FR2818149A1 - COMPOSITION, ESPECIALLY COSMETIC, COMPRISING 7-HYDROXY DHEA AND / OR 7-CETO DHEA AND AT LEAST ONE 5 ALPHA-REDUCTASE INHIBITOR - Google Patents

Abstract

The invention relates to a composition containing, 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 inhibitor of 5a- reductase. It also relates to the cosmetic use of this composition for preventing or treating disorders linked to an overactivity of 5a-reductase, such as acne and / or seborrhea and / or hirsutism and / or alopecia androgen-dependent. It also relates to a method of cosmetic treatment of the skin or the scalp, comprising the application to the skin or the scalp of this composition.

Description

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The present invention relates to a composition containing, in a physiologically acceptable medium: (a) at least one DHEA derivative chosen from 7hydroxy DHEA and 7-keto DHEA, and (b) at least one 5a-reductase inhibitor, as well as its uses, in particular cosmetic.

Androgens are hormones defined as belonging to the steroid family and which easily cross cell membranes. Their mechanism of action is through interaction with a specific receptor: the androgen receptor.

Testosterone appears as the major androgen. The metabolic pathways of androgens, testosterone in particular, are now well known. Thus, one of the metabolic pathways of testosterone is its conversion by 5a-reductase to dihydrotestosterone (DHT). Testosterone and DHT bind to the androgen receptor, but DHT has a much higher affinity for this receptor than testosterone. In addition, the DHT / receptor linkage is much more stable than the testosterone / receptor linkage.

Two isoforms of 5a-reductase have so far been isolated and cloned. 5a-reductase type 1 is mainly expressed in the skin and the various compartments of the hair follicle, particularly in the keratinocytes of the epidermis and / or of the follicle, in the cells of the dermal papilla, the outer sheath of the hair follicle, the sebaceous gland and in the sweat glands.

Type 2 5a-reductase is rather expressed in the epididymis, seminal vesicles, prostate, fetal genital skin or the internal sheath of the hair follicle or in fibroblasts of adult genital skin.

Since type 5a-reductase is mainly expressed in the skin and the various compartments of the hair follicle, the development of type 1 5a-reductase inhibitors represents a preferred approach for treating androgen-dependent disorders, particularly hirsutism or androgenic alopecia.

The development of 5a-reductase inhibitors is also of interest in the treatment of seborrhea and therefore acne.

Indeed, sebaceous hypersecretion, characteristic of oily skin, is most often linked to hyperandrogenism due either to a hyperproduction of androgens by a

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 endocrine gland, or to a peripheral hyperproduction in the sebaceous gland from surrounding androgens and / or proandrogens. The androgen which induces lipid synthesis in the nucleus of the sebocyte is dihydrotestosterone (DHT) which comes, as indicated above, from the reduction of testosterone by 5a-reductase. The general appearance of the skin is grainy and, depending on the case, has well-known imperfections such as white dots, black dots, small pimples, sebaceous microcysts, which are very often the prelude to the installation of acne disorders.

Acne vulgaris, commonly known as acne, is a skin disorder affecting a large number of people. It develops in people with hyperseborrhea. Acne occurs when the sebaceous follicles, located on the face and back, become clogged with sebum and epithelial cells. The obstruction of the follicle creates a micro-comedo which can develop into a comedo or an inflammatory lesion.

5a-reductase inhibitors have already been proposed in order to treat the abovementioned disorders. However, these compounds are not always active enough to effectively prevent or treat acne, seborrhea, hirsutism or androgen-dependent alopecia.

It has now appeared to the Applicant that the combination of a 5a-reductase inhibitor with certain DHEA derivatives makes it possible to more effectively prevent or treat these disorders linked to an overactivity of 5a-reductase.

DHEA, or dehydroepiandrosterone, is a natural steroid produced essentially by the adrenal cortex which, like its chemical or biological precursors and metabolites, has been the subject of numerous researches in recent years, having highlighted interesting anti-aging properties. .

Among the metabolites of DHEA, particular attention has been paid to 7a-hydroxy DHEA. 7a-hydroxy DHEA is, with 5-androstene 3ss, 17ss-diol, a major metabolite of DHEA, obtained by the action of 7a-hydroxylase on DHEA. Among the minor metabolites of DHEA, one can cite! a 7 (3-hydroxy DHEA, obtained by the action of 7ss-hydroxylase on DHEA and 7-keto DHEA, which is itself a metabolite of 7ss-hydroxy DHEA.

In the remainder of this description, the expression "7-hydroxy DHEA" will be used to

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désigner indifféremment la 7a-hydroxy DHEA et la 7ss-hydroxy DHEA.

designate indifferently 7a-hydroxy DHEA and 7ss-hydroxy DHEA.

It has already been shown that these metabolites of DHEA which do not possess the hormonal activity of DHEA, and in particular 7-OH DHEA, make it possible to increase the proliferation of fibroblasts and the viability of human keratinocytes and exhibit effects. anti-free radicals (WO 98/40074). It has also been demonstrated in rats (WO 00/28996) that 7a-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.

However, to the knowledge of the Applicant, it has never been suggested that these DHEA derivatives could make it possible to improve the effect on the skin or the scalp of compositions containing 5a-reductase inhibitors.

The subject of the present invention is therefore a composition containing, in a physiologically acceptable medium: (a) at least one DHEA derivative chosen from 7hydroxy DHEA and 7-keto DHEA, and (b) at least one 5a-reductase inhibitor .

7-hydroxy DHEA is preferably 7a-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, 7ss-OH DHEA is also suitable for use in the present invention.

The DHEA derivative can represent from 0.0001 to 10%, and preferably from 0.001 to 5%, of the total weight of the composition according to the invention. The latter is suitable for topical application to the skin or scalp and therefore generally contains a physiologically acceptable medium, that is to say compatible with the skin and its integuments (hair and hair in particular).

For its part, the 5a-reductase inhibitor can in particular be chosen from: - 4, 6-dimethoxy-indole-2-carboxylic acid and its derivatives; - ie 4-aza-5-atpha-androstane and its derivatives described in particular in the US patent -
5,543,417; your estrogens; - cyproterone and its acetate;

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! es rétino'tdes, et en particulier le rétinol ; le soufre et les dérivés soufrés ; les sels de zinc tels que le lactate, le gluconate, le pidolate, le carboxylate, le salicylate et/ou le cystéate de zinc ; te chlorure de sélénium ; ta vitamine B6 ou pyridoxine ; le mélange de capryloyl glycine, de sarcosine et d'extrait de cinnamomum zeylanicum commercialisé notamment par la société SEPPIC sous la dénomination commerciale Sep ! contro ! A5 : un extrait de Laminana saccharina commercialisé notamment par la société SECMA

sous la dénomination commerciale Phlorogines ; un extrait de Spiraea ulmaria commercialisé notamment par la société SILAB sous la dénomination commerciale Sebonormine ; des extraits de végétaux des espèces Arnica montana, Cinchona succirubra,
Eugenia caryophyllata, Humulus lupulus, Hypericum perforatum, Mentha piperita,
Rosmarinus officinalis, Salvia oficinalis et Thymus vulgaris, tous commercialisés par exemple par la société MARUZEN ; un extrait de Serenoa repens commercialisé notamment par la société EUROMED ; des extraits de plantes du genre Silybum ; et des extraits végétaux contenant des sapogénines et en particulier les extraits de
Dioscorées riches en diosgénine ou hécogénine.

! es retino'tdes, and in particular retinol; sulfur and sulfur derivatives; zinc salts such as lactate, gluconate, pidolate, carboxylate, salicylate and / or zinc cysteate; te selenium chloride; your vitamin B6 or pyridoxine; the mixture of capryloyl glycine, sarcosine and cinnamomum zeylanicum extract sold in particular by the company SEPPIC under the trade name Sep! contro! A5: an extract of Laminana saccharina marketed in particular by the company SECMA

under the trade name Phlorogines; an extract of Spiraea ulmaria sold in particular by the company SILAB under the trade name Sebonormine; plant extracts of the Arnica montana, Cinchona succirubra species,
Eugenia caryophyllata, Humulus lupulus, Hypericum perforatum, Mentha piperita,
Rosmarinus officinalis, Salvia oficinalis and Thymus vulgaris, all marketed for example by the company MARUZEN; an extract of Serenoa repens sold in particular by the company EUROMED; plant extracts of the genus Silybum; and plant extracts containing sapogenins and in particular extracts of
Dioscorea rich in diosgenin or hecogenin.

The preferred compounds are 4, 6-dimethoxy-indole-2-carboxylic acid and its derivatives, retinol, zinc salts, vitamin B6, extracts of Serenoa repens, and sapogenins.

The amount of 5a-reductase inhibitor in the composition according to the invention is of course a function of the desired effect and can therefore vary to a large extent. To give an order of magnitude, it can be used in an amount representing from 0.001 to 10% of the total weight of the composition and preferably in an amount representing from 0.01 to 5% of the total weight of this composition.

The composition according to the invention can be in all dosage forms normally used for topical application to the skin or scalp, in particular in the form of an oily, aqueous or hydroalcoholic solution, of an oil-in-water emulsion or water-in-oil or multiple, of a silicone emulsion, a microemulsion or nanoemulsion, an oily gel or a liquid, pasty or solid anhydrous product, or in the form of a patch.

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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. or a gel. It can optionally be applied to the skin or scalp in the form of an aerosol. It can also be in solid form, and for example in the form of a stick. It can be used as a care and / or toilet product and / or as a skin makeup product. Alternatively, it can be used as a shampoo or conditioner.

In a known manner, the composition of the invention may also contain the adjuvants usual in the cosmetic and dermatological fields, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, perfumes, fillers and more particularly fillers absorbing sebum and / or matifiers (dry flow, kaolin; silica derivative), pigments, hydrophilic filters, odor absorbers and coloring matters. The amounts of these various adjuvants are those conventionally used in the fields 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.

When the composition according to 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.

As fatty materials which can be used in the invention, it is possible to use mineral oils, oils of animal origin, synthetic oils, silicone oils and fluorinated oils. Fatty acids, waxes and gums and in particular silicone gums can also be used as fats.

The emulsifiers and co-emulsifiers optionally used in the composition in the form of an emulsion are chosen from those conventionally used in the field under consideration. These emulsifiers and coemulsifiers are preferably 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 emulsifiers and co-emulsifiers which can be used in the invention, it is particularly advantageous to use fatty acid and polyol esters such as PEG-100 stearate, PEG-50 stearate and PEG-40 stearate ; sorbitan tristearate, oxyethylenated sorbitan stearates available under the trade names Tweens 20 or Tweens

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 60, for example; and their mixtures.

Foaming surfactants can also be used in cleaning products. As examples of such surfactants, non-ionic, anionic or amphoteric foaming surfactants may be mentioned. It is particularly advantageous to use alkylpolyglucosides, alkylsulfates, alkyl ether sulfates, sulfonates, isethionates, sulfosuccinates, fatty acid soaps, amino acid derivatives, betaines and their derivatives.

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

Of course, those skilled in the art will take care to choose the optional compound (s) to be added to the compositions according to the invention, as well as their concentration, so that the advantageous properties of the combination of active agents according to the invention are not, or not substantially, altered by the proposed addition.

The composition according to the invention can be used for cosmetic or dermatological purposes, to prevent or treat disorders linked to an overactivity of 5areductase.

The present invention therefore also relates to the cosmetic use of the composition defined above for preventing or treating disorders linked to an overactivity of 5a-reductase, such as acne and / or seborrhea and / or hirsutism and / or androgen-dependent alopecia.

It also relates to the use of the abovementioned composition for the manufacture of a preparation intended to prevent or treat disorders linked to an overactivity of 5a-reductase, such as acne and / or seborrhea and / or hirsutism and / or androgen-dependent alopecia.

Finally, it relates to a process for the cosmetic treatment of the skin or the scalp, comprising the application to the skin or the scalp of this composition.

The invention will now be illustrated by the following nonlimiting examples. In these

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 examples, the quantities are indicated in percentage by weight.

EXAMPLE 1 Gel for Oily Skin Phase A
Acrylate / Cic-30 alkyl acrylate copolymer (Pemulen TR1) 0.5%
Water 12% Phase B Hexyldecanol 10% Isononyl isononanoate 10% 7a-OH DHEA 0.5% Phase C
0.5% triethanolamine
Water qs
Glycerin 6%
Preservatives 0.25%
0.5% zinc pyrrolidone carboxylate
Polyacrylamide and C13-14 isoparaffin and laureth-7 (Sepigel 305 sold by the company SEPPIC) 0.5%
Aluminum starch octenyl succinate 1% This composition can be prepared as follows.

The polymer of phase A is dispersed in water at 40oC. The constituents of phase B are heated to 70 C until complete dissolution, then the temperature is reduced to 40oC. The constituents of phase C are mixed at 50oC. Phase B is then introduced into phase A at 40 C with stirring, then phase C is added to them.

This cream is particularly well suited to the treatment of oily skin in single or twice daily application.

Example 2: Thickened anti-hair loss lotion This lotion can be prepared in a conventional manner for a person skilled in the art.

 Wild Yam Rhizome Extract (Dioscorea vilosa) titrated to 3% diosgenin 0.5% 7a-OH DHEA 0.01%

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Propylène glycol 20 % Hydroxypropyl cellulose 3, 5 %
Alcool éthylique qsp Exemple 3 : Gel de nettoyage Ce gel peut être préparé de manière classique pour l'homme du métier.

Propylene glycol 20% Hydroxypropyl cellulose 3,5%
Ethyl alcohol qs Example 3: Cleaning gel This gel can be prepared in a conventional manner for a person skilled in the art.

Tétrastéaratedepentaérythnty ! epo ! yoxyéthy ! éné (1500E) 0, 5 %
Glycérine 3,5 %
Sorbitol 3, 5 %
Hydroxyde de potassium 1, 7 %
Hydroxypropyl cellulose 0,2 %
EDTA ! Sod ! que 0. 05%
Chlorure de sodium 0,1 % 7&alpha;-OH DHEA 0,1 % Extrait de laminaria saccharina (Phlorogine# de SECMA) 1 %
Conservateurs 0,3 %
Eau qsp 100 % Exemple 4 : Crème teintée pour peaux grasses Cette crème peut être préparée de manière classique pour l'homme du métier. 75% lauryl mono-phosphate (MAP 20 # from KAO) CHEMICALS) 6.5%
Decyl glucoside 40% (MYDOL 10 # from KAO CHEMICALS) 16.25%
Polyquaternium-7 at 8% (MERQUAT Sus de CALGON) 5, 7%

Tetrasteareatepentaerythty! epo! yoxyethy! ené (1500E) 0.5%
Glycerin 3.5%
Sorbitol 3.5%
Potassium hydroxide 1.7%
0.2% hydroxypropyl cellulose
EDTA! Sod! than 0.05%
Sodium chloride 0.1% 7 &alpha; -OH DHEA 0.1% Laminaria saccharina extract (Phlorogin # from SECMA) 1%
Preservatives 0.3%
Water qs 100% Example 4: Tinted cream for oily skin This cream can be prepared in a conventional manner for a person skilled in the art.

2.4% hydrogenated lecithin
Apricot almond oil 6%
Ethylene glycol dimethacrylate copolymer /
Lauryl methacrylate 1%
Oxyethylenated soy sterols (5 EO) 1.6% 7 &alpha; -OH DHEA 0.5%
Serenoa repens extract 1%
Iron oxides 0.9%
Titanium oxide 5%
Polyacrylamide and C13-14 isoparaffin and laureth-7 (Sepigel 305 sold by the company SEPPIC) 4%
Cyclopentasiloxane 6%
Glycerin 6%

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Propylene glycol 6% Perfume qs
Water qs 100% Example 8: Camouflaging stick for oily skin This stick can be prepared in a conventional manner for the skilled person.

Carnauba and ozokerite waxes 14%
Liquid fraction of shea butter 4%
Titanium and zinc oxides 22%
Iron oxides 4% 7-keto DHEA 0.5%
Zinc salicylate 0.5% Polydimethyl siloxane / hydrated silica 0.1%
Cetyl alcohol 1.4%
Isoparaffin qs 100% This stick can be applied several times a day on the face to cleanse and camouflage skin imperfections.

Example 9: Patch in situ
Water 40
Ethyl alcohol qs
Glycerin 7 7a-OH DHEA 0.05
Salicylic acid 0. 1
Triclosan 0.1
Polyvinyl alcohol 5 This gel is intended to be applied to acne pimples. After drying, a thin film is formed which diffuses the active ingredients like a patch.

Claims (13)

 1. Composition containing, 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 5a-reductase inhibitor. 2. Composition according to claim 1, characterized in that the 7-hydroxy DHEA is 7a-OH DHEA. 3. Composition according to claim 1, characterized in that the 7-hydroxy DHEA is 7D-OH DHEA. 4. Composition according to any one of claims 1 to 3, characterized in that the DHEA derivative represents from 0.0001 to 10% of the total weight of the composition. 5. Composition according to claim 4, characterized in that the DHEA derivative represents from 0.001 to 5% of the total weight of the composition. 6. Composition according to any one of claims 1 to 5, characterized in that

 said 5a-reductase inhibitor is chosen from: 4, 6-dimethoxy-indole-2-carboxylic acid and its derivatives; - 4-aza-5-alpha-androstane and its derivatives; - estrogens; your cyproterone and its acetate; your retinoids, and in particular retinol; sulfur and sulfur derivatives;

 - zinc salts such as lactate, gluconate, pidolate, carboxylate, salicylate and / or zinc cysteate; - selenium chloride; your vitamin B6 or pyridoxine; an extract of Laminaria saccharina; - an extract of Spiraea ulmaria; plant extracts of the Arnica montana, Cinchona succirubra species, Eugenia caryophyllata, Humulus lupulus, Hypericum perforatum, Mentha piperita, Rosmarinus officinalis, Salvia oficinalis and Thymus vulgaris; an extract of Serenoa repens; - extracts of plants of the genus Silybum; and <Desc / Clms Page number 11> Dioscorea rich in diosgenin.  - plant extracts containing sapogenins and in particular extracts of 7. Composition according to any one of claims 1 to 6, characterized in that said 5a-reductase inhibitor represents from 0.001 to 10% of the total weight of the composition. 8. Composition according to Claim 7, characterized in that the said 5a-reductase inhibitor represents from 0.01 to 5% of the total weight of the composition. 9. Cosmetic use of the composition according to any one of claims 1 to 8 for preventing or treating disorders linked to an overactivity of 5a-reductase. 10. Cosmetic use of the composition according to any one of claims 1 to 8 for preventing or treating acne and / or seborrhea and / or hirsutism and / or androgen-dependent alopecia. 11. Use of the composition according to any one of claims 1 to 8 for the manufacture of a preparation intended to prevent or treat disorders linked to an overactivity of 5a-reductase. 12. Use of the composition according to any one of claims 1 to 8 for the manufacture of a preparation intended to prevent or treat acne and / or seborrhea and / or hirsutism and / or androgenic alopecia dependent. 13. A method of cosmetic treatment of the skin or scalp, comprising the application to the skin or the scalp of the composition according to any one of claims 1 to 8.