FR2808192A1 - EPICHATCHIN AS INHIBITOR OF NO-SYNTHASE AND USES - Google Patents

Abstract

The invention concerns the use of an efficient amount of epichatechin in a physiologically acceptable medium, in a composition or for preparing a composition, the epichatechin or the composition being designed to inhibit NO-synthase.

Description

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The present invention relates to the use of an effective amount of epichatechine, in a physiologically acceptable medium, in a composition or for the preparation of a composition, the epicacycin or the composition being intended to inhibit the NO-synthase .

The term NO-synthase covers a family of enzymes that enzymatically catalyze L-arginine to citrulline, a catalysis in which a multifunctional gas mediator, nitrogen monoxide or NO, is produced.

NO-synthases exist in three forms, two constitutive forms, nomenclature grouping the neuron NO-synthase (or NOS 1) and the endothelial NO-synthase (or NOS 3), and the inducible form (or NOS 2) (Medicine / Sciences 1992, 8, pp. 843-845).

It is also understood in the text that without indication to the contrary the term NO-synthase covers all the isoforms of the enzyme.

Thus, according to the invention, the term NO-synthase inhibitors means any product which, in spite of the NO-synthase isoform, reduces the concentration of NO. By way of example, products which reduce the amount of active NO-synthase, which block the enzymatic activity of NOsynthase or its induction or which inhibit the activity of NO produced.

Nitric oxide has an extra electron structure that makes it extremely chemically reactive. It is well known that such compounds are harmful and we try to limit their production as much as possible. Thus, in the case of nitric oxide, NO-synthase inhibitors have been widely studied.

NO is a multifunctional signal molecule active in a wide variety of body systems and tissues. In addition to its damaging effects on the cells linked to its hyper-reactivity due to its structure comprising an additional electron, it is recognized inter alia as intervening particularly in the cardiovascular system (regulator of the blood pressure with vasodilator effect, inhibitor of the platelet aggregation with effect anticoagulant), in the nervous system (memory, modulation of the release of neurotransmitters), in the immunological system (modulation of immune defenses, inflammation, involvement in autoimmune diseases).

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 immune).

It is now well accepted that NO plays a prominent role in the skin.

The NO can be synthesized by all the varieties of cells constituting the skin and as such it intervenes in multiple and complex processes of regulation such as the regulation of the differentiation and / or the cellular proliferation, the vasodilatation, the melanogenesis , the response to environmental variations (homeostasis).

Its involvement in differentiation and cell proliferation (stimulatory effect), particularly keratinocytes, combines it with epidermal growth and healing as well as hyperproliferative disorders (psoriasis).

Due to its electronic hyperreactivity that can lead to cell degradation or destruction, NO is involved in apoptotic processes and in the intrinsic and / or extrinsic aging of the skin.

It is involved in immunological and inflammatory skin processes. It is indeed commonly accepted that NO plays a role in contact hypersensitivity reactions, in cutaneous allergic manifestations, in the immune response of the skin. Likewise, in addition to its direct proinflammatory role, it is the mediator between neuropeptides such as substance P and / or calcitonin gene related peptide (CGRP) in cutaneous neurogenic inflammatory processes. involvement in so-called sensitive skin phenomena.

The involvement of NO in vasodilatation is associated with erythema of the skin, particularly erythema induced by ultraviolet radiation, localized or diffuse erythematous rashes of the skin such as those caused by drugs, toxins and / or viral or bacterial infections, with rosacea.

NO is recognized as an intermediate in the melanogenesis induced by ultraviolet radiation type B (UVB). It is also one of the factors involved in disorders of the hypermelanosis type.

Finally, NO seems to be involved in the control of sweating as well as lipolysis (inhibitory effect) or in hair loss.

We therefore understand the interest that exists to have inhibitors of NO-synthases.

In this respect, numerous inhibitors have already been proposed in the prior art.

More particularly, mention may be made of NG-monomethyl-L-arginine (NMMA), the methyl ester of N-nitro-L-arginine (NAME), N-nitro-L-arginine (NNA), NG

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 amino-L-arginine (NAA), NG.NG-dimethyl-arginine (asymmetric dimethylarginine, called ADMA), diphenyleneiodonium chloride, 2- (4-carboxyphenyl) -4,4,5,5-tetramethylimidazoline- 1-oxy-3-oxide, 7-nitroindazole, N (5) - (1-iminoethyl) -L-ornithine, aminoguanidine, canavanine and ebselen.

Without questioning the effectiveness of these products, it is noted that these are chemical compounds that can induce inconvenience to the user or adverse side effects, which generally prefers to use natural products.

The object of the present invention is to provide a novel NO-synthase inhibitor which is a natural inhibitor of NO-synthase.

Surprisingly and unexpectedly, the Applicant has demonstrated that epichatechin has the property of being a NO-synthase inhibitor, particularly inducible NO-synthase (NOS 2) which makes it a good candidate for use in applications where it is interesting to use a NO-synthase inhibitor, particularly in cosmetics.

Epichatechin or 2- [3,4-dihydroxyphenyl] -3,4-dihydro-1 [2H] -benzopyran-3,5,7-triol may be in the form of two enantiomers, namely: (+) epichatechine or [2S, 3S] -2- [3,4-dihydroxyphenyl] -3,4-dihydro-1 [2H] -benzopyran-3,5,7-triol; (-) - epichatechine or [2S, 3S] -2- [3,4-dihydroxyphenyl] -3,4-dihydro-1 [2H] -benzopyran-3,5,7-triol.

According to the invention, each of these compounds can be used alone. But the invention also relates to the use of a mixture in any proportion of (+) - epichatechin and (-) - epichatechin.

In addition to these two enantiomeric forms, the invention also relates to the analogues of epichatechin and / or its derivatives with the exception of epichatechinegallate.

Thus, furthermore in the text and for simplicity, the term epicatechin means unless otherwise indicated, as meaning (+) epichatechin or (-) epichatechin or a mixture in any proportion of (+) - epichatechin and (-) ) - epichatechine, as well as the analogs of epichatechin and / or its derivatives with the exception of epichatechin-gallate.

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Epichatechin is a natural component of green tea, known for example for its antioxidant properties, its antithrombic effects, its anticollagenase effects, its effects on lipids.

However, it is not described as NO-synthase inhibitor.

The invention therefore firstly relates to the use of an effective amount of epichatechine, in a physiologically acceptable medium, in a composition or for the preparation of a composition, the epichatechine or the composition being intended to inhibit NO synthase.

By physiologically acceptable medium, an environment compatible with the skin, the mucous membranes, the nails, the hair is understood.

The second subject of the invention is the use of an effective amount of epichatechine, in a physiologically acceptable medium, in a composition or for the preparation of a composition, the epichatechine or the composition being intended for application in all domains in which an inhibition of NO-synthases is necessary, particularly in the cutaneous and / or capillary domain.

Epichatechin or the composition containing it may be used to slow or even inhibit cell differentiation and / or proliferation, and / or vasodilatation, and / or melanogenesis, and / or response to environmental variations (homeostasis).

Thus, the third object of the invention is the use of an effective amount of epichatechine, in a physiologically acceptable medium, in a composition or for the preparation of a composition, the epichatechine or the composition being intended to slow or even inhibit differentiation and / or cell proliferation, particularly to regulate epidermal growth and / or treat hyperproliferative disorders such as psoriasis.

The fourth subject of the invention is the use of an effective amount of epichatechine, in a physiologically acceptable medium, in a composition or for the preparation of a composition, the epichatechine or the composition being intended to inhibit the degradation and / or the destruction of

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 cells and to inhibit apoptotic processes, particularly skin cells, very particularly keratinocytes and / or to treat the intrinsic and / or extrinsic aging of cells, particularly skin cells.

The fifth subject of the invention is the use of an effective amount of epichatechine, in a physiologically acceptable medium, in a composition or for the preparation of a composition, the epichatechine or the composition being intended to inhibit or even eliminate the immunological and / or inflammatory processes related to NO synthesis, such as contact hypersensitivity reactions and / or allergic manifestations and / or immune response, particularly at the level of the skin.

Especially epichatechin or the composition are intended to reduce or inhibit cutaneous inflammation, particularly neurogenic skin inflammatory processes, and therefore to treat so-called sensitive skin.

The sixth subject of the invention is the use of an effective amount of epichatechine, in a physiologically acceptable medium, in a composition or for the preparation of a composition, the epichatechine or the composition being intended for treating rosacea and or erythema of the skin, particularly erythema induced by ultraviolet radiation and / or localized or diffuse erythematous rashes of the skin, such as those caused by drugs, toxins and / or viral or bacterial infections.

The seventh object of the invention is the use of an effective amount of epichatechine, in a physiologically acceptable medium, in a composition or for the preparation of a composition, the epichatechine or the composition being intended to inhibit the induced melanogenesis. by ultraviolet radiation of type A and / or B and / or treating hypermelanosis type disorders.

The eighth object of the invention is the use of an effective amount of epichatechine, in a physiologically acceptable medium, in a composition or for the preparation of a composition, the epichatechine or the composition being intended to control sweating and or to stimulate lipolysis or to inhibit hair loss.

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According to the invention, the composition comprising epichatechine may be a cosmetic or dermatological composition. Preferably according to the invention, the composition is a cosmetic composition.

Preferably, according to the invention, the epichatechin or the composition comprising it is applied to the skin in a topical manner.

According to the invention, the amount of epichatechine used in the composition is of course a function of the desired effect and can therefore vary to a large extent.

To give an order of magnitude, according to the invention epichatechin can be used in a total amount of 10-5% to 10% of the total weight of the composition and preferably in an amount of 10-4% to 5% of the total weight of the composition.

Of course, according to the invention epichatechin may be combined with other inhibitors of NO synthases such as for example lipochroman-6, or plant extracts such as for example the extract of at least one plant of the species Olea europaea, an extract of Ginkgo biloba, an extract of Vitis vinifera or an extract of green tea or cocoa.

The ninth object of the invention is a cosmetic treatment method for treating disorders related to the synthesis of NO, characterized in that it is used by application to the skin, to the hair, and / or to the mucous membranes. , a cosmetic composition comprising at least epichatechine in a physiologically acceptable medium.

The cosmetic treatment method of the invention aims to improve the appearance of the individual affected by the disorders due to NO synthesis.

The cosmetic treatment method of the invention may be implemented in particular by applying the cosmetic compositions as defined above, according to the usual technique of use of these compositions. For example, it is possible to apply creams, gels, serums, lotions, cleansing milks or sunscreen compositions to the skin or to dry hair, applications of a hair lotion. on wet hair, shampoos, or toothpaste applications on the gums.

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Whatever the form of the composition according to the invention in which epichatechin is used, it may be ingested, injected or applied to the skin (on any cutaneous zone of the body), the hair, the nails or the mucous membranes ( oral, jugal, gingival, genital, conjunctival). Depending on the mode of administration, the composition according to the invention may be in any of the galenical forms normally used.

For a topical application to the skin, the composition may have the form in particular of an aqueous or oily solution or of the lotion or serum-type dispersion, of emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a phase in the aqueous phase (O / W) or vice versa (W / O), or suspensions or emulsions of soft consistency of the cream or gel type aqueous or anhydrous, or microcapsules or microparticles, or vesicular dispersions ionic type and or nonionic.

These compositions are prepared according to the usual methods.

They may also be used for hair in the form of aqueous, alcoholic or aqueous-alcoholic solutions, or in the form of creams, gels, emulsions, foams or in the form of aerosol compositions also comprising a propellant under pressure.

For injection, the composition may be in the form of an aqueous lotion, oily or in the form of serum. For the eyes, it can be in the form of drops and for ingestion, it can be in the form of capsules, granules of syrups or tablets.

The amounts of the various constituents of the compositions according to the invention are those conventionally used in the fields under consideration.

These compositions comprise creams for cleaning, protection, treatment or care 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), fluid foundations, make-up removing milks, body care or care milks, sunscreen lotions, lotions, gels or mousse for the care skin cleansing lotions, sunscreen lotions, artificial tanning lotions, bath compositions, deodorant compositions comprising a bactericidal agent, gels or

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 aftershave lotions, depilatory creams, insect bite compositions, pain relief compositions, compositions for treating certain skin conditions such as eczema, rosacea, psoriasis, lichens, severe pruritus .

The compositions according to the invention may also consist of solid preparations constituting soaps or cleaning bars.

The compositions may also be packaged in the form of an aerosol composition also comprising a propellant under pressure.

The composition according to the invention may also be a composition for hair care, and in particular a shampoo, a setting lotion, a treatment lotion, a cream or a styling gel, a dye composition (especially oxidation dyes) in the form of coloring shampoos, restructuring lotions for the hair, a permanent composition (in particular a composition for the first time of a perm), a lotion or an anti-fall gel, a pest control shampoo, etc.

The composition may also be for oral use, for example a toothpaste. In this case, the composition may contain adjuvants and additives customary for oral compositions and in particular surfactants, thickeners, humectants, polishing agents such as silica, various active ingredients such as fluorides, in particular especially sodium fluoride, and optionally sweetening agents such as sodium saccharin.

When the composition 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, the waxes, the emulsifiers and the coemulsifiers used in the composition in emulsion form are chosen from those conventionally used in the cosmetics field.

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. The emulsion may further contain lipid vesicles.

When the composition is a solution or an oily gel, the fatty phase may represent more than 90% of the total weight of the composition.

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In known manner, the cosmetic composition may also contain adjuvants customary in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, perfumes, fillers, filters, odor absorbers and dyestuffs. The amounts of these various adjuvants are those conventionally used in the cosmetics field, and for example from 0.01% to 10% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced into the fatty phase, into the aqueous phase and / or into the lipid spherules.

As oils or waxes that can be used in the invention, mention may be made of mineral oils (vaseline oil), vegetable oils (liquid fraction of shea butter, sunflower oil), animal oils (perhydrosqualene), synthetic oils ( Purcellin oil), silicone oils or waxes (cyclomethicone) and fluorinated oils (perfluoropolyethers), bees, carnauba or paraffin waxes. To these oils can be added fatty alcohols and fatty acids (stearic acid).

As emulsifiers that may be used in the invention, mention may be made, for example, of glycerol stearate, polysorbate 60 and the PEG-6 / PEG-32 / glycol stearate mixture sold under the name Tefose® 63 by the company Gattefosse.

As solvents that can be used in the invention, mention may be made of lower alcohols, in particular ethanol and isopropanol, and propylene glycol.

As hydrophilic gelling agents that may be used in the invention, mention may be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate / alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, natural gums and clays, and, as lipophilic gelling agents, mention may be made of modified clays such as bentones, metal salts of fatty acids such as aluminum stearates and hydrophobic silica, ethylcellulose and polyethylene.

The composition may contain other hydrophilic active agents such as proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, water-soluble vitamins, plant extracts and the like. hydroxy acids.

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As lipophilic active agents, it is possible to use retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides, essential oils, salicylic acid and its derivatives.

According to the invention the composition may combine at least one epichatechine extract with other active agents intended in particular for the prevention and / or treatment of cutaneous affections. Among these active agents, there may be mentioned by way of example: agents that modulate skin differentiation and / or proliferation and / or pigmentation such as retinoic acid and its isomers, retinol and its esters, vitamin D and its derivatives, kojic acid or hydroquinone; antibacterials such as clindamycin phosphate, erythromycin or antibiotics of the tetracycline class; antiparasitics, in particular metronidazole, crotamiton or pyrethrinoids; antifungals, in particular compounds belonging to the class of imidazoles such as econazole, ketoconazole or miconazole or their salts, polyene compounds, such as amphotericin B, compounds of the allylamine family, such as terbinafine, or octopirox; non-steroidal anti-inflammatory agents such as ibuprofen and its salts, diclofenac and its salts, acetylsalicylic acid, acetaminophen or glycyrrhetinic acid; anesthetic agents such as lidocaine hydrochloride and its derivatives; antipruritic agents such as thenaldine, trimeprazine or cyproheptadine; keratolytic agents such as alpha- and beta-hydroxycarboxylic acids or beta-ketocarboxylic acids, their salts, amides or esters and more particularly hydroxy acids such as glycolic acid, lactic acid, salicylic acid, citric acid and generally fruit acids, and n-octanoyl-5-salicylic acid; anti-free radical agents, such as alpha-tocopherol or its esters, superoxide dismutases, certain metal chelators or ascorbic acid and its esters; anti-seborrhoeic agents such as progesterone; anti-dandruff such as octopirox or zinc pyrithione; anti-acne drugs such as retinoic acid or benzoyl peroxide; plant or microbial extracts, peptides and their derivatives, for example the tripeptide Lys-Pro-Val.

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The following examples and compositions illustrate the invention without limiting it in any way. In the compositions, the proportions indicated are percentages by weight.

Example 1: Biological Activity of Epichatechin: The activity of (+) - epichatechin and (-) epichatechin on the inducible NO-synthase was evaluated in the test described by Heck et al. (BC, Vol 267, No. 30, 21277-21280, October 25, 1992).

This test aims to show the decrease in the concentration of nitrate and nitrite, in fine, after stimulation of NO-synthase 2.

The following controls were introduced into the tests: A: positive control (induction of the enzyme): mixtures of interferon-γ (1000 U / ml) and Interleukin 1-ss (100 U / ml); B: negative control (maximal inhibition): NG-monomethyl-L-arginine (L-form) at 200 M; C: specificity control of the inhibition: NG-monomethyl-L-arginine (form
D) at 200 M.

To determine the activity of the product to be tested, the amount of stable reaction products of NO (nitrites and nitrates) is measured using the "nitric colorimetric assay" kit sold by Boehringer under the reference 1756.28.

(+) - epichatechin and (-) - epichatechin were tested at concentrations of 100M and 500M in dimethyl sulfoxide (DMSO).

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Product <SEP> tested <SEP>% <SEP> inhibition
<tb> A <SEP> 0
<tb> B <SEP> 100
<tb> C <SEP> 0
<tb> (+) <SEP> 100 <SEP> M <SEP> 56
<tb> Epichatechin <SEP> 500 <SEP> M <SEP> 81
<tb> (-) <SEP> 100 M <SEP> 40
<tb> Epichatechin <SEP> 500 <SEP> M <SEP> 60
<Tb>
Epichatechin in any form has an inhibitory effect on inducible NO synthase.

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Example 2: Example of formulation illustrating the invention. This composition was obtained by simple mixing of the various components.

Composition 1: (-) - Epichatechin 1.00% Antioxidant 0.05% Isopropanol 40.00% Preservative 0.30% Water qs 100% Composition 2: Gel for the care (+) -Epichatechin 3.00% Hydroxypropylcellulose * 1 , 00% Antioxidant 0.05% Isopropanol 40.00% Preservative 0.30% Water qs 100% Composition 3: Care cream (oil-in-water emulsion) (+) -Epichatechin 5.00% Glycerol stearate 2.00% Polysorbate 60 ** 1.00% Stearic acid 1.40% Triethanolamine 0.70% Carbomer 0.40% Liquid fraction of shea butter 12.00% Perhydrosqualene 12.00% Antioxidant 0.05% Fragrance 0.50% Preservative 0.30% Water qs 100% Composition 4: Shampoo (-) - Epichatechin 0.10% Hydroxypropylcellulose *. 1.00% Perfume 0.50% Preservative 0.30%

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 Water qs 100% Composition 5: Care cream (oil / water emulsion) (+) -Epichatechin 5.00% Glycerol stearate 2.00% Polysorbate 60 ** 1.00% Stearic acid 1.40% N-octanoyl acid -5-salicylic 0.50% Triethanolamine 0.70% Carbomer 0.40% Liquid fraction of shea butter 12.00% Perhydrosqualene 12.00% Antioxidant 0.05% Fragrance 0.50% Preservative 0.30% Water qs 100% Composition 6: Anti-pain gel (+) -Epichatechin 4.00% Hydroxypropylcellulose * 1.00% Antioxidant 0.05% Hydrochloride lidocaine 2.00% Isopropanol 40.00% Preservative 0.30% Water qs 100% Composition 7: Sunscreen cream (oil-in-water emulsion) (+) -Epichatechin 5.00% Glycerol stearate 2.00% Polysorbate 60 ** 1.00% Stearic acid 1.40% Acid glycyrrhetinic 2.00% Triethanolamine 0.70% Carbomer 0.40% Liquid fraction of shea butter 12.00% Sunflower oil 10.00% Antioxidant 0.05% Perfume 0.50%

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 Preservative 0.30% Water qs 100% Composition 8: Gel for the treatment of acne (-) - Epichatechin 3.00% All trans retinoic acid 0.05% Hydroxypropylcellulose * 1.00% Antioxidant 0.05% Isopropanol 40 , 00% Preservative 0.30% Water qs 100% Composition 9: to eliminate scars due to acne (+) -Epichatechin 3.00% Glycolic acid 50.00% Hydroxypropylcellulose * 0.05% Preservative 0.30% NaOH qsp pH = 2.8 Ethanol qsp 100% *: Klucel H # sold by the company Hercules **: Tween 60 sold by the company ICI

Claims (21)

 1. Use of an effective amount of epichatechine, in a physiologically acceptable medium, in a composition or for the preparation of a composition, the epicacycin or the composition being intended to inhibit NO-synthase. 2. Use according to the preceding claim, characterized in that the epichatechin or the composition are intended to slow down or even inhibit cell differentiation and / or proliferation. 3. Use according to the preceding claim, characterized in that the epichatechine or the composition are intended to slow or inhibit the growth of the epidermis and / or to treat hyperproliferative disorders. 4. Use according to claim 1, characterized in that the epichatechin or the composition are intended to inhibit the degradation and / or destruction of the cells. 5. Use according to claim 1, characterized in that the epichatechin or the composition are intended to inhibit cellular apoptotic processes. 6. Use according to claim 1, characterized in that the epichatechin or the composition are intended to treat intrinsic aging and / or extrinsic. 7. Use according to claim 1, characterized in that the epichatechin or the composition are intended to inhibit or suppress the immunological and / or inflammatory processes. 8. Use according to claim 7, characterized in that the epichatechin or the composition are intended to treat contact hypersensitivity reactions and / or allergic manifestations and / or the immune response. 9. Use according to claim 7, characterized in that the epicacycin or the composition are intended to reduce or inhibit skin inflammation. 10. Use according to claim 9, characterized in that epichatechin <Desc / Clms Page number 16>  or the composition are intended to treat neurogenic skin inflammatory processes. 11. Use according to claim 1, characterized in that the epichatechin or the composition are intended to treat so-called sensitive skin 12. Use according to claim 1, characterized in that the epichatechin or composition are intended to treat erythema, particularly erythema induced by ultraviolet radiation. 13. Use according to claim 1, characterized in that the epichatechin or the composition is intended to treat localized or diffuse erythematous rashes of the skin. 14. Use according to claim 1, characterized in that the epichatechine or the composition are intended to treat rosacea. 15. Use according to claim 1, characterized in that the epichatechin or the composition is intended to inhibit the melanogenesis induced by ultraviolet radiation type A and / or B and / or to treat hypermelanosis type disorders. 16. Use according to claim 1, characterized in that the epichatechin or the composition are intended to control sweating. 17. Use according to claim 1, characterized in that the epichatechine or the composition are intended to stimulate lipolysis. 18. Use according to claim 1, characterized in that the epichatechin or the composition are intended to inhibit hair loss. 19. Use according to any one of the preceding claims, characterized in that the epichatechine is in an amount representing 10-5% to 10% of the total weight of the composition. 20. Use according to the preceding claim, characterized in that the epichatechine is in an amount representing 10-4% to 5% of the total weight of the composition. <Desc / Clms Page number 17>  21. Cosmetic treatment process for treating disorders related to the synthesis of NO, characterized in that a cosmetic composition comprising at least one embodiment is applied to the skin, to the hair, and / or to the mucous membranes. less than epichatechin in a physiologically acceptable medium.