: lipochroman-6, an extract of grape, olive or gingko biloba or epicatechin.

Lipochroman-6 is a compound corresponding to the general formula:

By "grape extract" is meant a plant extract of the species Vitis vinifera which is in particular marketed by the company Euromed under the name Leucocyanidines of extra grapes, or by the company Indena under the name Leucoselect ^® , or finally by the company Hansen under the name Extract of grape marc.

By "olive extract" means a plant extract of the species Olea europaea which is preferably obtained from olive leaves. This extract is in particular marketed by the company VINYALS in the form of dry extract, or by the company Biologia & Technologia under the trade name Eurol BT.

By "extract of Gingko biloba" means an extract of a plant of the species Gingko biloba. Preferably according to the invention, a dry aqueous extract of this plant is used, sold by the company Beaufour under the trade name Ginkgo biloba standard extract.

Epichatechin or 2- [3,4-dihydroxyphenyl] -3,4-dihydro-1 [2H] ~ benzopyran-3, 5, 7-triol is a natural component of green tea. It can be in the form of two enantiomers, namely: (+) - epichatechin or [2S, 3S] -2- [3,4-dihydroxyphenyl] -3,4-dihydro-1 [2H] - benzopyran-3 , 5, 7-triol; and (-) - epichatechin or [2S, 3S] -2- [3,4-dihydroxyphenyl] -3,4- dihydro-1 [2H] -benzopyran-3, 5, 7-triol.

According to the invention, each of these compounds can be used alone. However, the invention also relates to the use of a mixture in any proportion of (+) - epichatechin and (-) - epichatechin. In addition to these two enantiomeric forms, the invention also relates to analogs of epichatechin and / or its derivatives with the exception of epichatechin-gallate.

Thus, elsewhere in the text and for simplicity, the term epicatechin is understood, unless otherwise indicated, as meaning the (+) epichatechin or (-) epichatechin or a mixture in any proportion of (+) - epichatechin and (- ) -epichatechin, as well as analogues of epichatechin and / or its derivatives with the exception of epichatechin-gallate.

The composition according to the invention can be adapted for topical application to the skin. In this case, the DHEA derivatives can be present in an amount ranging from 0.0001 to 10% by weight, and preferably from 0.001 to 5% by weight, relative to the total weight of the composition. More preferably, the DHEA derivatives can be present in an amount of about 1% by weight, relative to the total weight of the composition. The NO synthase inhibitor can, for its part, represent from 0.001 to 1% of the total weight of the composition. The composition according to the invention can be in all dosage forms suitable for topical application, normally used in the cosmetic and dermatological fields, and it can in particular be in the form of an optionally gelled aqueous solution, of a dispersion of the type optionally two-phase lotion, of an emulsion obtained by dispersion of a fatty phase in an aqueous phase (O / W) or vice versa (W / O) or of a triple emulsion (W / O / W or O / W). These compositions are prepared according to the usual methods.

This composition can be more or less fluid and have the appearance of a white or colored cream, an ointment, a milk, a lotion, a serum, a paste, a foam. . It can optionally be applied to the skin in the form of an aerosol. It can also be in solid form, in particular in the form of a stick. It can be used as a care product and / or as a make-up product for the skin.

In known manner, the composition of the invention can also contain the adjuvants usual in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, perfumes, fillers, filters, pigments, odor absorbers and coloring matters. The amounts of these various adjuvants are those conventionally used in the field under consideration, and for example from 0.01 to 20% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced into the fatty phase or into the aqueous phase. In any event, these adjuvants, as well as their proportions, will be chosen so as not to harm the desired properties of the combination of active agents according to the invention.

When the composition of the invention is an emulsion, the proportion of the fatty phase can range from 5 to 80% by weight, and preferably from 5 to 50% by weight relative to the total weight of the composition. The oils, emulsifiers and coemulsifiers used in the composition in the form of an emulsion are chosen from those conventionally used in the field under consideration. The emulsifier and the coemulsifier are present in the composition in a proportion ranging from 0.3 to 30% by weight, and preferably from 0.5 to 20% by weight relative to the total weight of the composition. As oils which can be used in the invention, mention may be made of mineral oils (petrolatum oil), oils of vegetable origin (avocado oil, soybean oil), oils of animal origin (lanolin), oils of synthesis (perhydrosqualene), silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers). Fatty alcohols (cetyl alcohol), fatty acids, waxes (camauba wax, ozokerite) can also be used as fats.

As emulsifiers and coemulsifiers which can be used in the invention, there may be mentioned, for example, fatty acid esters of polyethylene glycol such as PEG-20 stearate, and fatty acid and glycerin esters such as glyceryl stearate .

As hydrophilic gelling agents, mention may in particular be made of carboxyvinyl polymers (carbomers), acrylic copolymers such as acrylate / alkyl acrylate copolymers, polyacrylamides, polysaccharides, natural gums and clays, and, as lipophilic gelling agents, cite modified clays such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylenes.

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 also compounds acting on the firmness of the skin by inhibiting elastase or increasing the synthesis of collagen.

According to another possibility, the composition according to the invention can be adapted for oral administration. In this case, the DHEA derivative can be administered at a rate of 1 to 100 mg / day, preferably 25 to 75 mg / day and the inhibitor of NO synthase can be administered at a rate of 1 to 100 mg / day. , preferably 25 to 75 mg / day.

This composition can be in any dosage form suitable for this mode of administration, for example in the form of breakable tablets or not, granules, capsules, capsules, solutes, suspensions or solutions comprising an appropriate excipient. In all cases, the composition according to the invention comprises an effective amount of DHEA derivative and an effective amount of NO synthase inhibitor, sufficient to obtain the desired effect, in a physiologically acceptable medium.

Whatever its mode of administration, the composition according to the invention can be used for cosmetic purposes, to prevent and / or treat irritation of the skin and / or sensitive skin and / or signs of skin aging, especially photo-aging.

The term "skin irritation" means any form of irritation resulting for example from the application to the skin of chemicals of natural or synthetic origin, and which can result, in particular, in redness, pain or tingling, or even resulting from exposure to ultraviolet radiation.

The expression "sensitive skin" covers both irritable and / or reactive skin and intolerant skin.

Irritable and / or reactive skin is skin that reacts with pruritus, that is, itching or tingling, to various factors such as the environment, emotions, food, wind, friction, razor, soap, surfactants, hard water with high concentration of limestone, temperature variations or wool. In general, these signs are associated with dry skin with or without sores or with skin that has an erythema.

Intolerant skin is skin that reacts with sensations of heating, tightness, tingling and / or redness, to various factors such as the environment, emotions, food and certain cosmetic products. In general, these signs are associated with hyperseborrheic or acne-prone skin with or without sores and erythema>

Finally, by "signs of skin aging" is meant all modifications of the external appearance of the skin due to aging whether it is chronic or otog / and / or photo-induced, as for example wrinkles and fine lines, or lack of elasticity and / or skin tone. The present invention therefore also relates to a cosmetic method for preventing and / or treating irritation of the skin and / or sensitive skin and / or signs of skin aging, comprising the topical or oral administration of a composition comprising a DHEA derivative according to the invention, in combination with at least one NO-synthase inhibitor.

The invention will be better understood, and its advantages will emerge more clearly in the light of the following examples, which are given by way of illustration, and without limitation. The amounts indicated in these examples are given in percentage by weight, unless otherwise indicated.

EXAMPLES

Example 1 Composition for Oral Administration

Soft capsules are prepared, conventionally for those skilled in the art, having the following composition:

Hydrogenated soybean oil 40 mg

Wheat oil 95 mg

Soy lecithin 20 mg

Natural tocopherols 5 mg

Dry extract of encapsulated Vitis vinifera (sold by the company INDENA under the trade name "Phytosome de Leucoselect") 300 mg

(corresponding to approximately 100 mg of Vitis vinifera extract)

7α-OH DHEA 50 mg

Example 2 - Composition for topical application

A treatment cream (oil-in-water emulsion) having the following composition is prepared, conventionally for a person skilled in the art: Dry aqueous extract of Ginkgo biloba sold by the company Beaufour under the trade name "Ginkgo biloba standard extract" 5%

7α-OH DHEA, 0.1%

Glycerol stearate 2% Ό Polysorbate 60 (Tween 60 ^® sold by the company ICI) 1%

Stearic acid 1.4% 0

0.7% triethanolamine

Carbomer 0.4% Ό

Liquid fraction of shea butter 12% Ό Perhydrosqualene 12%

Perfume 0.5%

QS Curator

100% QSP water

Claims

1. Composition comprising, in a physiologically acceptable medium: (a) at least one DHEA derivative chosen from 7-hydroxy DHEA and 7-keto DHEA, and (b) at least one NO-synthase inhibitor.

2. Composition according to claim 1, characterized in that the 7-hydroxy DHEA is 7α-OH DHEA.

3. Composition according to claim 1, characterized in that the 7-hydroxy DHEA is 7β-OH DHEA.

4. Composition according to any one of claims 1 to 3, characterized in that the NO-synthase inhibitor is chosen from: lipochroman-6, an extract of grape, olive or gingko biloba or epicatechin .

5. Composition according to any one of claims 1 to 4, characterized in that it is suitable for topical application to the skin.

6. Composition according to claim 5, characterized in that the DHEA derivative is present in an amount ranging from 0.0001 to 10% by weight, relative to the total weight of the composition.

7. Composition according to claim 6, characterized in that the DHEA derivative is present in an amount ranging from 0.001 to 5% by weight, relative to the total weight of the composition.

8. Composition according to Claim 7, characterized in that the DHEA derivative is present in an amount of approximately 1% by weight, relative to the total weight of the composition.

9. Composition according to any one of claims 5 to 8, characterized in that the NO-synthase inhibitor represents from 0.001 to 1% of the total weight of the composition.

10. Composition according to any one of claims 1 to 4, characterized in that it is suitable for administration by the oral route.

11. Cosmetic use of the composition according to any one of claims 1 to 10, for preventing and / or treating irritation of the skin and / or sensitive skin and / or signs of skin aging.

12. Cosmetic process for preventing and / or treating irritation of the skin and / or sensitive skin and / or signs of skin aging, comprising the topical or oral administration of a composition according to one any of claims 1 to 10.

13. The method of claim 12, characterized in that said DHEA derivative is administered orally at a rate of 1 to 100 mg / day, preferably from 25 to 75 mg / day.