WO2003075882A2

WO2003075882A2 - Method of depigmenting skin and hairs

Info

Publication number: WO2003075882A2
Application number: PCT/IB2003/000856
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Carlo Ghisalberti
Priority date: 2002-03-11
Filing date: 2003-03-10
Publication date: 2003-09-18
Also published as: AU2003207903A1; WO2003075882A3; ITMI20020509A0; ITMI20020509A1

Abstract

The present invention relates to a method of depigmenting human skin and hairs by the topical application of a composition comprising a gentisic acid lower esters with a penetration enhancer in a cosmetically acceptable vehicle.

Description

"METHOD OF DEPIGMENTING SKIN AND HAIRS"

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Skin hyperpigmentation may arise from a variety of aetiologies, including the local hyperpigmentation deriving from drug use (e.g. Ca-antagonists), the cyanic melasma, the senile melasma. Other local hyperpigmentations can occur during other contexts, such as in pregnancy ("gravidic chloasma"), following estro-progestative contraception, and by photosensibilization.

In many case a high pigmented skin may be even considered an unaestheticisms for some individuals belonging to ethnic groups, who aim to reduce the usual skin colour. There is also a wide-spread demand for pale and blond hair, as alternative to the direct discoloration by the application on hair of the hydrogen peroxide and related compounds.

The first depigmenting cream appeared in Korea more than 50 years ago, corresponding to the aesthetic need of the Asian women to exhibit a pale facial complexion. These creams contained a mercury compound, whose action was based on the substitution of copper, essential cofactor of the tyrosinase enzyme. Mercurials were actually banned due to their neurotoxicity.

A skin whitening . agent which shall actually act by the inhibition or antagonism of one of the biosynthetic step in melanogenesis, at the same time this depigmentor shall bring about low toxic effects on skin or scalp melanocytes. On the contrary, most effective inhibitors of melanogenesis often produce cytostatic or cytotoxic effects, specifically in melanocytes, as oulined by Dooley TP et al. in Skin Pharmacol 1994, 7(4): 188-200 and Curto E et al. in Biochem.

Pharmacol. 1999, 15:57(6):663-72).

According to these works, most candidate molecules for skin depigmentation have been found either non-toxic but low-effective, or highly effective but cytotoxic, except for alkyl gentisates which uniquely inhibit the synthesis of melanin with limited cytotoxicity.

However, gentisate esters own low solubility in water-based cosmetic preparations and a characteristic low penetration onto the skin layer.

Therefore, a method which employ a topical formulation capable of optimizing the lightening action by an effective delivery on melanocytes in skin and scalp, thereby characterized by low toxic and effective depigmenting action was still sought. DESCRIPTION OF THE INVENTION

It is an object of this invention to provide a method for treating hyperpigmented skin and for discolouring hair.

It is another and more specific object of the invention to provide a topical composition and method for treating hyperpigmented skin and for lightning human hairs.

The method of invention comprises applying to the skin in affected areas a topical composition containing an effective amount of at least one active ingredient a gentisic acid lower esters ("GALE"), and a penetration enhancer in a cosmetically acceptable vehicle.

Therefore, according to one of its aspects, the present invention concerns a topical composition to treat the hyperpigmented skin and to discolour hair which comprises: i) a gentisic acid lower ester (GALE); ii) a penetration enhancer; iii) a cosmetically acceptable vehicle.

Accordingly, the topical composition of the present invention can be applied in the treatment of all sort of skin hypeφigmentation and dyschromias, for instance they can be useful for depigmenting melasma, or for voluntary whitening the skin in physiological pigmentation in ethnical subjects as well as in obtaining a pale color of the human hairs.

The gentisic acid lower ester (GALE) which is the primary active ingredients of the present invention is a compound of formula (I):

wherein R¹ represents lower alkyl, lower alkenyl, lower alkoxy, lower alkoxymethyloxy, lower cyclalkyl, and lower hydroxyalkyl.

The term "lower" is intended to mean 1 to 6, preferably 1 to 4 carbon atom(s). The term "alkoxy" is intended a straight or branched chain hydrocarbon ether group of six or less carbon atoms, including methoxy, ethoxy, 2-propoxy, butoxy, 3- pentoxy, and the like.

The term "alkyl" is intended to mean a straight or branched acyclic hydrocarbon radical, "alkenyl" refers to unsaturated cis- or trans-unsaturated alkyl chains, linear or branched, in so much as it contains at least one double bond, and "alkoxy" similarly refers to alkoxy groups having 1 to 6 carbon atoms.

The term "alkoxymethyloxy" is intended to mean the methylether groups which are substituted with one alkoxy group; typical alkoxymethyloxy groups include methoxymethyloxy, ethoxymethyloxy, isopropoxymethyloxy, and the like. The term "alkoxymethyloxy" is intended a methylether groups substituted with one alkoxy group.

The term "hydroxyalkyl" is intended to mean a radical preferably having 2 or 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical. The term "cycloalkyl" is intended to mean cyclic hydrocarbon groups of three to seven carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, and the like.

Examples of compounds of formula (I) are GALE such as methyl gentisate, ethyl gentisate, π-propyl gentisate, z-propyl gentisate, n-butyl gentisate, n-pentyl gentisate, allyl gentisate, cyclopropyl gentisate, hydroxymethyl gentisate, methoxymethyl gentisate, and methoxyethyl gentisate.

The gentisic acid lower ester are either known compounds or compounds that can be prepared by known procedures, for exemples by the esterification reaction of gentisic acid with an excess of the alcohol R^H, thereby with both the function of solvent and reactant, in the presence of an acid catalyst, e.g. p-toluen sulfonic acid or sulphuric acid

Preferred GALE for our purposes are methyl gentisate and ethyl gentisate due to their optimum efficacy coupled with a limited toxicity. Typical embodiments contain from about 0.1% to 10% by weight, more narrowly from about 0.25% to about 7%, even more narrowly, from about 3% to 5%, GALE. Lower amounts of active compound are included in some formulations having especially efficacious penetration enhancer; for example, some embodiments thus contain from about 0.25% to about 3% active compound. Other embodiments contain higher amounts, e.g., from about 1% to about 7% active compound. Many embodiments contain from about 2% to 5% active compound.

In accordance with the present invention, at least one GALE, in association with a cosmetically acceptable carrier in which the active compound is dispersed or solubilized, is topically applied in effective amounts to skin hypeφigmented areas, or which are susceptible to hypeφigmentation, in combination with a penetration enhancer in a delivery system so that the GALE are delivered to the melanocytes.

Penetration enhancers include both chemical and physical enhancers, and mixtures thereof.

Any chemical penetration enhancer known to skilled workers can be used in the practice of the invention. Preferred enhancers are pharmacologically and chemically inert and chemically stable, potent, nonirritating, nonsensitizing, nonphototoxic, noncomedogenic, odorless, tasteless, colorless, and cosmetically acceptable.

Chemical enhancers also include, but are not limited to, sulfoxides such as dimethylsulfoxide and decylmethylsulfoxide; alcohols such as ethanol, propanol, butanol, pentanol, hexanol, octanol, nonanol, decanol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, linolenyl alcohol and benzyl alcohol; polyols such as propylene glycol, polyethylene glycol, ethylene glycol, diethylene glycol, dipropylene glycol, glycerol, propanediol, butanediol, pentanediol, hexanetriol; fatty acids such as valeric, heptanoic, pelargonic, capric, lauric, myristic, stearic, oleic, and caprylic acids; esters such as methyl acetate, ethyl acetate, butyl acetate, methyl valerate, methyl propionate, diethyl sebacate, ethyl oleate, isopropyl butyrate, isopropyl hexanoate, isopropyl myristate, isopropyl palmitate; amines and amides such as urea, dimethylacetamide, diethyltoluamide, dimethylformamide, dimethyldecamide, biodegradable cyclic urea (l-alkyl-4-imidazolin-2-one), pyrrolidone derivatives (l-methyl-2-pyrrolidone, 1- lauryl-2-pyrrolidone, l-hexyl-4-carboxy-2-pyrrolidone, 1-lauryl- 4- methoxycarbonyl-2 -pyrrolidone, N-dimethylamino-propylpyrrolidone), cyclic amides (e.g., l-dodecylazacycloheptane-2-one (Azone™), 1-geranylazacycloheptan- 2-one, and l-farnesylazacycloheptan-2-one), hexamethylenelauramide and its derivatives; diethanolamine, triethanolamine; teφenes, including hydrocarbon (e.g.: D-limonene, alpha-pinene, and beta-carene), alcohol (alpha-teφinol, teφinen-4-ol, menthol, and carvol), ketones (e.g., Carvone™, pulegone, piperitone, and menthone), oxide (e.g., cyclohexene oxide, limonene oxide, alpha-pinene oxide, cyclopentene oxide, and 1,8-cineole), and oil derivatives (e.g., Ylang ylang, anise chenopodium, and eucalyptus); surfactants, including anionic (e.g., sodium laurate and/or sodium lauryl sulfate), cationic (e.g., cetyltrimethyl ammonium bromide, benzalkonium chloride, octadecyltrimethylammonium chloride, cetylpyridinium chloride, and hexadecyltrimethylammonium chloride), nonionics (Poloxamer™, Brij™, Span™, Tween™, Myrj™, and Miglol™ products), bile salts (e.g., sodium chlolate and/or the sodium salts of taurocholic, glycolic, and desoxychohc acids), and lecithin; cyclodextrins; alkanones (e.g., N-heptane, N-octane, N-decane, N-undecane, N- dodecane, N-tridecane, N-tetradecane, and N-hexadecane); and mixtures thereof, such those discussed in Smith, E. W. and Maiback H. I., "Percutaneous Penetration Enhancers", 1995, Book pp. 1-405.. Compositions may also contain acrylate/ceteth copolymers or compounds that interrupt the stratum corneum barrier disclosed in Smith and Maibach, cited above.

Among chemical enhancers, particularly preferred are alpha- or beta-hydroxy acid, which are compounds represented by the formulae (TJ) and (III):

wherein R₂ and R , each independently, represent hydrogen atoms or (C₁-C₂₀)-alkyl, arylalkyl or aryl groups, with R₃ may also have OH, CHO, COOH and (Cι_.-C₉)- alkoxy group; R₄ represents a hydrogen, or OH or a (C₁-C₂₀)-acyl group which can be linear or branched, saturated or unsaturated, optionally substituted.

The typical alkyl, aralkyl and aryl groups for R₂ and R₃ include methyl, ethyl, propyl, isopropyl, butyl, pentyl, octyl, lauryl, stearyl, benzyl and phenyl, etc.

Examples of suitable hydroxy acids include but are not limited to: glycolic acid, lactic acid, malic acid, citric acid, alpha-hydroxycaprylic acid, mixed fruit acid, alpha-hydroxylauric acid, salycilic acid, etc.

Salts of hydroxy acids (e.g., potassium, sodium, ammonium, triethanolammonium salts) are also meant to be included within the term "hydroxy acid". A mixture of the salt and the acid may be present in order to produce a proper pH of the composition. Preferably the pH is kept below 5.5 to allow swelling of horney layer.

The preferred alpha-hydroxy acids are lower hydroxymonocarboxylic such as lactic acid, glycolic acid, mandelic acid, and mixtures thereof. The preferred beta- hydroxy acid is salicylic acid, and esters and ether thereof

The weight ratio of the GALE to the hydroxy acid is in the range of from 1:1000 to 4:1, preferably in the range of from 1:50 to 2:1, most preferably in the range of from 1:24 to 1:1, in order to both maximize the solubility of the GALE in the cosmetic formulation and to optimize their in-vivo performances.

Penetration enhancers are added in amounts effective to deliver active ingredient to melanocytes when compositions of the invention are topically applied. Enhancers are typically present in compositions of the invention at a level of about 0.5% to 50%, more narrowly from about 1% to 10%, by weight.

Physical penetration enhancers may also be employed, alone, or in combination with chemical enhancers. Physical enhancers include, but are not limited to, those enhancing skin hydration, occlusion devices, hydrocolloid patches and other transdermal delivery systems, lipophilic penetrants including liposomes, delipidization, electroporation, ultrasound, iontophoresis, and the like methods known to skilled workers which increase skin permeability without toxicity and destruction of overlying stratum corneum.

Penetration enhancers are added in amounts effective to deliver active ingredient to the melanocytes when compositions of the invention are applied topically to hypeφigmented skin or to produce discoloration on human skin or hairs. In many preferred embodiments, the active ingredient is admixed in a formulation that further contains at least one additional depigmenting agent that directly or indirectly enhances the inhibition of tyrosinase or a further step in melanogenesis.

Illustrative, non limiting examples of said additional depigmenting agents include kojic acid and ester thereof; retinoic acid; hydroquinone and the derivatives thereof, such as hydroquinone benzyl and monomethyl ethers; ascorbic acid and the derivatives thereof, such as magnesium ascorbyl phosphate; hydroxycinnamic and caffeic acids and esters thereof, benzofurans such as 5- or 6-hydroxybenzofuran; azelaic acid and semiesters thereof; niacinamide; L-2-oxothiazolidine-4-carboxylic acid; N,N'-dibenzylethylenediamine-N,N'-diacetic acid and derivatives thereof; gamma-L-glutamyl-L-cystine, oxidized glutathione and derivative thereof; retinoids and carotenoids; melatonin; plant extracts such as licorice (e.g. glabridine), mulberry (e.g. oxyresveratrol), heather and angelica ashitaba, Arctostaphylos patula and A. viscida, pearl extracts. Anti-inflammatory agents actually promote the depigmentation of the skin, in particular when they are associated with a depigmenting agent, thus include steroidal anti-inflammatory agents of hydrocortisone type and the like; nonsteroidal anti- inflammatory agents such as acetylsalicylic acid, acetaminophen, naproxen and fenamic acid derivatives and salts; natural anti-inflammatory agents such as alphabisabolol, beta-glycyrrhetinic acid, allantoin, aloe extract, rosmarinic acid, azulene, asiaticoside, sericoside, ruscogenin, escin, escolin, quercetin, rutin, betulinic acid, catechins and derivatives thereof.

The compounds of formula used in the method of the present invention are most preferably applied in the form of appropriate cosmetic or dermatological compositions. Compositions of the invention are typically applied in admixture with a

^• cosmetically acceptable carrier or vehicle (e.g., as a lotion, cream, ointment, soap, or the like), but, as mentioned above, the penetration enhancer or mixture of enhancers may also serve as carrier. It is necessary that the carrier be inert in the sense of not bringing about a deactivation of active ingredients, and in the sense of not bringing about any adverse effect on the skin to which it is applied.

Many preferred carriers function well as penetration enhancers or augment the effect of other ingredients so that GALE are efficiently delivered to the melanocytes in epidermis or to the melanocytes associated to the pilosebaceous units in scalp. Compositions according to the invention may take a wide variety of forms such as, for example, solid forms, e.g. powders; liquid forms, e.g. solutions, gelled solutions or suspensions in aqueous or oily mediums; semi-liquid formulations, e.g. creams, gellies, pastes, ointments, salves, shampoos. Other compositions are preparations of the cosmetic type, such as toilet waters, packs, lotions, skin milks or milky lotions.

The composition according to the invention may also comprise other cosmetically acceptable ingredients, for example those included in the INCI list drawn by the European Cosmetic Toiletry and Perfumery Association (COLTPA) and issued in 96/335/EC "Annex to Commission Decision of 8 May 1996" and further modifications.

Thus, said compositions may contain components usually employed in such preparations, examples of such components being oils, fats, waxes, surfactants, humectants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, dyestuffs. If desired, further ingredients may be incoφorated in the compositions, e.g. antibacterials, antifungals, vitamins, sunscreens, anti-acne agents, antibiotics, anti-wrinkling agents, etc. For the intended treatment, the compositions of the invention are administered 2 to 4 times per day, preferably 1 to 3 times, advantageously at least 2 times per day.

In order to perform the treatment of the invention, the composition is applied on the skin or scalp, preferably with soft massage to enhance the penetration of

GALE.

Generally, the composition is topically applied to the affected skin areas or in the scalp in a predetermined or as-needed regimen to bring about improvement, it generally being the case that gradual improvement is noted with each successive application, hisofar as has been determined based upon clinical studies to date, no adverse side effects are encountered.

The following examples are intended to illustrate the scope of the present invention but not to limit it.

Example la - Skin whitening composition #1 100 g of o/w cream contain: mineral oil 4.0 g ethyl gentisate 2.0 g cetyl ether-(10)-POE 4.0 g cetyl alcohol 4.0 g triethanolamine 0.75 g glycolic acid 5.0 g menthol 2.0 g butane- 1,3-diol 5.0 g xanthan gum 0.3 g parfum, additives, preservatives qb demineralized water qb to 100 g

Example 2a - Skin whitening composition #2 100 g of emulsion contain: methyl gentisate 2.1 g silicone oil 200 cts 7.5 g glycerylmonooleate 5.0 g cetosteryl alcohol 1.6 g cetyl alcohol (20)-POE 1.4 g xanthan gum 0.5 g octyl methoxycinnate 3.0 g parfum, additives, preservatives qb demineralized water qb to 100 g

Example 3a - Skin whitening composition #3 100 g of emulsion contain: propyl gentisate 1.0 g

1 -hexyl-3 -hydroxy-4-p yridone 1.4 g propyleneglycol monostearate 2.7 g isopropyl lanolate 3.5 g bentone gel of propylene glycol caprate and caprylate 6.0 g isopropyl myristate 6.5 g silicone oil 3.0 g sorbitan stearate 1.8 g polyoxyethylenated sorbitanstearate 1.5 g cetyl alcohol 0.6 g aluminium silicate 0.8 g carboxymethylcellulose 0.15 g propylene glycol 4.0 g parfum, additives, preservatives qb demineralized water qb to 100 g

Example lb - Hair discoloring composition #1 100 g of gel contain: ethyl gentisate 5.0 g glycolic acid 15.0 g retinol 0.2 g xanthan gum 1.2 g parfum, additives, preservatives qb demineralized water qb to lOO g

Example 2b - Hair discoloring composition #2

100 g of alcoholic lotion contain: methyl gentisate 2.0 g perfume 0.3 g

BHT 0.01 g ethyl alcohol 45° v/v qb to 100 g

Example 3b - Hair discoloring composition #3 100 g of hydroalcoholic lotion contain: idroxyethyl cellulose 0.4 g methoxyethyl gentisate 1.5 g ethanol 25 g propylenglycol 30 g parfum, additives, preservatives qb demineralized water qb to lOO g

Applicative Example A

In one blinded study, eight subjects aged 25 to 58 diagnosed with melasma on face or chloasma on legs and arms and were given the 2% ethyl gentisate cream of Example la and an identical composition containing neither glycolic acid nor butane- 1,3-diol. The patients were not informed which was which, but instructed to apply one cream to one side of their faces, legs or arms twice daily during the duration of the study, and apply the other cream to the other countrateral side at the same time. Patients were evaluated every four weeks. In every patient, marked improvement and a decrease in hypeφigmentation was observed on the side treated with the composition of Example 1 after four weeks. After eight weeks, hypeφigmentive spots were even more markedly reduced on the side to which the composition of Example 1 had been applied in every patient. Applicative Example B

Dark-haired subjects instructed to apply the ethyl gentisate gel of Example lb were observed to experience the progressive growth of hair with pale hues during the course of the treatment.

Claims

1. A cosmetic method for the treatment of hypeφigmented skin and for discolouring hair which comprises topically applying a composition comprising:

(i) a gentisic acid lower esters of formula (I):

wherein R¹ represents lower alkyl, lower alkenyl, lower alkoxy, lower alkoxymethyloxy, lower cyclalkyl, and lower hydroxyalkyl. (ii) an effective amount of a penetration enhancer;. (iii) a cosmetically acceptable vehicle.

2. Method according to claim 1 wherein the composition comprises from about 2% to about 5% by weight of at least a compound of formula (I).

3. Method according to claim 1 wherein the penetration enhancer is a chemical enhancer.

4. Method according to claim 3 wherein the chemical enhancer is an alpha-hydroxy acid, a beta-hydroxy acid, or mixture thereof.

5. Method according to claim 4 wherein the enhancer is selected from the group consisting of lactic acid, glycolic acid, salicylic acid, and ester and mixtures thereof.

6. Method according to claim 3 wherein the pH of the composition is less than or equal to 5.5.

7. Method according to claim 3 wherein the chemical enhancer is selected from the group consisting of sulfoxides, alcohols, polyols, alkanes, fatty acids, esters, amines, amides, teφenes, surface-active agents, cyclodextrins, and mixtures thereof.

8. Method according to claim 1 wherein the penetration enhancer is a physical enhancer.

9. Method according to claim 8 wherein the physical enhancer is selected from the group consisting of a skin hydration enhancer, an occlusion device, a hydrocolloid patch, a lipophilic penetrant, a delipidization agent, electroporation, iontophoresis, and ultrasound.

10. Method according to claim 1 for treating hypeφigmented skin comprising administering to the overlying epidermis a composition comprising a gentisic acid lower ester and a chemical penetration enhancer selected from the group consisting of alpha- and beta-hydroxy acid, sulfoxides, alcohols, polyols, alkanes, fatty acids, esters, amines and amides, tepenes, surface-active agents, cyclodextrins, and mixtures thereof in amounts effective to deliver a gentisic acid lower ester to melanocytes.

11. Method according to claim 1 for lightning human hairs comprising administering to the scalp a composition comprising a gentisic acid lower ester and a chemical penetration enhancer selected from the group consisting of alpha- and beta-hydroxy acid, sulfoxides, alcohols, polyols, alkanes, fatty acids, esters, amines and amides, tepenes, surface-active agents, cyclodextrins, and mixtures thereof in amounts effective to deliver a gentisic acid lower ester to melanocytes.

12. A cosmetic and dermatologic composition comprising:

(i) a gentisic acid lower ester of formula (I) as described in claim 1;

(ii) an effective amount of a penetration enhancer;

(iii) a cosmetically acceptable vehicle; wherein R¹ represents a linear (Cι-C₆)-alkyl.

13. Composition according to claim 12 wherein said lower ester is ethyl gentisate.

14. Composition according to claim 13 containing from about 1% to about 3% by weight ethyl gentisate.

15. Composition according to claim 12 wherein said lower ester is methyl gentisate.

16. Composition according to claim 15 containing from about 1% to about 3% by weight methyl gentisate.

17. Composition according to claim 12 comprising further ingredients suitable for the treatment of hypeφigmented skin.

18. Composition according to claim 12 comprising further ingredients suitable for the hairs discolouring.