WO2008009860A2

WO2008009860A2 - Use of calcium channel antagonist compounds for depigmenting the skin

Info

Publication number: WO2008009860A2
Application number: PCT/FR2007/051687
Authority: WO
Inventors: Lionel Breton
Original assignee: L'oreal
Priority date: 2006-07-21
Filing date: 2007-07-18
Publication date: 2008-01-24
Also published as: WO2008009860A3

Abstract

The present invention relates to the use of at least one calcium channel antagonist compound for depigmenting and/or bleaching the skin.

Description

Use of calcium channel antagonist compounds to depigment the skin

The present invention relates to the use of at least one calcium channel antagonist compound, also referred to as calcium channel blockers, for depigmenting and / or bleaching the skin.

The color of human skin is a function of various factors including seasons of the year, race and sex, it is mainly determined by the nature and concentration of melanin produced by melanocytes. Melanocytes are specialized cells that, via particular organelles, melanosomes, synthesize melanin. In addition, at different periods of their life, some people see on the skin and especially on the hands, darker spots and / or more colorful, giving the skin a heterogeneity. These spots are also due to a high concentration of melanin in keratinocytes located on the surface of the skin.

The use of harmless topical depigmenting substances with good efficacy is particularly sought for treating regional hyperpigmentations by melanocytic hyperactivity such as idiopathic melasmas, occurring during pregnancy ("pregnancy mask" or chloasma) or a oestro-progestative contraception, hyperpigmentations localized by hyperactivity and benign melanocyte proliferation, such as senile pigmentary spots known as actinic lentigo, accidental hyperpigmentations, possibly due to photosensitization or post-injury healing, as well as certain leukoderma, such as vitiligo. For the latter (the scarring may result in a scar giving the skin a whiter appearance), failing to repigment the damaged skin, it completes depigmenting the areas of residual normal skin to give the whole skin a homogeneous white color.

The mechanism of formation of skin pigmentation, that is to say the formation of melanin is particularly complex and schematically involves the following main steps: Tyrosine -> Dopa -> Dopaquinone -> Dopachrome -> Melanin Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxido-reductase EC 1.14.18.1) is the essential enzyme involved in this series of reactions. In particular, it catalyzes the transformation reaction of tyrosine into Dopa (dihydroxyphenylalanine) thanks to its hydroxylase activity and the conversion reaction of Dopa into dopaquinone thanks to its oxidase activity. This tyrosinase only acts when it is maturing under the influence of certain biological factors.

Depigmenting substances can directly affect the vitality of epidermal melanocytes where melanogenesis takes place and / or interfere with one of the stages of melanin biosynthesis either by inhibiting one of the enzymes involved in melanogenesis or by intercalating as a structural analogue one of the chemical compounds of the melanin synthesis chain, which can then be blocked and thus ensure depigmentation.

The substances most used as depigmenting agents are more particularly hydroquinone and its derivatives, in particular its ethers such as monomethyl ether and hydroquinone monoethyl ether. However, these compounds may cause undesirable effects, such as the appearance of skin rashes in particular situations, such as use at high concentrations, sensitive skin or dermatological disorders.

On the other hand, commonly used as the inhibitor of tyrosinase activation is kojic acid which complexes the copper present in the active site of this enzyme. However, this compound may prove unstable in solution, which complicates its formulation.

There remains the need for new whitening agents for human skin that are as effective as those known and non-irritating, non-toxic and / or non-allergenic for the skin, while being stable in a composition, or alternatively having a reinforced action. so that it can be used in a smaller quantity, which considerably reduces the possible harmful side effects.

Melanocytes develop from the embryonic neural crest. The precursors of melanocytes leave the neural crest and so migrate into the mesenchyme over long distances, and they invade ^the skin before colonize the hair follicle formation, where they differentiate into functional melanocytes. The Applicant has studied and has surprisingly demonstrated the presence of functional calcium-dependent ion channels on the membrane surface of melanocytes, the distinctive metabolic function of melanocytes is the synthesis of melanin pigments. She then showed that the function of melanocyte melanin pigment metabolic synthesis could be modulated by the control of the calcium ion exchange that intervenes through its plasma membrane.

The Applicant has thus demonstrated that calcium channel antagonist compounds showed good depigmenting activity without exhibiting cytotoxicity. Unlike many depigmenting substances, calcium-dependent channel antagonists slow down the overall functionality of the cells, which explains the absence of cytotoxicity of these substances.

As early as 1965, T. Godfraind's work on smooth muscle cells was conducted to investigate the mechanisms by which certain drug substances inhibited the contractile response to vasoactive agents. The hypothesis proposed was that the permeability of the calcium membrane could be inhibited by pharmacological agents, which would be the common mechanism on which polyvalent antagonists would act, which would cause a global relaxing effect.

The simplest experimental technique to show that a pharmacological agent is able to inhibit the entry of calcium consists in preincubating a smooth muscle in physiological solution free of calcium, depolarizing it in a rich solution. in KCI and gradually increase the calcium concentration in the infusion solution. This causes an increase in muscle tension whose value evolves to a maximum depending on the calcium concentration. When this protocol is repeated in the presence of a substance thought to inhibit calcium entry as was first achieved with cinnarizine, the contractile responses are inhibited in a dose-dependent manner. A similar concept has been applied to describe the effect of verapamil on the heart. Verapamil was initially considered a β-blocker, its action is more complex since it exerts an inhibitory action on excitation-contraction coupling. On the papillary muscle, verapamil abolishes the contraction by very slightly modifying the action potential. It is this observation that leads to considering verapamil as a calcium antagonist.

For a substance to be recognized as a calcium channel blocker, otherwise known as calcium channel blocker, it must be able to decrease the concentration within cellular calcium or decrease the binding of calcium to intracellular proteins such as calmodulin, as described in particular in; J. Biol. Chem. 1987, 262, 694, Galizzi, JP et al - Eur. J. Pharmacol. 1991, 205, 49; Y. Okamiya et al - J. Neurosci. 1988, 8, 3354, JA Wagner et al - Eur. J. Pharmacol. 1985, 111, 273; Schoemaker H. and Lauger S. - J. Pharmacol. Exp. Ther. 1986, 237, 731, IJ. Reynolds et al.

More precisely, the subject of the invention is therefore the cosmetic or pharmaceutical use, in particular dermatological use, of at least one calcium channel antagonist compound as a whitening and / or anti-browning agent for the skin.

As calcium channel blocking agents, there may be mentioned for example:

active agents on the plasma membrane, complexing calcium and / or calcium entry inhibitors such as phenylalkylamines such as, for example, verapamil, antipamil, gallopamil, devapamil, falipamil, tiapamil, dihydropyridines such as nifedipine, amlodipine, dazodipine, felodipine, isradipine, nicardipine, nimodipine, nisoldipine, nitrendipine, ryosidine, benzothiazepines such as diltiazem, diphenylpiperazines as per for example, cinnarazine, flunarizine; or - active agents inside the cell intervening on the release of the intracellular calcium reserves or on the inhibition of the formation of the calcium / calmodulin complex. For example, agents acting on the sarcoplasmic reticulum such as, for example, dantrolene and TMB-8, calmodulin antagonists such as, for example, phenothiazine, trifluoperazine, chlorpromazine or naphthalene derivatives or local anesthetics such as dibucaine or dopamine antagonists such as pimozide, haloperidol or calmidazolium.

- manganese and / or one of its salts that block the penetration of calcium to the cytoplasm in many cells, including manganese from natural extracts, plants or microorganisms, particularly bacterial, rich in manganese or manganese salt, but excluding manganese salts derived from hydroxyaniline. Manganese organic salts that may be mentioned include manganese gluconate or manganese carbonate or manganese acetate or manganese citrate or manganese oleate or manganese oxalate. As inorganic salts of manganese, mention may be made of inorganic salts such as manganese chloride or manganese borate or manganese nitrate or manganese phosphate or manganese sulfate. - adenosine and its derivatives.

alverine or one of its salts.

According to the invention, the term "alverine salts" means the organic or inorganic salts of alvein. As organic salts that may be used according to the invention, mention may be made of alverine gluconate or alverine acetate or alverine citrate or alverine oleate or alverine oxalate. As inorganic salts of alverine, mention may be made of mineral salts such as alverine chloride or alverine borate or alverine nitrate or alverine phosphate or alverine sulfate or alverine carbonate. It is thus understood that in the text, unless otherwise indicated, the use of the term alverine should be understood to mean both alverine in ionic form and in the form of salts.

Preferably, according to the invention, the organic salt is alverine citrate and the inorganic salt is alverine chloride.

the compounds of formula (I) described in FR05 / 51025:

(I) in which:

^* Each of the groups Z independently denotes a fluorine atom, a linear al- Kyle -C ₆ or branched C ₃ -C _6, a linear alkenyl, C ₂ -C ₆ alkyl or branched C ₃ -C ₆ C ₃ -C ₆ cycloalkyl radical, CF ₃ group, OR ₁ group, NR ₁ R ₂ group, COR 1 group, COOR ₁ group, CONR ₁ R ₂ group or NR ₁ COR _{2 group} ;

^* N ranges from O to 5; * A means:

a hydrogen atom,

- a linear alkyl radical C ₁ -C ₂₀ alkyl or branched C ₃ -C ₂₀ - alkenyl radical at C ₂ -C ₂₀ linear or C ₃ -C ₂₀ branched,

a C ₃ -C ₂₀ cycloalkyl radical, said radicals being optionally substituted with at least one group chosen from: an oxo radical, a group OR ₁ , a group NR ₁ R ₂ , a group COR ₁ , a group COOR ₁ , a group CONR ₁ R ₂ , a group NR ₁ COR ₂ , or a phenyl radical optionally substituted with one to five groups Z as defined above,

a phenyl radical optionally substituted with one to five Z groups as defined above ^* B denotes a hydrogen atom, a linear alkyl radical dC ₆ or branched C ₃ -C ₆ alkenyl, linear C ₂ -C ₆ alkyl or branched C ₃ -C ₆ cycloalkylene radical Kyle C ₃ -C ₆ , an ORi group, an NR 1 R ₂ group, a COR ₁ group, a COOR ₁ group, a CONR ₁ R ₂ group or a NR ₁ COR _{2 group} ; where R ₁ and R ₂ independently denote a hydrogen atom, a linear C ₁ -C ₆ or branched C ₃ -C ₆ alkyl radical optionally substituted by a phenyl radical, a C ₂ -C linear alkenyl radical; ₆ or branched C ₃ -C ₆ cycloalkyl C ₃ -C ₆ or phenyl; the groups R ₁ , respectively R ₂ , which may be identical or different from each other; dotted lines denote a potential double bond, it being understood that A is distinct from a hydrogen atom when this double bond is present, and their salts, optical isomers and solvates.

at least one ((dialkylamino) alkoxy) ethanol derivative of formula (I) described in FR05 / 51704:

in which :

^* Ri and R ₂ independently denote a linear alkyl C ₁ -C ₁₀ linear alkenyl or C ₂ -C ₁₀ alkyl or alkenyl or branched C ₃ -C _10; or a carbocycle having from 5 to 7 carbon atoms; or R ₁ and R ₂ together with the nitrogen atom to which they are attached form a saturated heterocycle comprising from 5 to 6 atoms; * R ₃ designates:

• a hydrogen atom; or

A linear C ₁ -C ₂₅ alkyl or C ₂ -C ₂₅ linear alkenyl group; or a C ₃ -C ₂₅ branched alkyl or alkenyl group, or a C ₃ -C ₂₅ cycloalkyl group, optionally substituted with at least one radical chosen from: a saturated or unsaturated carbocycle containing from 5 to 7 carbon atoms; a phenyl group; an OR radical; a COOR group; or an NRR 'group; or

A phenyl group; where R and R 'independently denote a hydrogen atom or a linear C ₁ -C ₆ alkyl or linear C ₂ -C ₆ alkenyl group or a C ₃ -C ₆ branched alkyl or alkenyl group; * n is an integer ranging from 1 to 10, or its acid addition salt.

Of course, according to the invention, the calcium channel antagonists can be used alone or in mixture and in any proportion.

The calcium channel antagonist compounds that can be used according to the invention make it possible to depigment and / or effectively lighten the skin of human beings.

Skin pigmentation is a normal physiological process resulting from exposure of the skin to sunlight. It may, for aesthetic purposes, be desirable to beautify the appearance of the skin by limiting the pigmentation and thus reduce the appearance of darker skin areas.

It also happens that the pigmentation leads to skin disorders that may, for example, be related to a local proliferation of active melanocytes.

The calcium channel antagonists are intended in particular to be administered to individuals with brownish pigmentation spots, senescence spots, or to individuals wishing to combat the appearance of a brownish color originating from metallogenesis, for example to following exposure to ultraviolet radiation.

Thus, calcium channel antagonists may be used as a skin whitening agent and / or as an anti-browning agent, in particular for preventing the formation and / or amelioration of pigment spots, ephelides, senescence spots and / or for lightening and / or whiten and / or uniformize the color of a burnished skin.

These compounds are particularly effective in preventing and / or treating actinic spots. Actinic spots, also called senile lentigo, are characterized by circumscribed brown macules corresponding to a greater local production of melanin induced by chronic sun exposure. They are usually found on the face, back of the hands, forearms, upper back and décolleté, even the scalp areas of the scalp devoid of hair.

The subject of the invention is also the use of at least one calcium channel antagonist compound as described above for the manufacture of a dermatological composition for treating pigmentary disorders of the skin as well as a calcium channel antagonist for use in the treatment of pigmentary disorders of the skin.

The calcium channel antagonist compounds may thus be useful for treating regional hyperpigmentations by melanocytic hyperactivity such as forearm melasma, idiopathic melasmas, occurring during pregnancy ("pregnancy mask" or chloasma) or contraception oestro-progestative, puva-lentigines, post-inflammatory hyperpigmentation, accidental hyperpigmentations, possibly due to photosensitization or post-lesion scarring, as well as certain leucoderma, such as vitiligo.

Depigmenting substances also find application in the whitening of integuments, in particular hairs that may be desirable to lighten in order to make them less visible.

Whether the calcium channel antagonist compounds are used for cosmetic or pharmaceutical purposes, they can be administered by different routes, for example the oral route, these compounds will then be formulated in compositions adapted to this mode of administration. For ingestion, many embodiments of oral compositions and in particular dietary supplements are possible. The active ingredient (s) according to the invention may in particular be incorporated into any other form of food supplements or enriched foods, for example food bars, or compacted powders or not. The powders can be diluted with water, in soda, dairy products or soy derivatives, or incorporated into food bars.

The subject of the invention is therefore also a cosmetic process for bleaching human skin and / or scalp and / or mucous membranes, comprising ingestion or application to the skin and / or the scalp and / or mucous membranes. at least one calcium channel antagonist.

In the case of topical application, the calcium channel antagonist compound may be left in contact with the skin and / or the scalp and / or mucous membranes, and then possibly rinsed. The method is particularly suitable for removing brownish pigment spots and / or senescence spots, and / or for lightening browned skin. For topical use, the calcium channel antagonist compounds may be formulated in a composition comprising a physiologically acceptable medium. In particular, the composition is suitable for topical application to the skin. The physiologically acceptable medium will preferably be a cosmetically or dermatologically acceptable medium, that is to say without any unpleasant appearance, and which does not generate tingling, tightness or redness that is unacceptable to the user.

By physiologically acceptable medium, an environment compatible with keratin materials of human beings such as the skin, the mucous membranes, the nails, the scalp and / or the hair is understood.

The composition according to the invention may be intended for a cosmetic or pharmaceutical application, particularly dermatological.

The quantity of calcium channel antagonist compounds that can be used in the context of the invention obviously depends on the desired effect.

By way of example and for topical administration, this amount may range, for example, from 0.000001% to 25% by weight, 0.00001% to 10% by weight, preferably from 0.0001% to 5%. by weight, especially from 0.01 to 2% by weight, relative to the total weight of the composition.

In the case of oral administration, the amount of calcium channel antagonist compounds may range from 0.001 to 1000 mg weight / kg body weight / day.

In the case of oral administration, the composition may be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, suspensions of microspheres or nanospheres or lipid or polymeric vesicles for controlled release. Preferably, the composition is in the form of complement.

In the case of topical administration, the composition may comprise the constituents usually employed in the intended application.

It may especially be mentioned water, solvents, oils of mineral, animal and / or vegetable origin, waxes, pigments, fillers, surfactants, cosmetic or dermatological active agents, UV filters, polymers, gelling agents, preservatives. Of course those skilled in the art will take care to choose this or these optional additional compounds, and / or their quantity, in such a way that the advantageous properties of the compounds according to the invention are not, or not substantially, impaired by the adjunct. envisaged.

The composition according to the invention may be in any galenical form normally used in the cosmetic and dermatological fields; it may especially be in the form of an aqueous solution, hydroalcoholic, optionally gelled, a dispersion of the lotion type possibly two-phase, an oil-in-water or water-in-oil or multiple emulsion, an aqueous gel , an oil dispersion in an aqueous phase using spherules, these spherules may be polymeric nanoparticles such as nanospheres and nanocapsules or lipid vesicles of ionic and / or nonionic type.

When the composition of the invention is an emulsion, the proportion of the fatty phase can range from 5 to 80% by weight, and preferably from 5 to 50% by weight relative to the total weight of the composition. The oils, emulsifiers and optional coemulsifiers used in the composition in emulsion form are chosen from those conventionally used in the field under consideration. The emulsifier and the coemulsifier are present in the composition in a proportion ranging from 0.3 to 30% by weight, and preferably from 0.5 to 20% by weight relative to the total weight of the composition.

This composition may 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 mousse . It can optionally be applied to the skin 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 product and / or as a makeup product.

This composition may constitute a cream for cleaning, protecting, treating or caring for the face, for the hands, for the feet, for large anatomical folds or for the body (for example, day creams, night creams). , make-up removing creams, foundation creams, sunscreen creams); a fluid foundation, a make-up removal milk, a body care or protection milk, an anti-sun milk; a lotion, gel or mousse for the care of the skin, such as a cleaning lotion. In an advantageous aspect of the invention, the compositions used may also comprise at least one depigmenting agent and / or a soothing agent, and / or an organic photoprotective agent and / or an inorganic photoprotective agent, preferably less than one depigmenting agent and / or a soothing agent.

The use of at least one calcium channel antagonist compound in combination with another depigmenting agent may in particular allow to use a smaller amount of each of the depigmenting agent. By "depigmenting agent" is meant, for example, depigmenting or anti-pigmenting agents the following compounds: kojic acid; ellagic acid; arbutin and its derivatives such as those described in EP-895,779 and EP-524,109; hydroquinone; aminophenol derivatives such as those described in applications WO 99/10318 and WO 99/32077, and in particular N-cholesteryloxycarbonyl-para-aminophenol and N-ethyloxycarbonyl-para-aminophenol; iminophenol derivatives, in particular those described in application WO 99/22707; L-2-oxothiazolidine-4-carboxylic acid or procysteine, as well as its salts and esters; calcium d-panthétéine sulfonate, ascorbic acid and its derivatives, in particular ascorbyl glucoside; and plant extracts, in particular licorice, mulberry, skullcap and Bacopa monnieri, without this list being limiting.

By "desquamating agent" is meant any compound capable of acting:

or directly on 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, citric, lactic, tartaric, malic or mandelic acids; urea; gentisic acid; oligofucoses; cinnamic acid; Saphora japonica extract; resveratrol;

or on the enzymes involved in the desquamation or degradation of corneodesmosomes, glycosidases, stratum corneum chymotryptic enzyme (SCCE) or even other proteases (trypsin, chymotrypsin-like). Mention may be made of the chelating agents for mineral salts: EDTA; N-acyl-N, N ', N', ethylene diaminetriacetic acid; aminosulfonic compounds and in particular (N-2-hydroxyethylpiperazine-N-2-ethane) sulfonic acid (HEPES); 2-oxothiazolidine-4-carboxylic acid derivatives (procysteine); glycine-type alpha amino acid derivatives (as described in EP 0 852 949, as well as sodium methyl glycine diacetate marketed by BASF under the trade name TRILON M); honey ; sugar derivatives such as O-octanoyl-6-D-maltose and N-acetyl glucosamine. As soothing agents that may be used in the composition according to the invention, mention may be made of: pentacyclic triterpenes and plant extracts (eg Glycyrrhiza glabra) containing them, for example β-glycyrrhetinic acid and its salts and / or derivatives thereof (I monoglucuronide glycyrrhetinic acid, stearyl glycyrrhetinate, 3-stearoyloxy glycyrrhetic acid), Rosa sp. extracts, in particular Rosa gallica, ursolic acid and its salts, oleanolic acid and its salts, betulinic acid and its salts, an extract of Paeonia suffruticosa and / or lactiflora, salts of salicylic acid and in particular zinc salicylate, phycosaccharides from Codif, an extract of Laminaria saccharina, canola oil, bisabolol and extracts of chamomile, allantoin, EPP Seppic Seperate Seppivital EPC (diesterphosphoric vitamin E and C), omega 3 unsaturated oils such as rosehip musk, blackcurrant, ecchium, fish, plank extracts thyme, capryloyl glycine, Seppic Seppicalm VG (sodium palmitoylproline and water-lily alba), an extract of Pygeum, an extract of Boswellia serrata, an extract of Centipeda cunnighami, an extract of Helianthus annuus, an extract of Linum usitatissimum, the tocotrienols, extracts of Cola nitida, piperonal, clove extract, Epilobium Angustifolium extract, aloe vera, Bacopa moniera extract, phytosterols, cortisone, hydrocortisone, indomethacin and beta methasone.

The organic photoprotective agents are in particular chosen from anthranilates; cinnamic derivatives; dibenzoylmethane derivatives; salicylic derivatives, camphor derivatives; triazine derivatives such as those described in US 4,367,390, EP 0 863 145, EP 0 517 104, EP 0 570 838, EP 0 796 851, EP 0 775 698, EP 0 878 469, EP 0 933 376, EP 0 507 691, EP 0 507 692, EP 0 790 243, EP 0 944 624; benzophenone derivatives; derivatives of β, β-diphenylacrylate; benzotriazole derivatives; benzalmalonate derivatives; benzimidazole derivatives; imidazolines; bis-benzoazolyl derivatives as described in patents EP 0 669 323 and US 2,463,264; p-aminobenzoic acid derivatives (PABA); methylene bis- (hydroxyphenylbenzotriazole) derivatives as described in US applications 5,237,071, US 5,166,355, GB 2303549, DE 197 26 184 and EP 0 893 1 19; and filter polymers and silicone filters such as those described in particular in the application WO-93/04665; dimers derived from α-alkylstyrene such as those described in patent application DE 198 55 649.

The inorganic photoprotective agents are chosen from pigments or even nanopigments (average size of the primary particles: generally between 5 nm and

100 nm, preferably between 10 nm and 50 nm) coated or uncoated metal oxides as for example nanopigments of titanium oxide (amorphous or crystallized in rutile and / or anatase form), iron, zinc, zirconium or cerium which are all UV photoprotective agents well known per se. Conventional coating agents are, moreover, alumina and / or aluminum stearate. Such nanopigments of metal oxides, coated or uncoated, are in particular described in patent applications EP 0 518 772 and EP 0 518 773.

The photoprotective agents are generally present in the composition according to the invention in proportions ranging from 0.1 to 20% by weight relative to the total weight of the composition, and preferably ranging from 0.2 to 15% by weight relative to to the total weight of the composition.

Preferably, the calcium channel antagonist compound (s) will be associated with at least one depigmenting agent and / or at least one photoprotective agent.

The examples which follow illustrate the invention without limiting its scope.

EXAMPLE 1 Demonstration of the Calcium-dependent Ion Channels on Melanovirus - Quantitative Digital Imaging Study

The study concerns the identification and localization of the L-type calcium channel in cultured human melanocytes.

The use of specific immunofluorescent markers allows the identification of this channel by a 3D multispectral digital imaging system, the Pathfinder ™ system of IMSTAR (Patent FR 00 0441 1; PCT FR01 / 00994), allowing the studies in multiple fluorescent marking.

Sample Preparation Four different cultures of human melanocytes were prepared and cultured on slides. The cultures lasted two weeks in order to have as many cells as possible. The culture properties of melanocytes make it possible to obtain only 100 to 150 cells that can be analyzed by culture. All slides were fixed prior to application of antibodies in 10% Paraformaldehyde.

Antibody detection The primary antibody used for channel detection was the L-type calcium channel antibody. For each culture, a blade pair was made. On a slide, detection for the L-type channel has been performed. The secondary antibody is Alexa 488 (green).

Analysis and achievement of results

The three snapshots in Figure 1 show the presence of L-type calcium channels on the surface of human melanocytes.

EXAMPLE 2 Demonstration of the Amping Activity of Cinnarizine

Cinnarizine has been tested for its activity on the melanogenesis of co-culture of normal human keratinocytes and melanocytes.

The synthesis of melanin is evaluated by the incorporation of thiouracil and the specific activity on melanogenesis is estimated by the ratio of the incorporation of thiouracil to the incorporation of leucine relative to 100% of the control.

A significant decrease in melanin synthesis is measured in the presence of cinnarizine.

Example 3 Example of a Topical Composition

An oil-in-water emulsion-type whitening cream, comprising (% by weight), is prepared:

- cinnarizine 0,005%

- glycerol stearate 2%

- polysorbate 60 (ICI Tween 60) 1%

- stearic acid 1, 4% - triethanolamine 0.7% - 0.4% carbomer

- liquid fraction of shea butter 12% ^r o

- perhydrosqualene 12% ^r o

- antioxidant 0.05%

- perfume, preservative qs

- water qs 100%

Example 4 Example of a Topical Composition

A depigmenting gel for the skin comprising (% by weight) is prepared: 1,4-bis (3-phenylpropyl) piperazine 2% ^r

- hydroxypropylcellulose (Klucel H from Hercules) 1%

- antioxidant 0.05%

40% isopropanol

- perfume, preservative qs - water qs 100%

Example 5 Example of an Oral Composition

Dreads containing (% by weight) are prepared:

Active substances mα / draαée

Manganese citrate 6

Excipient of the core of the dragee

Minocrystalline cellulose 70

Encompress ™ 60 Magnesium Stearate 3

Anhydrous colloidal silica 1

Coating agent

Sucrose 265

Shellac 5 Talc 61

Polyvidone 6

2.5 titanium dioxide

Carnauba wax 0.4

Colorants (E120, E129) 0.1 This type of candy can be taken 1 to 4 times a day.

Claims

1. Use of at least one calcium channel antagonist compound as a whitening and / or anti-browning agent of the skin.

2. Use according to claim 1 for lightening and / or whitening and / or uniformizing the color of a burnished skin, preventing the formation and / or eliminating brownish pigment spots and / or senescence spots and / or ephelides.

3. Use of at least one calcium channel antagonist compound for the preparation of a composition for treating disorders of pigmentation.

4. Use according to claim 3, characterized in that the composition is intended to treat melasma forearms, idiopathic melasmas, hyperpigmentations associated with pregnancy or estrogen-progestative contraception, puva-lentigines, hyperpigmentations accidental hyperpigmentation due to leukoderma, vitiligo.

5. Use according to any one of the preceding claims, characterized in that the calcium channel antagonist is selected from active agents on the plasma membrane, complexing calcium and / or calcium entry inhibitors; active agents inside the cell intervening on the release of intracellular stores of calcium; inhibitors of calcium / calmodulin complex formation; manganese and / or one of its salts; adenosine and its derivatives; alverine or one of its salts; the compounds of formula (I):

(I) in which:

^* Each of the groups Z independently denotes a fluorine atom, a linear al- Kyle dC ₆ or branched C ₃ -C _6, a linear alkenyl, C ₂ -C ₆ alkyl or branched C ₃ -C ₆ C ₃ -C ₆ cycloalkyl radical, CF ₃ group, OR 1 group, NR ₁ R ₂ group, COR 1 group, COOR ₁ group, CONR ₁ R ₂ group or NR ₁ COR ₂ group; n is from 0 to 5; ^* A means:

a hydrogen atom,

- a linear alkyl radical -C ₂₀ or branched C ₃ -C _20,

- an alkenyl radical with C ₂ -C ₂₀ linear or C ₃ -C ₂₀ branched, - a cycloalkyl radical in C ₃ -C ₂₀ radical, said radicals being optionally substituted by at least one group selected from: an oxo group, a group ORi, a group NRi R ₂ , a group CORi, a group COORi, a group CONRi R ₂ , a group NRiCOR ₂ , or a phenyl radical optionally substituted with one to five groups Z as defined above, - a phenyl radical optionally substituted with one to five Z groups as defined above

^* B denotes a hydrogen atom, a linear alkyl radical dC ₆ or branched C ₃ -C _6, a linear alkenyl, C ₂ -C ₆ alkyl or branched C ₃ -C ₆ cycloalkyl C ₃ -C ₆ , an OR 1 group, an NR 1 R ₂ group, a COR 1 group, a COOR 1 group, a CONR 1 R ₂ group or a NR ₁ COR ₂ group; where R 1 and R ₂ independently denote a hydrogen atom, a linear C ₆ -C ₆ branched C ₁ -C ₆ alkyl radical optionally substituted by a phenyl radical or a linear C ₂ -C ₆ or branched C ₃ alkenyl radical; -C ₆ , a C ₃ -C ₆ cycloalkyl radical or a phenyl radical; the groups R ₁ , respectively R ₂ , which may be identical or different from each other;

^* The dotted lines represent a potential double bond, provided that A is other than a hydrogen atom when the double bond is present, and the salts, optical isomers and solvates. derivatives of ((dialkylamino) alkoxy) ethanol of formula (I):

in which :

^* Ri and R ₂ independently denote a linear alkyl C ₁ -C ₁₀ linear alkenyl or C ₂ -C ₁₀ alkyl or alkenyl or branched C ₃ -C _10; or a carbocycle having from 5 to 7 carbon atoms; or R ₁ and R ₂ together with the nitrogen atom to which they are attached form a saturated heterocycle comprising from 5 to 6 atoms; R ₃ denotes: a hydrogen atom; or A linear C ₁ -C ₂ OU alkyl or C ₂ -C ₂ S linear alkenyl group or a C ₃ -C ₂₅ branched alkyl or alkenyl group, or a C ₃ -C ₂₅ cycloalkyl group, optionally substituted with at least one radical chosen from: a saturated or unsaturated carbocycle containing from 5 to 7 carbon atoms; a phenyl group; an OR radical; a COOR group; or an NRR 'group; or

A phenyl group; where R and R 'independently denote a hydrogen atom or a linear alkyl group or linear dC ₆ alkenyl or C ₂ -C ₆ alkyl or alkenyl, branched C ₃ -C ₆ alkyl; * n is an integer from 1 to 10, or its addition salt with an acid.

6. Use according to any one of the preceding claims, characterized in that said compound is used in an amount representing from 0.0001% to 25% of the total weight of the composition.

7. Use according to claim 6, characterized in that said derivative is used in an amount representing from 0.001% to 10% of the total weight of the composition.

8. Use according to any one of the preceding claims, characterized in that said calcium channel antagonist compound is associated with at least one depigmenting agent and / or at least one organic photoprotective agent and / or at least one inorganic photoprotective agent.

9. A cosmetic process for bleaching the skin and / or the scalp and / or the mucous membranes comprising ingestion or application to the skin and / or the scalp and / or the mucous membranes of at least one antagonist compound of the calcium channels.

10. Composition comprising at least one calcium channel antagonist compound and at least one compound selected from a depigmenting agent, a soothing agent and a photoprotective agent.