WO2004054533A1 - Use of an alkyl ether of hydroxystilbene for the treatment of dry skin - Google Patents

Use of an alkyl ether of hydroxystilbene for the treatment of dry skin Download PDF

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Publication number
WO2004054533A1
WO2004054533A1 PCT/EP2003/012507 EP0312507W WO2004054533A1 WO 2004054533 A1 WO2004054533 A1 WO 2004054533A1 EP 0312507 W EP0312507 W EP 0312507W WO 2004054533 A1 WO2004054533 A1 WO 2004054533A1
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Prior art keywords
acid
composition
derivatives
skin
hydroxystilbene
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PCT/EP2003/012507
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French (fr)
Inventor
Maria Dalko
Gilles Rubinstenn
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L'oreal
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Priority claimed from FR0216113A external-priority patent/FR2848844B1/en
Application filed by L'oreal filed Critical L'oreal
Priority to EP03779872A priority Critical patent/EP1575544A1/en
Priority to AU2003288019A priority patent/AU2003288019A1/en
Priority to JP2005502413A priority patent/JP2006510738A/en
Priority to US10/538,662 priority patent/US20070015840A1/en
Publication of WO2004054533A1 publication Critical patent/WO2004054533A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/007Preparations for dry skin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair

Definitions

  • the present invention relates to a method for the cosmetic treatment of dry skin or of a dry scalp, comprising the topical application to the skin or the scalp of a composition containing, in a physiologically acceptable medium, at least one alkyl ether of hydroxystilbene with a saturated or unsaturated, linear or branched Ci-C ⁇ alcohol .
  • a composition containing, in a physiologically acceptable medium, at least one alkyl ether of hydroxystilbene with a saturated or unsaturated, linear or branched Ci-C ⁇ alcohol .
  • Sebum is the natural product of the sebaceous gland which, together with the sweat produced by the eccrine or apocrine glands, constitutes a natural moisturizer for the epidermis. It consists essentially of a more or less complex mixture of lipids .
  • the sebaceous gland produces squalene, triglycerides, aliphatic waxes, cholesterol waxes and, possibly, free cholesterol (Stewart, M. E., Se in . Dermatol . 11, 100-105 (1992)).
  • the action of bacterial lipases converts a variable portion of the triglycerides into free fatty acids .
  • the ⁇ ebocyte is the competent cell of the sebaceous gland.
  • the production of sebum is associated with the programme of terminal differentiation of this cell.
  • the metabolic activity of the sebocyte is essentially focussed on lipid biosynthesis (lipogenesis) and more precisely on the neosynthesis of fatty acids and of squalene.
  • a compound for stimulating the production of the lipids constituting sebum, by the cells of the sebaceous gland (the sebocytes) would therefore be of definite advantage in treating oligoseborrhoeic dry skin, i.e. skin exhibiting a sebum content of less than 100 ⁇ g/cm 2 on the forehead.
  • Hydroxystilbenes such as resveratrol and pinosylvin are stilbenes produced by plants, in particular grapevine (leaves, shoots, fruit) and plants of the Polygonum genus, in particular Polygonum cuspidatum. These compounds have in particular been described as being capable of reducing the adhesion of microorganisms to the skin and of being useful, as a result, in cosmetic or dermatological products intended to treat acne, dandruff or unpleasant odours, and more particularly in body hygiene products (EP-0 953 345) . It has also been suggested to use them in combination with retinoids, for potentiating the effect of the latter, in particular with a view to lightening the skin (WO 01/43705) .
  • document WO 03/055444 discloses a vast family of resveratrol analogues, comprising alkyl ethers, which can be used to treat signs of skin ageing, in particular by stimulating collagen synthesis and fibroblast proliferation.
  • a subject of the present invention is therefore a method for the cosmetic treatment of dry skin or of a dry scalp, comprising the topical application to the skin or the scalp of a composition containing, in a physiologically acceptable medium, at least one alkyl ether of hydroxystilbene of formula (I):
  • Ri and R 2 denote, independently, a saturated or unsaturated, linear or branched C ⁇ -C 6 alkyl group, and m and n are independently integers between 0 and 3 , it being understood that m and n cannot simultaneously be zero.
  • a subject of the invention is also the cosmetic use of at least one alkyl ether of hydroxystilbene of formula (I) , as defined above, as an agent for treating dry skin or a dry scalp.
  • composition used according to the invention is particularly suitable for treating oligoseborrhoeic skin and an oligoseborrhoeic scalp, and it is therefore advantageously applied on individuals exhibiting a sebum content of less than 100 ⁇ g/cm 2 , measured on the forehead, for example by means of the method described in FR-2 368 708.
  • composition according to the invention makes it possible to restore the production of sebum by the sebocytes and, by the same token, to improve the comfort of dry skin and of a dry scalp.
  • a subject of the invention is also the use of an alkyl ether of hydroxystilbene, as defined above, for preparing a composition, in particular a dermatological composition, intended to treat disorders associated with oligoseborrhoeic dry skin, in particular forms of dermatitis.
  • alkyl ethers of hydroxystilbenes according to the invention can be prepared according to synthetic processes consisting in using various coupling reactions, for example those known as Mc Murry (N. A. Ali, K. Kondo, Y. Tsuda, Chem. Phana. Bull . ,
  • Resveratrol trimethyl ether can in particular be obtained by synthesis according to the process described in Phytochemistry, 24(7), 2309-12 (1998). and illustrated in Figure 1.
  • Pinosylvin dimethyl ether is, moreover, commercially available from the company APIN CHEMICALS.
  • the amount of alkyl ether of hydroxystilbene which can be used in the invention depends, of course, on the desired effect and may therefore vary within a large range.
  • the alkyl ether of hydroxystilbene can be used in an amount representing from 0.001% to 5% of the total weight of the composition, preferably in an amount representing from 0.05% to 1% of the total weight of the composition.
  • composition according to the invention is generally suitable for topical application to the skin and/or the scalp, and it therefore contains a physiologically acceptable medium, i.e. a medium which is compatible with the skin, its integuments (eyelashes, nails and hair) and/or the mucous membranes.
  • a physiologically acceptable medium i.e. a medium which is compatible with the skin, its integuments (eyelashes, nails and hair) and/or the mucous membranes.
  • This composition may be in any presentation form normally used in cosmetics and dermatology, and it may in particular be in the form of an optionally gelled oily solution, a dispersion, optionally two-phase, of the lotion type, an emulsion obtained by dispersing a fatty phase in an aqueous phase (0/W) or inversely (W/O) , or a triple emulsion (W/O/W or 0/W/O) or a vesicular dispersion of the ionic and/or non-ionic type.
  • These compositions are prepared according to the usual methods.
  • a composition in the form of an oil-in-water emulsion is preferably used according to this invention.
  • This composition may be more or less fluid and may have the appearance of a white or coloured cream, an ointment, a milk, a lotion, a serum, a paste or a mousse. It may optionally be applied in the form of an aerosol. It may also be in solid form, in particular in stick form. It may be used as a care product and/or a cleansing/makeup-removing and/or a makeup product for the skin. It may also be used as a shampoo or conditioner.
  • the composition used according to the invention may also contain adjuvants which are common in the cosmetics field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preserving agents, antioxidants, solvents, fragrances, fillers, screening agents, pigments, odour absorbers and colorants.
  • adjuvants which are common in the cosmetics field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preserving agents, antioxidants, solvents, fragrances, fillers, screening agents, pigments, odour absorbers and colorants.
  • the amounts of these various adjuvants are those conventionally used in the field under consideration, for example from 0.01 to 20% of the total weight of the composition. Depending on their nature, these adjuvants can be introduced into the fatty phase, into the aqueous phase or into the lipid vesicles.
  • these adjuvants will be chosen so as not to harm the desired properties of the alkyl ethers of hydroxystilbenes according to the invention.
  • the proportion of the fatty phase may 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 co-emulsifiers used in the composition in emulsion form are chosen from those conventionally used in the field under consideration.
  • the emulsifier and the co-emulsifier 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.
  • mineral oils liquid petroleum jelly
  • oils of plant origin oils of plant origin
  • lanolin oils of animal origin
  • synthetic oils perhydrosqualene
  • silicone oils cyclomethicone
  • fluoro oils perfluoropolyethers
  • Fatty alcohols cetyl alcohol
  • fatty acids and waxes may also be used as fatty substances.
  • emulsifiers and co-emulsifiers which can be used in the invention, mention may, for example, be made of fatty acid esters of polyethylene glycol, such as PEG-100 stearate, and fatty acid esters of glycerol, such as glyceryl stearate.
  • Hydrophilic gelling agents which may be mentioned in particular include carboxyvinyl polymers (carbomer) , acrylic copolymers such as acrylate/alkyl- acrylate copolymers, polyacrylamides , polysaccharides, natural gums and clays, and lipophilic gelling agents which may be mentioned include modified clays, such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylenes .
  • composition used according to the invention at least one compound chosen from: desquamating agents; antibacterial agents; moisturizers; calmatives; and agents for stimulating keratinocyte proliferation and/or differentiation.
  • the stimulation of seborrhoea with the alkyl ethers of hydroxystilbenes according to the invention may, in certain individuals, provide a terrain of proliferation for the resident microflora of the follicular ostium (in particular PropioniJacterium acnes) , thus giving rise to considerable hydrolysis of • the triglycerides of the sebum into free fatty acids and the reduction of the unsaturations of the polyunsaturated fatty acids (in particular lirioTeic """' acid) .
  • These two phenomena may contribute towards keratinization of the infundibulum and to the formation of a microcomedone .
  • This may degenerate into a co edone, producing unaesthetic blockage and dilation of the pore. At a more advanced stage, this blockage may change into an inflammatory acneic lesion.
  • desquamating agents or agents regulating keratinocyte proliferation or differentiation to the composition according to the invention makes it possible to avoid the formation of these comedones.
  • antibacterial or bacteriostatic agents would make it possible to obtain the same effect, by modifying the proliferatio . of the resident microflora.
  • moisturizers may supplement the effect obtained using the alkyl ethers of hydroxystilbenes according to the invention, and the calmatives are useful for improving the level of comfort of oligoseborrhoeic dry skin.
  • the term "desquamating agent” is intended to mean any compound capable of acting: either directly on the desquamation by promoting exfoliation, such as ⁇ -hydroxy acids, in particular salicylic acid and its derivatives
  • ⁇ -hydroxy acids such as glycolic acid, citric acid, lactic acid, tartaric acid, malic acid or mandelic acid; urea; gentisic acid; oligofucoses; cinnamic acid; extract of Saphora japonica ; resveratrol; or on the enzymes involved in the desquamation or degradation of the comeodesmosomes, glycosidases, stratum corneum chymotryptic enzyme (SCCE) , or even other proteases (trypsin, chymotrypsin-like) .
  • SCCE stratum corneum chymotryptic enzyme
  • agents for chelating mineral salts include EDTA; N-acyl-N,N' ,N' - ethylenediaminetriacetic acid; aminosulphonic compounds and in particular (N-2-hydroxyethylpiperazine-N-2- ethane) sulphonic acid (HEPES) ; derivatives of 2-oxothiazolidine-4-carboxylic acid (procysteine) ; derivatives of alpha-amino acids of the glycine type (as described in EP-0 852 949) , and sodium methylglycmediacetate marketed by BASF under the trade name Trilon M) ; honey, sugar derivatives such as O-octanoyl-6-D-maltose and N-acetylglucosamine.
  • moisturizer is intended to mean: either a compound acting on the barrier function, in order to maintain the moisturization of the stratum corneum, or an occlusive compound. Mention may be made of cera ides, sphingoid-based compounds, lecithins, glycosphingolipids, phospholipids, cholesterol and its derivatives, phytosterols (stigmasterol, ⁇ -sitosterol or campesterol) , essential fatty acids, 1, 2-diacylglycerol, 4-chromanone, pentacyclic triterpenes such as ursolic acid, petroleum jelly and lanolin; or a compound which directly increases 5 the water content of the stratum corneum, such as threalose and its derivatives, hyaluronic acid and its derivatives, glycerol, pentanediol, sodium pidolate, serine, xylitol, sodium lactate, polyglyceryl acrylate,
  • agents for stimulating keratinocyte proliferation which can be used in the composition according to the invention comprise in particular
  • the agents for stimulating keratinocyte differentiation comprise, for example, minerals such as
  • pentacyclic triterpenes such as ⁇ -glycyrrhetinic acid, its salts and/or its derivatives (glycyrrhetinic acid onoglucuronide, stearyl glycyrrhetinate, 3- stearoyloxyglycyrrhetic acid) , ursolic acid and its salts, oleanolic acid and its salts, betulinic acid and its salts; extracts of Paeonia suffruticosa and/or lactiflora, of Rosmarinus officinalis, of epilobium, of Pygeum, of Boswellia serrata, of Centipeda cunnighami, of Helianthus annuus, of Cola nitida, of clove and of Bacopa moniera; salicylic acid salts
  • the antibacterial agents which can be used in the present invention may in particular be chosen from 2 , 4, 4 '-trichloro-2 ' -hydroxydiphenyl ether (or triclosan) , 3 , 4, 4 ' -trichlorobanilide, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, undecylenic acid and its salts, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, phytic acid, N-acetyl-L-cystein acid, lipoic acid, azelaic acid and its salts, arachidonic acid, 2, 4, 4 '-trichloro-2 '-hydroxydiphenyl ether, 3,4,4'- trichlorocarbanalide, octopirox, octoxyglycerine, octanoylglycine, caprylyl glycol, 10-hydroxy-2-decanoic acid, dichlorophenyl imidazol dioxo
  • composition used according to the invention does not comprise any retinoid.
  • the amounts are indicated as percentages by weight.
  • Resveratrol trimethyl ether was tested on a model of immortalized human sebocytes in culture, derived from the SZ95 line described in Zouboulis, C.C., Seltmann, H. , Neitzel, H. & Orfanos, C.E., Establishment and Characterization of an Immortalized Human Sebaceous Gland Cell Line, J. Invest. Dermatol . , 113, 1011-1020 (1999) .
  • the test consisted in measuring the amount of lipids produced by the sebocytes of the line (at confluence) , in the presence or absence of an active agent diluted in DMSO, at two different concentrations, such that the final amount of DMSO in the culture medium is 0.1% and the amount of resveratrol trimethyl ether is 0.01% (4xl0 ⁇ 4 M) and 0.001% (4xl0 ⁇ 5 M) , respectively. After treatment for 24 hours, the adherent cells are treated with Nile Red (1 ⁇ g/ml) .
  • the lipid content is then quantified by measuring the fluorescence of the dye (two excitation/emission pairs: 485-540 nm for the neutral lipids and 540-620 nm for the non-neutral lipids) . The results are given for the total lipids (combination of the two measurements) .
  • the experiment is performed in sextuplicate (products assayed and control) in 96-well plates and repeated four times .
  • composition is prepared in a manner that is conventional for those skilled in the art.
  • the amounts given in these examples are indicated as percentages by weight.
  • This cream applied twice daily, makes it possible to revive the radiance of dry skin.

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Abstract

The present invention relates to a method for the cosmetic treatment of dry skin or of a dry scalp, comprising the topical application to the skin or the scalp of a composition containing, in a physiologically acceptable medium, at least one alkyl ether of hydroxystilbene with a saturated or unsaturated, linear or branched C1-C6 alcohol. The composition may be used for cosmetic purposes, for treating drying out of the skin, in particular after the menopause, or for dermatological purposes, for treating disorders associated with oligoseborrhoeic dry skin, in particular forms of dermatitis.

Description

use of an alkyl ether of hydroxystilbene for the treatment of dry skin
The present invention relates to a method for the cosmetic treatment of dry skin or of a dry scalp, comprising the topical application to the skin or the scalp of a composition containing, in a physiologically acceptable medium, at least one alkyl ether of hydroxystilbene with a saturated or unsaturated, linear or branched Ci-Cε alcohol . From the age of thirty-five, and more particularly after the menopause, many women frequently complain of having dry skin and of discomfort or unaesthetic effects resulting therefrom (desquamation, dull complexion, skin atony, facial tautness) . This dryness is caused, as is now known, by a decrease in the production of sebum with age.
Moreover, children whose sebaceous function is not yet active often show signs of dry skin, which can progress to atopic dermatitis. Sebum is the natural product of the sebaceous gland which, together with the sweat produced by the eccrine or apocrine glands, constitutes a natural moisturizer for the epidermis. It consists essentially of a more or less complex mixture of lipids . Conventionally, the sebaceous gland produces squalene, triglycerides, aliphatic waxes, cholesterol waxes and, possibly, free cholesterol (Stewart, M. E., Se in . Dermatol . 11, 100-105 (1992)). The action of bacterial lipases converts a variable portion of the triglycerides into free fatty acids .
The εebocyte is the competent cell of the sebaceous gland. The production of sebum is associated with the programme of terminal differentiation of this cell. During this differentiation, the metabolic activity of the sebocyte is essentially focussed on lipid biosynthesis (lipogenesis) and more precisely on the neosynthesis of fatty acids and of squalene.
A compound for stimulating the production of the lipids constituting sebum, by the cells of the sebaceous gland (the sebocytes) , would therefore be of definite advantage in treating oligoseborrhoeic dry skin, i.e. skin exhibiting a sebum content of less than 100 μg/cm2 on the forehead.
To this end, it was proposed, in patent US-4, 496, 556, to use DHEA, a steroid secreted by the adrenal glands, or esters thereof, administered topically, to increase the production of sebum.
However, for regulatory reasons, it is not always possible to use this type of compound in the cosmetics field. In addition, it is not sufficiently effective on oligoseborrhoeic skin. There is thus still the need for cosmetically acceptable compounds for efficiently stimulating the sebaceous function with a view to treating oligoseborrhoeic dry skin. The applicant has now discovered, surprisingly, that certain hydroxystilbene ethers make it possible to satisfy this need.
Hydroxystilbenes such as resveratrol and pinosylvin are stilbenes produced by plants, in particular grapevine (leaves, shoots, fruit) and plants of the Polygonum genus, in particular Polygonum cuspidatum. These compounds have in particular been described as being capable of reducing the adhesion of microorganisms to the skin and of being useful, as a result, in cosmetic or dermatological products intended to treat acne, dandruff or unpleasant odours, and more particularly in body hygiene products (EP-0 953 345) . It has also been suggested to use them in combination with retinoids, for potentiating the effect of the latter, in particular with a view to lightening the skin (WO 01/43705) .
Finally, document WO 03/055444 discloses a vast family of resveratrol analogues, comprising alkyl ethers, which can be used to treat signs of skin ageing, in particular by stimulating collagen synthesis and fibroblast proliferation.
However, to the applicant's knowledge, it has never yet been suggested that alkyl ethers of hydroxystilbenes could be useful in the treatment of dry skin, in particular of oligoseborrhoeic skin. On the contrary, resveratrol has been described as an inhibitor of 5α-reductase and therefore naturally finds an application in the treatment of greasy skin (F -2 816 843). In fact, the applicant verified that resveratrol decreased the ability of sebocytes to produce sebum.
Now, against all expectations, the applicant discovered that alkyl ethers of hydroxystilbenes increased the ability of sebocytes to produce sebum. A subject of the present invention is therefore a method for the cosmetic treatment of dry skin or of a dry scalp, comprising the topical application to the skin or the scalp of a composition containing, in a physiologically acceptable medium, at least one alkyl ether of hydroxystilbene of formula (I):
Figure imgf000005_0001
(I)
or its cis-isomer, in which Ri and R2 denote, independently, a saturated or unsaturated, linear or branched Cι-C6 alkyl group, and m and n are independently integers between 0 and 3 , it being understood that m and n cannot simultaneously be zero. A subject of the invention is also the cosmetic use of at least one alkyl ether of hydroxystilbene of formula (I) , as defined above, as an agent for treating dry skin or a dry scalp. The composition used according to the invention is particularly suitable for treating oligoseborrhoeic skin and an oligoseborrhoeic scalp, and it is therefore advantageously applied on individuals exhibiting a sebum content of less than 100 μg/cm2, measured on the forehead, for example by means of the method described in FR-2 368 708.
The composition according to the invention makes it possible to restore the production of sebum by the sebocytes and, by the same token, to improve the comfort of dry skin and of a dry scalp.
It also makes it possible to combat the tautness of the skin and/or the dull and/or lifeless appearance of the skin and/or of the hair resulting from them drying out . A subject of the invention is also the use of an alkyl ether of hydroxystilbene, as defined above, for preparing a composition, in particular a dermatological composition, intended to treat disorders associated with oligoseborrhoeic dry skin, in particular forms of dermatitis.
The compounds of formula (I) which are preferred for use in the present invention are those for which n = 2 and = 0 or 1, i.e. the alkyl ethers of resveratrol and of pinosylvin, in particular the methyl ethers of these hydroxystilbenes, i.e. the compounds in which all the Ri and R2 groups denote a methyl radical .
The alkyl ethers of hydroxystilbenes according to the invention can be prepared according to synthetic processes consisting in using various coupling reactions, for example those known as Mc Murry (N. A. Ali, K. Kondo, Y. Tsuda, Chem. Phana. Bull . ,
40(5), 1130-1136, (1992)), Wittig (N. A. Ali, K. Kondo, Y. Tsuda, Chem. Pharm. Bull . , 40(5), 1130-1136, (1992)), Perkin (Spath E., Kromp K. , Chem. Ber. , 1941, 74, 189-192) and Heck (Synlett, 1998, 792) reactions. Resveratrol trimethyl ether can in particular be obtained by synthesis according to the process described in Phytochemistry, 24(7), 2309-12 (1998). and illustrated in Figure 1.
According to this process, commercial dimethoxybenzyl alcohol is converted into the corresponding bromide, which is itself converted into diethyl phosphonate. The yield is 84% after purification and distillation. The key step in the synthesis is the Wittig-Horner reaction. The desired olefin is formed from the diethyl phosphonate and from para-methoxybenzaldehyde, in the presence of sodium methoxide in THF, with a yield of 88%, after purification by filtration on silica.
Pinosylvin dimethyl ether is, moreover, commercially available from the company APIN CHEMICALS. The amount of alkyl ether of hydroxystilbene which can be used in the invention depends, of course, on the desired effect and may therefore vary within a large range. To give an order of magnitude, the alkyl ether of hydroxystilbene can be used in an amount representing from 0.001% to 5% of the total weight of the composition, preferably in an amount representing from 0.05% to 1% of the total weight of the composition.
The composition according to the invention is generally suitable for topical application to the skin and/or the scalp, and it therefore contains a physiologically acceptable medium, i.e. a medium which is compatible with the skin, its integuments (eyelashes, nails and hair) and/or the mucous membranes.
This composition may be in any presentation form normally used in cosmetics and dermatology, and it may in particular be in the form of an optionally gelled oily solution, a dispersion, optionally two-phase, of the lotion type, an emulsion obtained by dispersing a fatty phase in an aqueous phase (0/W) or inversely (W/O) , or a triple emulsion (W/O/W or 0/W/O) or a vesicular dispersion of the ionic and/or non-ionic type. These compositions are prepared according to the usual methods. A composition in the form of an oil-in-water emulsion is preferably used according to this invention.
This composition may be more or less fluid and may have the appearance of a white or coloured cream, an ointment, a milk, a lotion, a serum, a paste or a mousse. It may optionally be applied in the form of an aerosol. It may also be in solid form, in particular in stick form. It may be used as a care product and/or a cleansing/makeup-removing and/or a makeup product for the skin. It may also be used as a shampoo or conditioner. In a known manner, the composition used according to the invention may also contain adjuvants which are common in the cosmetics field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preserving agents, antioxidants, solvents, fragrances, fillers, screening agents, pigments, odour absorbers and colorants. The amounts of these various adjuvants are those conventionally used in the field under consideration, for example from 0.01 to 20% of the total weight of the composition. Depending on their nature, these adjuvants can be introduced into the fatty phase, into the aqueous phase or into the lipid vesicles. In any event, these adjuvants, and also the proportions thereof, will be chosen so as not to harm the desired properties of the alkyl ethers of hydroxystilbenes according to the invention. When the composition used according to the invention is an emulsion, the proportion of the fatty phase may 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 co-emulsifiers used in the composition in emulsion form are chosen from those conventionally used in the field under consideration. The emulsifier and the co-emulsifier 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 may be used in the invention, mention may be made of mineral oils (liquid petroleum jelly) , oils of plant origin (avocado oil, soybean oil) , oils of animal origin (lanolin) , synthetic oils (perhydrosqualene) , silicone oils (cyclomethicone) and fluoro oils (perfluoropolyethers) . Fatty alcohols (cetyl alcohol) , fatty acids and waxes (carnauba wax, ozokerite) may also be used as fatty substances. As emulsifiers and co-emulsifiers which can be used in the invention, mention may, for example, be made of fatty acid esters of polyethylene glycol, such as PEG-100 stearate, and fatty acid esters of glycerol, such as glyceryl stearate.
Hydrophilic gelling agents which may be mentioned in particular include carboxyvinyl polymers (carbomer) , acrylic copolymers such as acrylate/alkyl- acrylate copolymers, polyacrylamides , polysaccharides, natural gums and clays, and lipophilic gelling agents which may be mentioned include modified clays, such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylenes .
As active agents, it will be advantageous to introduce into the composition used according to the invention at least one compound chosen from: desquamating agents; antibacterial agents; moisturizers; calmatives; and agents for stimulating keratinocyte proliferation and/or differentiation.
In fact, the stimulation of seborrhoea with the alkyl ethers of hydroxystilbenes according to the invention may, in certain individuals, provide a terrain of proliferation for the resident microflora of the follicular ostium (in particular PropioniJacterium acnes) , thus giving rise to considerable hydrolysis of • the triglycerides of the sebum into free fatty acids and the reduction of the unsaturations of the polyunsaturated fatty acids (in particular lirioTeic """' acid) . These two phenomena may contribute towards keratinization of the infundibulum and to the formation of a microcomedone . This may degenerate into a co edone, producing unaesthetic blockage and dilation of the pore. At a more advanced stage, this blockage may change into an inflammatory acneic lesion. The addition of desquamating agents or agents regulating keratinocyte proliferation or differentiation to the composition according to the invention makes it possible to avoid the formation of these comedones. Similarly, antibacterial or bacteriostatic agents would make it possible to obtain the same effect, by modifying the proliferatio . of the resident microflora.
In addition, the moisturizers may supplement the effect obtained using the alkyl ethers of hydroxystilbenes according to the invention, and the calmatives are useful for improving the level of comfort of oligoseborrhoeic dry skin.
, Examples of such additional active agents are given below. Desquamating agents
The term "desquamating agent" is intended to mean any compound capable of acting: either directly on the desquamation by promoting exfoliation, such as β-hydroxy acids, in particular salicylic acid and its derivatives
(including 5-n-octanoyl salicylic acid) ; α-hydroxy acids, such as glycolic acid, citric acid, lactic acid, tartaric acid, malic acid or mandelic acid; urea; gentisic acid; oligofucoses; cinnamic acid; extract of Saphora japonica ; resveratrol; or on the enzymes involved in the desquamation or degradation of the comeodesmosomes, glycosidases, stratum corneum chymotryptic enzyme (SCCE) , or even other proteases (trypsin, chymotrypsin-like) . Mention may be made of agents for chelating mineral salts: EDTA; N-acyl-N,N' ,N' - ethylenediaminetriacetic acid; aminosulphonic compounds and in particular (N-2-hydroxyethylpiperazine-N-2- ethane) sulphonic acid (HEPES) ; derivatives of 2-oxothiazolidine-4-carboxylic acid (procysteine) ; derivatives of alpha-amino acids of the glycine type (as described in EP-0 852 949) , and sodium methylglycmediacetate marketed by BASF under the trade name Trilon M) ; honey, sugar derivatives such as O-octanoyl-6-D-maltose and N-acetylglucosamine. Moisturizer The term "moisturizer" is intended to mean: either a compound acting on the barrier function, in order to maintain the moisturization of the stratum corneum, or an occlusive compound. Mention may be made of cera ides, sphingoid-based compounds, lecithins, glycosphingolipids, phospholipids, cholesterol and its derivatives, phytosterols (stigmasterol, β-sitosterol or campesterol) , essential fatty acids, 1, 2-diacylglycerol, 4-chromanone, pentacyclic triterpenes such as ursolic acid, petroleum jelly and lanolin; or a compound which directly increases 5 the water content of the stratum corneum, such as threalose and its derivatives, hyaluronic acid and its derivatives, glycerol, pentanediol, sodium pidolate, serine, xylitol, sodium lactate, polyglyceryl acrylate, ectoin and its derivatives, chitosan, oligosaccharides 0 and polysaccharides, cyclic carbonates, N-lauroyl- pyrrolidonecarboxylic acid and N-α-benzoyl-L-arginine; or a compound which activates the sebaceous glands, such as DHEA and its derivatives and vitamin D and its derivatives. 5 Agents for stimulating keratinocyte proliferation and/or differentiation
The agents for stimulating keratinocyte proliferation which can be used in the composition according to the invention comprise in particular
20 phloroglucinol ; the walnut cake extracts marketed by the company Gattefosse; and the Solanum tuberosum extracts marketed by the company Sederma.
The agents for stimulating keratinocyte differentiation comprise, for example, minerals such as
25. calcium; the extract of lupin marketed "by "the company" Silab under the trade name Photopreventine®; sodium beta-sitosteryl sulphate marketed by the company Seporga under the trade name Phytocohesine®; and the extract of com marketed by the company Solabia under the trade name Phytovityl®. Calmatives Among the raw materials which are effective as calmatives, mention may be made, in a non-limiting manner, of the following active agents: pentacyclic triterpenes, such as β-glycyrrhetinic acid, its salts and/or its derivatives (glycyrrhetinic acid onoglucuronide, stearyl glycyrrhetinate, 3- stearoyloxyglycyrrhetic acid) , ursolic acid and its salts, oleanolic acid and its salts, betulinic acid and its salts; extracts of Paeonia suffruticosa and/or lactiflora, of Rosmarinus officinalis, of epilobium, of Pygeum, of Boswellia serrata, of Centipeda cunnighami, of Helianthus annuus, of Cola nitida, of clove and of Bacopa moniera; salicylic acid salts and in particular zinc salicylate; extracts of algae, in particular of Laminaria saccharina; Canola oil, omega-3-unsaturated oils such as musk rose oil, blackcurrant oil, ecchium oil, fish oil; α-bisabolol and extracts of camomile; allantoin; the phosphoric diester of vitamin E and C; capryloylglycine; tocotrienols; piperonal; aloe vera; phytosterols; strontium salts; spring waters and in particular the spring water of the Vichy basin and the spring water of La Roche Posay; bacterial extracts and in particular the extract of non-photosynthetic filamentous bacteria described in patent application EP-0 761 204, preferably prepared from bacteria belonging to the order Beggiatoales, and more particularly a strain of Vi treoscilla filiformis ; an extract of cells (preferably undifferentiated cells) of at least one plant from the Iridacea family, obtained by in vi tro culturing, preferably an aqueous extract of Jris pallida, as described in particular in patent application EP-0 765 668; an extract of a plant of the Rosaceae family, preferably cultivated in vivo, advantageously of the species .Rosa gallica, more preferably a water-glycol extract of Rosa gallica petals, as described in particular in patent application EP-0 909 556. Antibacterial agents
The antibacterial agents which can be used in the present invention may in particular be chosen from 2 , 4, 4 '-trichloro-2 ' -hydroxydiphenyl ether (or triclosan) , 3 , 4, 4 ' -trichlorobanilide, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, undecylenic acid and its salts, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, phytic acid, N-acetyl-L-cystein acid, lipoic acid, azelaic acid and its salts, arachidonic acid, 2, 4, 4 '-trichloro-2 '-hydroxydiphenyl ether, 3,4,4'- trichlorocarbanalide, octopirox, octoxyglycerine, octanoylglycine, caprylyl glycol, 10-hydroxy-2-decanoic acid, dichlorophenyl imidazol dioxolane and its derivatives, described in patent WO 93/18743, famesol and phytosphingosines, and mixtures thereof.
Preferably, the composition used according to the invention does not comprise any retinoid. The invention will now be illustrated with the following non-limiting examples. In these examples, the amounts are indicated as percentages by weight.
EXAMPLES Example 1: Demonstration of the activity of the alkyl ethers of hydroxystilbenes on lipogenesis
Resveratrol trimethyl ether was tested on a model of immortalized human sebocytes in culture, derived from the SZ95 line described in Zouboulis, C.C., Seltmann, H. , Neitzel, H. & Orfanos, C.E., Establishment and Characterization of an Immortalized Human Sebaceous Gland Cell Line, J. Invest. Dermatol . , 113, 1011-1020 (1999) .
The test consisted in measuring the amount of lipids produced by the sebocytes of the line (at confluence) , in the presence or absence of an active agent diluted in DMSO, at two different concentrations, such that the final amount of DMSO in the culture medium is 0.1% and the amount of resveratrol trimethyl ether is 0.01% (4xl0~4 M) and 0.001% (4xl0~5 M) , respectively. After treatment for 24 hours, the adherent cells are treated with Nile Red (1 μg/ml) . The lipid content is then quantified by measuring the fluorescence of the dye (two excitation/emission pairs: 485-540 nm for the neutral lipids and 540-620 nm for the non-neutral lipids) . The results are given for the total lipids (combination of the two measurements) .
The experiment is performed in sextuplicate (products assayed and control) in 96-well plates and repeated four times .
The results are given in the table below:
Concentration of VARIATION IN P resveratrol LIPIDS (relative (Student's test) trimethyl ether to the control)
0.01% + 46% 0.004
0.001% + 36% 0.009
As emerges from this table, the resveratrol trimethyl ether induces a significant increase in the sebocytic lipogenesis. In comparison, resveratrol, tested under the same conditions and at the same concentrations, significantly inhibits the lipogenesis, respectively by 20% and 67%. Example 2 : Cosmetic composition
This composition is prepared in a manner that is conventional for those skilled in the art. The amounts given in these examples are indicated as percentages by weight.
Resveratrol trimethyl ether 0.5%
5-n-octanoylsalicylic acid 1%
Methylparaben 0.1% Propylparaben 0.1%
Lanolin 5%
Liquid petroleum jelly 4%
Sesame oil 4%
Cetyl alcohol 5%
Glyceryl monostearate 2%
Triethanolamine 1%
Propylene glycol 5%
Carbomer 940 0.1% Water qs 100%
This cream, applied twice daily, makes it possible to revive the radiance of dry skin.

Claims

1. Method for the cosmetic treatment of dry skin or of a dry scalp, comprising the topical application to the skin or the scalp of a composition containing, in a physiologically acceptable medium, at least one alkyl ether of hydroxystilbene of formula (I) :
Figure imgf000020_0001
(I)
or its cis-iso er, in which Ri and R2 denote, independently, a saturated or unsaturated, linear or branched Ci-Cβ alkyl group, and m and n are independently integers between 0 and 3 , it being understood that m and n cannot simultaneously be zero.
2. Method according to Claim 1, characterized in that n = 2 and m = 0 or 1.
3. Method according to Claim 1 or 2 , characterized in that all the Ri and R2 groups denote a methyl radical .
4. Method according to any one of Claims 1 to 3, characterized in that the alkyl ether of hydroxystilbene represents from 0.05% to 1% of the total weight of the composition.
5. Method according to any one of Claims 1 to 4, characterized in that said composition does not contain any retinoid.
6. Method according to any one of Claims 1 to 5 , characterized in that said composition also contains at least one desquamating agent .
7. Method according to Claim 6, characterized in that said desquamating agent is chosen from: salicylic acid and its derivatives (including 5-n-octanoyl salicylic acid) ; α-hydroxy acids, such as glycolic acid, citric acid, lactic acid, tartaric acid, malic acid or mandelic acid; urea; gentisic acid; oligofucoses; cinnamic acid; extract of Saphora japonica; resveratrol; EDTA; N-acyl-N,N' ,N' - ethylenediaminetriacetic acid; ammosulphonic compounds and in particular (N-2-hydroxyethylpiperazine-N-2- ethane) sulphonic acid (HEPES) ; derivatives of 2-oxothiazolidine-4-carboxylic acid (procysteine) ; derivatives of alpha-amino acids of the glycine type (such as sodium methylglycmediacetate) ; honey; and sugar derivatives such as O-octanoyl-6-D-maltose and N- acetylglucosamine .
8. Method according to any one of Claims 1 to 7, characterized in that said composition also contains a moisturizer.
9. Method according to Claim 8, characterized in that said moisturizer is chosen from: ceramides, sphingoid-based compounds, lecithins, glycosphingolipids, phospholipids, cholesterol and its derivatives, phytosterols (stig asterol, β-sitosterol or campesterol) , essential fatty acids, 1, 2-diacylglycerol, 4-chromanone, pentacyclic triterpenes such as ursolic acid, petroleum jelly and lanolin; threalose and its derivatives, hyaluronic acid and its derivatives, glycerol, pentanediol, sodium pidolate, serine, xylitol, sodium lactate, polyglyceryl acrylate, ectoin and its derivatives, chitosan, oligosaccharides and polysaccharides, cyclic carbonates, N-lauroylpyrrolidonecarboxylic acid, N-α-benzoyl-L-arginine; DHEA and its derivatives; and vitamin D and its derivatives.
10. Method according to any one of Claims 1 to 9, characterized in that the composition also contains at least one calmative.
11. Method according to Claim 10, characterized in that said calmative is chosen from: pentacyclic triterpenes, such as β-glycyrrhetinic acid, its salts and/or its derivatives, ursolic acid and its salts, oleanolic acid and its salts, betulinic acid and its salts; extracts of Paeonia suffruticosa and/or lactiflora, of Rosmarinus officinalis, of epilobium, of Pygeum, of Boswellia serrata, of Centipeda cunnighami, of Helianthus annuus, of Cola nitida, of clove and of Bacopa moniera; salicylic acid salts and in particular zinc salicylate; extracts of algae, in particular of Laminaria saccharina; Canola oil, omega-3-unsaturated oils such as musk rose oil, blackcurrant oil, ecchium oil, fish oil; α-bisabolol and extracts of camomile; allantom; the phosphoric diester of vitamin E and C; capryloylglycine; tocotrienols; piperonal; aloe vera; phytosterols; a strain of Vitreoscilla filiformis, an aqueous extract of Iris pallida and a water-glycol extract of Rosa gallica petals.
12. Method according to any one of Claims 1 to 11, characterized in that the composition also contains at least one antibacterial agent.
13. Method according to Claim 13 , characterized in that said antibacterial agent is chosen from: triclosan, phenoxyethanol, octoxyglycerine, octanoylglycme, 10-hydroxy-2-decanoic acid, caprylyl glycol, famesol and azelaic acid.
14. Method according to any one of Claims 1 to 11, characterized in that the composition also contains at least one agent for stimulating keratinocyte proliferation and/or differentiation.
15. Method according to any one of Claims 1 to 14, characterized in that the composition is in the form of an oil-in-water emulsion.
16. Method according to any one of Claims 1 to 15, characterized in that the composition is applied on individuals exhibiting a sebum content of less than 100 μg/cm2 on the forehead.
17. Method according to any one of Claims 1 to 16, characterized in that it is intended to combat tautness of the skin and/or the dull and/or lifeless appearance of the skin and/or of the hair.
18. Cosmetic use of at least one alkyl ether of hydroxystilbene of formula (I) , as defined in any one of Claims 1 to 3 , as an agent for treating dry skin or a dry scalp.
19. Use of at least one alkyl ether of hydroxystilbene of formula (I) , as defined in any one of Claims 1 to 3 , for preparing a composition intended to treat disorders associated with oligoseborrhoeic dry skin.
20. Use according to Claim 19, characterized in that said disorders are forms of dermatitis.
PCT/EP2003/012507 2002-12-18 2003-11-10 Use of an alkyl ether of hydroxystilbene for the treatment of dry skin WO2004054533A1 (en)

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