WO2002047644A1 - COMPOSITION COMPRISING 7-HYDROXY DHEA AND/OR 7-KETO DHEA AND AT LEAST A 5α-REDUCTASE INHIBITOR - Google Patents

Abstract

The invention concerns a composition for topical application on the skin or the scalp containing, 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 5 alpha -reductase inhibitor. The invention also concerns cosmetic use of said composition for preventing or treating disorders related to excessive activity of 5 alpha -reductase, such as acne and/or seborrhoea and/or hirsutism and/or androgenetic alopecia.

Description

COMPOSITION COMPRISING 7-HYDROXY DHEA AND / OR 7-CETO DHEA AND AT LEAST ONE 5 G (A) -REDUCTASE INHIBITOR

The present invention relates to a composition suitable for topical application to the skin or scalp, containing, in a physiologically acceptable medium: 5 (a) at least one DHEA derivative chosen from 7-hydroxy DHEA and 7-keto DHEA , and (b) at least one 5α-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 well known today. One of the metabolic pathways of testosterone is therefore its conversion by 5α-reductase to dihydrotestosterone (DHT). Testosterone and DHT bind to the androgen receptor, but DHT has a much higher affinity for this receptor than testosterone. Furthermore, the DHT / receptor bond is much more stable than the testosterone / receptor bond.

To date, two 5α-reductase isoforms have been isolated and cloned. 5α-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 5α-reductase is rather expressed in the epididymis, the seminal vesicles, the prostate, the fetal genital skin or even the internal sheath of the hair follicle or in the fibroblasts of adult genital skin.

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

The development of 5α-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 an 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 5α-reductase. The general appearance of the skin is grainy and, depending on the case, has well known imperfections such as white spots, black spots, 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.

5α-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 5α-reductase inhibitor with certain DHEA derivatives makes it possible to prevent or more effectively treat these disorders linked to an overactivity of 5α-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 7-hydroxy DHEA. 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.

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 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.

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 5α-reductase inhibitors.

A subject of the present invention is therefore a composition suitable for topical application to the skin or scalp, 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 5α-reductase inhibitor.

7-hydroxy DHEA is preferably 7oc-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 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 5α-reductase inhibitor can in particular be chosen from:

- 4,6-dimethoxy-indole-2-carboxylic acid and its derivatives; - 4-aza-5-alpha-androstane and its derivatives described in particular in US Pat. No. 5,543,417;

- estrogens;

- cyproterone and its acetate; - retinoids, and in particular retinol;

- sulfur and sulfur derivatives;

- zinc salts such as lactate, gluconate, pidolate, carboxyiate, salicylate and / or zinc cysteate;

- selenium chloride; - 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 Sepicontrol A5 ^® ;

- an extract of Laminaria saccharina sold in particular by the company SEC A under the trade name Phlorogine ^® ; - an extract of Spiraea ulmaria sold in particular by the company SILAB under the trade name Sebonormine ^® ;

- plant extracts of the species Arnica montana, Cinchona succirubra, Eugenia caryophyllata, Humulus lupulus, Hypericu perforatum, entha piperita, Rosmarinus officinalis, Salvia oficinalis and Thymus vulgaris, all marketed for example by the company MARUZEN;

- an extract from Serenoa repens marketed in particular by the company EUROMED;

- extracts of plants of the genus Silybum; and

- plant extracts containing sapogenins and in particular Dioscorea extracts 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 5α-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 the dosage forms normally used for topical application to the skin or the scalp, especially in the form of an oily, aqueous or hydroalcoholic solution, an oil-in-water or water-in-oil or multiple emulsion, 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.

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 known manner, the composition of the invention may also contain the adjuvants customary 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 (starch modified by actenylsuccinic anhydride, kaolin; silica), 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, the oxyethylenated sorbitan stearates available under the tradenames Tween ^® 20 or Tween ^® 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 / alkyl acrylate 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 possible compound (s) to add to the compositions according to the invention, as well as their concentration, in such a way as the advantageous properties, of the combination of active 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 5α-reductase.

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 5-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 5o-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 examples, the quantities are indicated in percentage by weight.

EXAMPLE 1 Gel for Oily Skin

Phase A Acrylate / C ₁₀ copolymer. ₃₀ alkyl acrylate (Pemulen TR1) 0.5%

Water 12%

Phase B

Hexyldecanol 10% Isononyl isononanoate 10%

7α-OH DHEA 0.5%

Phase C

Triethanolamine 0.5% Water qs

Glycerin 6%

Preservatives 0.25%

0.5% zinc pyrrolidone carboxylate

Polyacrylamide and C ₁₃ .ι ₄ isoparaffin and laureth-7 (Sepigel 305 sold by the company SEPPIC) 0.5%

Aluminum starch octenyl succinate 1%

This composition can be prepared in the following manner.

The polymer of phase A is dispersed in water at 40 ° C. The constituents of phase B are heated to 70 ° C until complete dissolution, then the temperature is reduced to 40 ° C. The components of phase C were mixed at 50 ^C C. Phase B is then added to Phase A to 40 ° C under 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%

7α-OH DHEA 0.01%

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.

75% lauryl mono-phosphate (MAP 20 ^® from KAO) CHEMICALS) 6.5%

Decyl glucoside 40% (MYDOL 10 ^® from KAO CHEMICALS) 16.25%

Polyquatemium-7 at 8% (MERQUAT S ^® by CALGON) 5.7%

Polyoxyethylene pentaerythrityl tetrastearate (150 EO) 0.5%

Glycerin 3.5%

Sorbitol 3.5%

Potassium hydroxide 1.7%

0.2% hydroxypropyl cellulose

0.05% disodium EDTA

0.1% sodium chloride

7α-OH DHEA 0.1%

Laminaria saccharina extract (Phlorogine ^® from SECMA) 1%

Preservatives 0.3%

Water qs 0%

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%

7α-OH DHEA 0.5%

Serenoa repens extract 1%

Iron oxides 0.9% Titanium oxide 5%

Polyacrylamide and C-o-u isoparaffin and laureth-7

(Sepigel 305 marketed by SEPPIC) 4%

Cyclopentasiloxane 6%

Glycerin 6%

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 / o

Cetyl alcohol 1.4%

Isoparaffin qs 100%

This stick can be applied several times a day to the face to cleanse and camouflage skin imperfections.

Example 9: Patch in situ

Water 40

Ethical alcohol qs

Glycerin 7

7α-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 forms which diffuses the active ingredients like a patch.

Claims

1. Composition suitable for topical application to the skin or scalp, 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 5α-reductase 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 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 5-reductase inhibitor is chosen from; - 4,6-dimethoxy-indole-2-carboxylic acid and its derivatives; - 4-aza-5-alpha-androstane and its derivatives; - estrogens; - cyproterone and its acetate; - retinoids, and in particular retinol; - sulfur and sulfur derivatives; - zinc salts such as lactate, gluconate, pidolate, carboxylate, salicylate and / or zinc cysteate; - selenium chloride; - vitamin B6 or pyridoxine; - an extract of Laminaria saccharina; - an extract of Spiraea ulmaria; - plant extracts of the species Arnica montana, Cinchona succirubra, 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 - plant extracts containing sapogenins and in particular Dioscόrees extracts rich in diosgenin. 7. Composition according to any one of claims 1 to 6, characterized in that said 5-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 5α-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 5α-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 5α-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.