WO2013093880A1

WO2013093880A1 - Use of steviol, of a steviol glycoside derivative or of one of their isomers to prevent, reduce and/or treat a detrimental change in the complexion of the skin

Info

Publication number: WO2013093880A1
Application number: PCT/IB2012/057613
Authority: WO
Inventors: Julien Laboureau; Myrian Kauffmann; Francine Baldo; Yann Mahe
Original assignee: LOreal SA
Current assignee: LOreal SA
Priority date: 2011-12-23
Filing date: 2012-12-21
Publication date: 2013-06-27
Anticipated expiration: 2014-06-23
Also published as: FR2984742A1

Abstract

The present invention relates to the use by the topical route of steviol, of a steviol glycoside derivative or of one of their isomers to prevent, reduce and/or treat a detrimental change in the complexion of the skin.

Description

USE OF STEVIOL, OF A STEVIOL GLYCOSIDE DERIVATIVE OR OF ONE OF THEIR ISOMERS TO PREVENT, REDUCE AND/OR TREAT A DETRIMENTAL

CHANGE IN THE COMPLEXION OF THE SKIN

The invention relates to the field of cosmetic active agents and more particularly active agents devoted to acting with regard to the melanocytes and the complexion of the skin and/or semi-mucous membranes.

Human skin consists of several compartments, three of which cover the whole of the body, namely a superficial compartment, which is the epidermis, the dermis and a deep compartment, which is the hypodermis.

The epidermis is a keratinized stratified pavement epithelium. In some regions, such as the lips, it is less keratinized and brings about the transition with the buccal mucous membrane (the term "semimucous membrane" is used). It is composed mainly of keratinocytes but also of other cells, in particular melanocytes. These cells are located in a basal membrane which separates them from the dermis. The dermis is a connective tissue. The keratinocytes differentiate on migrating from the basal membrane toward the surface of the epidermis, where they desquamate. The melanocytes are specialized dendritic cells, the function of which is to synthezise melanin. The latter is composed of two pigments, pheomelanins and eumelanins, the pheomelanins being red-yellow pigments and the eumelanins being brown-black pigments.

The dermis is a connective tissue composed of collagen fibers and elastin fibers, and also of glycosaminoglycans, proteoglycans and fibroblasts. Its architecture results from the arrangement and the interactions between the constituents of the extracellular matrix and the fibroblasts, which carry out the synthesis thereof and the degradation thereof. The other cellular constituents are involved in the immune system (macrophages and mastocytes, Langerhans' cells), vascular system (endothelial cells), nervous system or neurosensory system. The dermis is subdivided into two layers, the papillary layer and the reticular layer. The dermis makes up the main bulk of the skin.

Finally, the hypodermis, the deepest compartment and which can be the thickest compartment of the skin, invaginates into the dermis and is attached to the overlying dermis via collagen and elastin fibers. It is essentially composed of a type of cell which is specialized in the accumulation and storage of fats, the adipocytes. The skin tissue also comprises sweat glands, pilosebaceous follicles, body hair, head hair or nails.

Over time, in particular during chronological and/or photoinduced aging, the skin is subjected to numerous modifications and types of damage which are reflected, at the tissue level, by disruption of the architecture of the epidermis, of the dermal-epidermal junction of the dermis and also of the blood irrigation and innervation systems, and a slowing down of or imbalance in various types of cell metabolism, such as those involved in the equilibrium of the barrier function or involved in melanogenesis. At the cell level, aging is reflected by a detrimental change in the physiology or metabolism of the main cell types, such as the fibroblasts of the dermis, keratinocytes of the epidermis, and also melanocytes. Thus, there is observed, in the melanocytes, an imbalance in the processes involved in the production of melanin. Furthermore, the distribution of this melanin at the surface of the skin appears to be detrimentally affected, thus resulting in a deterioration in the uniformity of the complexion, in the darkening thereof or in the appearance of pigment blemishes, or naevi, or depigmented regions, in particular in the regions exposed to the light, in particular on the face, neckline, arms, hands and shoulders.

There thus exists a need to be able to have available cosmetic active agents for improving the complexion of the skin, in particular its uniformity, promoting the whitening and/or lightening of the skin and preventing, reducing or treating defects of pigmentation of the skin and/or semimucous membranes, such as the lips, in particular the number, the size, the intensity and the extent of pigment blemishes.

There also exists a need to have available cosmetic active agents which exhibit an improved effectiveness with regard to the skin, in particular elderly skin and/or skin which has been subjected to repeated exposure to the sun.

It is an object of the present invention to satisfy these needs.

Thus, according to a first of its aspects, a subject matter of the invention is the cosmetic use of steviol, of a steviol glycoside derivative or of one of their isomers to stimulate, restore or regulate the metabolism of melanocytes of the skin and/or semimucous membranes.

The term "metabolism" is intended to denote, within the meaning of the present invention, the group of molecular and energy transformations which take place in a living cell and which contribute to its homeostasis, that is to say its maintenance of biological activity and of physiological balance.

More particularly, the present invention relates to the cosmetic use of steviol, of a steviol glycoside derivative or of one of their isomers to reduce the melanin synthesis.

The present invention also relates to the cosmetic use of steviol, of a steviol glycoside derivative or of one of their isomers to prevent, reduce and/or treat a detrimental change in the complexion of the skin or in the complexion of the semimucous membranes.

More particularly, the present invention relates to the cosmetic use of steviol, of a steviol glycoside derivative or of one of their isomers to for decreasing pigmentation of the skin and/or promoting depigmentation of the skin.

According to another of its aspects, the present invention relates to the cosmetic use of steviol, of a steviol glycoside derivative or of one of their isomers to prevent, reduce and/or treat a defect of pigmentation of the skin.

According to yet another of its aspects, the present invention relates to the cosmetic use of steviol, of a steviol glycoside derivative or of one of their isomers to lighten the skin.

Within the meaning of the present invention, the term "to prevent" is understood to mean the fact of reducing, at least in part, the risk of the appearance of a given phenomenon, i.e., in the present invention, a detrimental change in the metabolism of the melanocytes, in particular of elderly melanocytes, or a detrimental change in the complexion of the skin or in the complexion of the semimucous membranes.

Unexpectedly, and as shown in the examples indicated below, the inventors have observed that steviol and in particular a steviol glycoside derivative proves to be particularly advantageous in regulating the metabolism of melanocytes and in particular melanogenesis. In particular, the inventors have observed that rebaudioside A proves to be particularly effective in promoting the depigmentation of melanocytes.

Admittedly, some of these compounds have already been proposed as sweetener (EP 1 856 967) or as promoter of the dissolution of compounds which are insoluble or only sparingly soluble in an aqueous medium (WO 2009/126950). The scientific literature furthermore suggests that rebaudioside A might be a molecule of interest in regulating glycemia or the metabolism of the cells of the pancreas and treating diabetes (Abudula et al, Metabolism, 2004, 53, 1378 ; WO 02/060419), in improving cognitive functions (WO 2009/071277) or in treating cardiovascular diseases (WO 2008/134828).

Some authors furthermore describe their use in particular for treating greasy skin or acne by regulating the metabolism of the sebocytes (US 5 110 801) or alternatively for combating inflammatory phenomena (allergy, dermatitis) (JP-08325156-A). Finally, WO 07/094312 proposes the use of steviosides to promote the penetration of vitamin C into cells.

However, to date, no direct effect on cells of the skin, such as melanocytes, nor an effect on the semimucous membranes accessible by the topical route, other than the production of sweet sensations, had been demonstrated. What is more, to the knowledge of the inventors, the activity of steviol, of these glycoside derivatives and of these isomers with regard to the metabolism of the melanocytes has, to date, never been described.

Consequently, according to yet another of its aspects, the present invention is targeted at steviol, a steviol glycoside derivative or one of their isomers as agent for stimulating, restoring or regulating the metabolism of the melanocytes of the skin and/or semimucous membranes.

It is also targeted at steviol, a steviol glycoside derivative or one of their isomers as agent for preventing, reducing and/or treating a detrimental change in the complexion of the skin or in the complexion of the semimucous membranes.

According to another of its aspects, the present invention relates to a cosmetic or dermatological composition comprising an effective amount of steviol, of a steviol glycoside derivative or of one of their isomers, in particular as defined below, in combination with at least one additional active agent chosen from polyols, vitamins, keratolytic and/or desquamating agents, soothing agents and their mixtures.

According to yet another aspect, the present invention relates to a kit comprising at least one container containing a composition comprising steviol, a steviol glycoside derivative or one of their isomers and at least one device arranged in order to make possible the administration of said composition to an individual, and/or to increase the effectiveness of said composition for an individual, and/or to promote the topical penetration for an individual of said composition.

According to yet another aspect, the present invention relates to a cosmetic method for stimulating, restoring or regulating the metabolism of the melanocytes, in particular elderly melanocytes, of the skin or semimucous membranes, comprising at least one stage of administration, to an individual having need thereof, of steviol, of steviol glycoside derivative or of one of their isomers.

According to yet another of its aspects, it is targeted at a cosmetic method for lightening the skin, comprising at least one stage of administration, to an individual having need thereof, of steviol, of steviol glycoside derivative or of one of their isomers.

According to yet another of its aspects, the present invention relates to a cosmetic method for preventing, reducing and/or treating a detrimental change in the complexion of the skin, comprising at least one stage of administration, to an individual having need thereof, of steviol, of steviol glycoside derivative or of one of their isomers.

In the context of the present invention, the favoured administration route is the topical route, that is to say the application of the active agent considered according to the present invention directly in contact with the target surface of the skin or of a semimucous membrane.

According to one of its advantages, the present invention provides a novel cosmetic active agent which is particularly effective in regulating melanogenesis, in particular on the skin and semimucous membranes.

According to another of its advantages, the present invention provides a novel cosmetic active agent of natural origin and thus makes it possible to respond to an increasing demand from consumers in this direction.

Steviol and derivatives

The present invention relates to the use of an active agent chosen from a steviol, a steviol glycoside derivative or one of their isomers.

Steviol is represented by the formula (I):

Steviol is the common precursor of the steviol glycosides.

The term "precursor" is understood to mean, within the meaning of the present invention, any compound participating in a reaction which produces one or more other compounds.

The term " steviol glycoside derivative" is understood to mean any compound represented by the formula (II):

(II)

in which Rl and R2, respectively positioned on carbons C19 and C₁₃ of the formula (II), represent, independently of one another, a hydrogen atom or a cyclized or noncyclized, linear or branched, sugar residue.

Preferably, Rl and R2 are other than hydrogen.

In particular, Rl and R2, which are identical or different and preferably different, represent a sugar residue composed of one or more glucose and/or rhamnose entities.

Mention may in particular be made, by way of illustration and without implied limitation of these sugar residues, of the groups consisting of:

- just one sugar entity, in particular glucose, referred to as Glu,

- a sequence of two sugars, such as a diholoside, for example a sequence of two glucose entities, or

- a sequence of three sugar units, such as a linear or branched and preferably branched triholoside, for example a branched radical formed of three glucose units and a branched radical formed of a glucose entity substituted by a glucose entity and a rhamnose entity.

According to a specific alternative form, Rl represents a glucose entity.

According to a more preferred alternative form, Rl represents a glucose unit and R2 represents a branched triholoside. The detailed structures of some steviol glycoside derivatives of formula (II) suitable for the invention are reported in table I below.

Table I

Thus, a steviol glycoside derivative according to the invention can be chosen from stevioside, rebaudioside A, rebaudioside C (or dulcoside B), dulcoside A, rebaudioside B, rebaudioside D, rebaudioside E, rebaudioside F, steviolbioside, rubusoside, and their mixtures.

More preferably, a steviol glycoside derivative according to the invention is chosen from stevioside, rebaudioside A, rebaudioside C (or dulcoside B), dulcoside A, and their mixtures.

More preferably still, a steviol glycoside derivative according to the invention is rebaudioside A.

The term "isomer" is intended to denote, within the meaning of the present invention, at least two molecules having the same empirical formula but having different semi-expanded formulae or expanded formulae.

Preferably, isomers according to the invention are stereoisomers, in particular enantiomers, diastereomers, and mixtures thereof, including racemic mixtures. Mention may in particular be made, as isomer according to the invention, of isosteviol, represented by the formula (III) below:

(III)

The present invention naturally employs an effective amount of steviol, steviol glycoside derivative or isomers of these, so as to obtain the desired effect. This effective amount can vary with regard to various parameters which are in particular the indication targeted, the characteristics of the individual treated, the pharmaceutical dosage formulation adopted, the nature of the formulation excipients or the presence of additional active agent(s).

Within the meaning of the present invention, the term "effective amount" is understood to mean a sufficient and necessary amount of a given active agent to exert the desired effect and in particular to regulate melanogenesis.

Such an amount can be determined by any method known to a person skilled in the art, for example by means of in vitro, ex vivo or in vivo trials, such as clinical trials.

In order to give an order of magnitude, steviol, a steviol glycoside derivative or an isomer of these can be used in a composition in a proportion of 0.01 to 50% by weight, preferably from 0.05 to 30% by weight, in particular from 0.1 to 10% by weight and more preferably from 0.5 to 5% by weight, with respect to the total weight of the composition in which it is present.

According to a preferred embodiment, a main active agent according to the invention, that is to say steviol, a steviol glycoside derivative or one of their isomers, is employed in the form of an extract of at least one plant of the Stevia genus.

The use of the main active agent according to the invention in the form of an extract of at least one plant of the Stevia genus is particularly advantageous in that it makes it possible to provide a novel cosmetic active agent of natural origin and thus to meet an increasing demand from consumers in this direction. The Stevia genus belongs to the family of the Asteraceae, which brings together from 150 to 200 species of shrubs or aromatic herbs, some of which comprise natural sweeteners. The Stevia plants are plants originating from the tropical regions of Latin America.

According to the invention, the extract of a plant from the Stevia genus can be chemically modified (it is then semisynthetic), but it is preferably a native extract.

An extract of a plant of the Stevia genus, within the meaning of the present invention, can be prepared from any plant material resulting from said plant or from its cells cultivated according to conventional methods or by biotechnology in vivo or resulting from culturing in vitro.

The term "cultivating in vivo" is understood to mean any cultivation of conventional type, that is to say in soil in the open air or in a greenhouse, or alternatively without soil.

The term "culturing in vitro" is understood to mean all the techniques known to those skilled in the art which make it possible to artificially obtain a plant or a plant part. The selection pressure imposed by the physicochemical conditions during the growth of plant cells in vitro makes it possible to obtain a standardized plant material which is available throughout the year, in contrast to plants cultivated in vivo.

An extract of a plant of the Stevia genus employed in the present invention can be obtained from any plant material resulting from this whole plant or from any part of this plant, such as, for example, the leaves, stems, flowers and flowering tops, seeds, buds and roots, undifferentiated cells or plant stem cells.

Preferably, an extract of a plant of the Stevia genus in accordance with the invention is obtained from the leaves.

More preferably still, an extract of a plant of the Stevia genus in accordance with the invention originates from a plant of the species Stevia rebaudiana (Bertoni), also known as Eupatorium rebaudianum or "sweet leaf .

Such a species is today cultivated in many countries and on other continents than Latin America, in particular in Singapore, Taiwan, Malaysia, South Korea, China, Israel or even Australia.

Preferably, an extract of a plant of the Stevia genus according to the present invention is a native extract. Within the invention, the term "native" intends to mean an extract that is not modified after the extraction process, especially by fermentation or by chemical synthesis.

Preferably, an extract of a plant of the Stevia genus according to the present invention is not a fermented extract.

Preferably, an extract of a plant of the Stevia genus according to the present invention is employed in a composition in a proportion of from 0.00001% to 50% by weight, preferably from 0.0001% to 10% by weight and better still from 0.01% to 4% by weight, with respect to the total weight of said composition.

Steviols have already been provided commercially.

Mention may in particular be made, as rebaudioside A which can be used in the present invention, of the Stevia extract comprising 99% of rebaudioside A sold by Blue California under the name Good'n sweet™ as well as the Stevia extract comprising 97% of rebaudioside A sold by Chengdu Wagott Pharmaceutical under the name ViaSweet™.

Also concerned may be the Stevia extract fermented by a yeast described in the document WO2003/035090.

The intrinsic properties of a main active agent according to the invention, that is to say a steviol, a steviol glycoside derivative or one of their isomers, are such that they allow the use, within a composition according to the invention, of compounds or active agents which normally cannot be used on account of being difficult to formulate, dissolve, deliver in a controlled fashion or vectorize.

Thus, as indicated above, an extract according to the invention can advantageously be combined with at least one additional active agent chosen from polyols, in particular glycerol and propylene glycol, vitamins, keratolytic and/or desquamating agents, soothing agents and their mixtures.

The term "desquamating agent" is understood in particular to mean the compounds capable of influencing the desquamation by promoting exfoliation, such as β- hydroxy acids, in particular salicylic acid and its derivatives (including 5-(n- octanoyl)salicylic acid); a-hydroxy acids, such as glycolic, citric, lactic, tartaric, malic or mandelic acid; urea; gentisic acid; ohgofucoses; cinnamic acid; Saphora japonica extract and resveratrol. The choice and the content of these additional active agents depend in particular on the administration route under consideration, which falls within the competence of a person skilled in the art.

These additional active agents can be present in a composition according to the invention in a content ranging from 0.001% to 50% by weight, preferably from 0.01% to 10% by weight and more preferably from 0.01% to 5% by weight, with respect to the total weight of the composition in which they are present.

Uses

Imbalances in the metabolism of the melanocytes, in particular related to age, can be the cause of various esthetic disorders of the skin. These disorders can affect the complexion and/or the pigmentation of the skin and furthermore occur in an exacerbated fashion in aged skin.

Defects in pigmentation of the skin are frequent and can occur in a variety of different forms. However, the defects in skin pigmentation with which the invention is concerned can be defined as involving the appearance of at least one skin region having a darker or lighter color than the average color of the skin surface of the individual examined. This region can be macroscopic or microscopic in size.

Within the meaning of the invention, the term "defects in pigmentation of the skin" is understood to mean any event of appearance of a change in the color or in the complexion of all or part of the surface of the skin, which encompasses an overall or local change in the complexion of the skin, and also hyperpigmentation, hypopigmentation or dyspigmentation defects.

Within the meaning of the invention, the term "hyperpigmentation defect of the skin" is understood to mean any event of appearance of a skin region affected by an excess of pigmentation, in comparison with the average level of pigmentation of the skin surface of an individual.

It can relate, for example on dark skin types, to skin regions close to the joints, such as the interphalangeal regions, elbows, knees, nape of the neck or also the back of the hand, heels at the rear of the talus. The level of pigmentation of a skin surface can be measured using any appropriate type of color-analysing device, for example with an appropriate spectrocolorimetry device, or else a reflectometer device, which are well known in the art.

Preferably, the level of pigmentation of a skin surface is measured using an appropriate standard color chart. For the measurement of the level of pigmentation, the standard color chart is applied to the skin so that at least one edge of said chart is placed beside the skin region to be measured. The value of degree of color on the chart which is the closest to the color of the skin region which is analysed is recorded by visual comparison.

The defects of pigmentation of the skin can be marked by the presence of more or less extensive surface skin blemishes, having a darker or lighter color than the normal color of the skin of the individual which surrounds said skin blemishes.

The defects of pigmentation of the skin encompass in particular melasma and lentigines, including liver spots and actinic lentigo.

Melasma (also known as chloasma) is most frequently encountered in pregnant women and in women taking anti-ovulatory medicaments. Melasma is also known as "mask of pregnancy". Melasma appears as a broad dark reticular macula with uneven edges which is found mainly on the cheeks, upper lip and forehead. Melasma is also encountered in men or women not suffering from detectable endocrinal imbalance, but exposure to the sun is necessary for its development.

In particular, the melasma or chloasma considered by the invention can be triggered by exposure to UV rays, or can occur on photosensitive skin, photoallergic skin or skin subject to a phototoxicity reaction.

Lentigines arise in the form of hyperpigmented skin blemishes which can appear at any age and are usually darker and more extensive than freckles. A lentigo is characterized in particular by an increase in the number of melanocytes in the basal layer. Lentigines encompass in particular (i) solar lentigines, which appear in light-skinned individuals on skin regions exposed for a long time to the sun, (ii) lentiginous pigmentation resulting from skin therapies involving UV-A radiation (320-400 nanometers - also known as PUVA therapy), (iii) multiple lentigines, especially on the palms, soles of the feet, mucous membranes or unexposed skin, or also (iv) lentigines affecting the lips, vulva or penis. Defects of pigmentation of the skin also encompass hyperpigmentation situations resulting from inflammation or scarring. Postinflammatory hyperpigmentation is quite independent of the degree of inflammation and depends more on the nature of the trauma which brought about the inflammation. Postinflammatory hyperpigmentation can be severe after certain lesions, such as thermal burns or of acne type, or resulting from insect stings, cuts and other mechanical traumas of the skin, in particular during shaving, and pseudo folliculitis due to body hairs becoming ingrown as a result of shaving or depilation. Postinflammatory hyperpigmentation can persist for months, indeed even for years.

The defects of pigmentation of the skin targeted by the invention also concern the dyspigmentations resulting from a dys functioning of the metabolism of the melanocytes of the skin. Mention may be made, as examples of dyspigmentations targeted by the invention, of vitiligo, pityriasis versicolor or depigmentations due to burns or to surgery, the aftereffects of spots due to acne, and postshaving cuts.

A defect of pigmentation of the skin more particularly considered by the invention can be chosen from melasma, chloasma, lentigines, liver spots, vitiligo, postinflammatory hyperpigmentations due to an abrasion and/or a burn and/or a scar, genetically-determined hyperpigmentations, hyperpigmentations of metabolic or drug origin, or any other pigmentation lesions.

The present invention can also be employed to prevent, reduce and/or treat the mask of pregnancy.

An active agent of the invention can more particularly be employed to lighten or whiten the skin.

The present invention also relates to esthetic disorders of the skin affecting the complexion of the skin.

Thus, the invention may suitably be employed to prevent, reduce and/or treat a lack of uniformity in the complexion of the skin, indeed even to improve the complexion of the skin, in particular of aged skin.

The invention advantageously makes it possible to promote and maintain the radiance of the complexion of the skin and in particular a uniform complexion.

According to one embodiment, a use according to the invention can make it possible to treat and/or prevent a detrimental change in the radiance of the complexion or a loss in the radiance of the complexion of the skin. A use according to the invention can make it possible to confer, on the skin, a uniform, luminous, more radiant, indeed even more glowing, complexion indicative of skin in good health.

The invention advantageously makes it possible to prevent, reduce and/or treat a muddy skin complexion, a lifeless skin complexion, a nonuniform skin complexion or imperfections of the skin chosen in particular from spots, dry patches, dyschromias or blackheads or also to prevent, reduce and/or treat a waxen, sallow, grayish or ashen, indeed even sickly, complexion.

Steviol, a steviol glycoside derivative or an isomer of these can more preferably be employed to prevent, reduce and/or treat a detrimental change in the complexion of the skin chosen from a detrimental change in the radiance of the complexion of the skin, a muddy skin complexion, a lifeless skin complexion, a nonuniform skin complexion, spots, dry patches, dyschromias and/or blackheads.

According to one embodiment, the present invention can relate more particularly to aged skin.

Preferably, indications subject-matter of the uses according to the invention are indications not involving the production and/or release of stem cell factor (SCF).

The present invention relates to the entire surface of the skin of an individual. Preferably, the present invention can be employed with regard to the skin regions more regularly exposed to the sun, to UV radiation or to external stress factors, such as pollution, irritation due to rubbing, or cigarette smoke. In particular, the present invention can advantageously be employed with regard to the skin of the hands, face or neckline.

Composition

Advantageously, the active agent according to the invention, namely steviol, steviol glycoside derivative or one of their isomers, as or not as a mixture with other additional active agent(s), can be formulated in a cosmetic or dermatological composition.

Preferably, a composition of the invention is a cosmetic composition.

According to a first alternative embodiment, the main active agent according to the invention is intended for topical administration.

Thus, the compositions comprising the main active agent according to the invention can be in the form of products for caring for the skin or semimucous membranes, such as a protective, treatment or care composition for the face, for the lips, for the hands, for the feet, for the anatomical folds or for the body (for example, day cream, night cream, make-up-removing cream, make-up base, antisun composition, protective or care body milk, aftersun milk, lotion, gel or foam for the care of the skin or scalp, serum, powder, mask, artificial tanning composition, aftershave composition, hair composition, product for the region of the armpits, or hygiene and cleaning product.

According to a second alternative embodiment, the main active agent according to the invention is intended for oral administration.

Thus, the composition of the invention can be provided in any suitable form, particularly in the form of a solution to be taken orally, a drink, a tablet, a capsule, including a hard gelatin capsule, a nutritional food or a nutritional supplement.

According to a third alternative embodiment, the main active agent according to the invention is intended for intracutaneous administration, such as intradermal or subcutaneous administration. This administration can, for example, be carried out by means of a device which makes possible intracutaneous injection (syringe, implant or reservoir and microneedles) or alternatively by means of an ultrasound or iontophoresis device, indeed even a light or thermal device. Such an administration can also be carried out by mesotherapy.

The intracutaneous use of a composition of the invention is to be distinguished from a surgical operation and is targeted only at exerting a surface treatment of the skin for esthetic, protective, repair or comfort purposes. In other words, the intracutaneous administration route in the present invention is expressed only by superficial penetration of the skin and thus does not come within any medical, surgical or therapeutic context.

It is alternatively possible, intracutaneously, to favor administration using a topical patch.

Preferably, a main active agent according to the invention is intended for topical administration, that is to say, for administration by application at the surface of the keratinous substance under consideration.

Preferably, a main active agent in accordance with the invention, when it is present in a composition, can be formulated in a physiologically acceptable medium. Within the meaning of the present invention, the term "physiologically acceptable medium" is intended to denote a medium suitable for the topical, oral or intracutaneous, such as intraepidermal, intradermal or subcutaneous, administration of a composition.

A physiologically acceptable medium is preferably a cosmetically or dermato logically acceptable medium, that is to say a medium which is devoid of unpleasant odor or appearance and which is entirely compatible with the administration route under consideration.

When the composition is intended for topical administration, that is to say for administration by application at the surface of the keratinous substance under consideration, such a medium is considered to be physiologically acceptable when it does not cause stinging, tightness or redness unacceptable to the user.

When the composition is intended for oral administration, such a medium is considered to be physiologically acceptable when it does not cause digestive intolerance.

Furthermore, when the composition is intended for intracutaneous administration, such a medium is considered to be physiologically acceptable when it does not cause a reaction experienced as unpleasant by the user, for example stinging, tightness or redness, indeed even does not cause inflammatory, allergic, edematous or pruritic reactions.

The composition according to the invention can be provided in any formulation form normally used in cosmetics and dermatology.

It can in particular be in the form of an aqueous solution, aqueous/alcoholic solution or oily solution, which is optionally gelled, of a dispersion of the lotion type, which is optionally a two-phase or three-phase lotion, of an oil-in-water or water-in-oil or multiple emulsion, of an aqueous gel, of a dispersion of oils in an aqueous phase, in particular using spherules, it being possible for these spherules to be polymer particles or, better still, lipid vesicles of ionic and/or nonionic type, or alternatively in the form of a powder, of a serum, of a paste, of a solid cake which can disintegrate by rubbing an applicator or of a soft or rigid stick which can melt on the skin or semimucous membranes. It can have a solid, pasty or more or less fluid liquid consistency.

With regard to the pharmaceutical dosage formulation under consideration, the active agent according to the invention can be formulated with the usual constituents. Mention may in particular be made, by way of illustration and without implied limitation of these normal components, of water, volatile or nonvolatile oils, in particular as described in detail below, waxes, pigments, fillers, surfactants, gelling agents, preservatives, coloring materials, antioxidants, UV screening agents and their mixtures.

Of course, a person skilled in the art will take care to choose the optional additional compound(s) and/or their amount so that the advantageous properties of the main active agent according to the invention are not, or not substantially, detrimentally affected by the envisaged addition and so that the properties of the compositions resulting therefrom are compatible with the administration route favored.

A composition according to the invention can advantageously be provided in the form of an emulsion, obtained in particular by dispersion of an aqueous phase in a fatty phase (W/O) or of a fatty phase in an aqueous phase (O/W), of liquid or semi-liquid consistency of the milk type, or of soft, semi-solid or solid consistency of the cream or gel type, or alternatively of a multiple emulsion (W/O/W or 0/W/O). These compositions are prepared according to the usual methods.

Thus, a composition according to the invention can advantageously comprise from 0.1% to 99.9% by weight and preferably from 30% to 95% by weight of water, with respect to the total weight of said composition.

A composition according to the invention can also advantageously comprise at least one fatty phase which is liquid at ambient temperature and atmospheric pressure.

The amount of oily phase present in the compositions according to the invention can range, for example, from 0.01% to 50% by weight and preferably from 0.1% to 30%) by weight, with respect to the total weight of the composition.

Mention may be made, as examples of oils which can be used in the composition according to the invention, of hydrocarbon oils of animal origin, hydrocarbon oils of vegetable origin, synthetic esters and ethers, in particular of fatty acids, linear or branched hydrocarbons of mineral or synthetic origin, fatty alcohols and silicone oils and their mixtures.

Other fatty substances which can be present in the oily phase are, for example, waxes and fatty acids comprising from 8 to 30 carbon atoms, such as stearic acid, lauric acid, palmitic acid and oleic acid. These fatty substances can be chosen in a manner varied by a person skilled in the art in order to prepare a composition having the desired properties, for example of consistency or texture.

Likewise, a composition according to the invention can additionally comprise at least one coloring material chosen, for example, from pigments, pearlescent agents, dyes, effect materials and their mixtures.

These coloring materials can be present in a content ranging from 0.01% to 50%) by weight and preferably from 0.01% to 30%> by weight, with respect to the total weight of the composition.

A composition according to the invention can additionally comprise at least one filler, in particular in a content ranging from 0.01% to 50% by weight and preferably ranging from 0.01% to 30% by weight, with respect to the total weight of the composition. These fillers can be inorganic or organic and their choice comes within the competence of a person skilled in the art.

As indicated above, the administration of the active agent under consideration according to the invention can be carried out via the use of a device adjusted to the method of administration under consideration, that is to say topical, oral or intracutaneous. The choice of such devices, made in particular from the viewpoint of the type of administration route favored, comes within the general knowledge of a person skilled in the art.

In addition to the devices already described above, the following can also be considered from the viewpoint more particularly of an intracutaneous administration:

- devices for direct topical delivery or for delivery by means of a specific applicator, such as, for example, intracutaneous microinjections, or simple or iontophoretic patches;

- electrical, electromagnetic or magnetic devices which make possible a physical stimulation simultaneous with the application of said composition at the application site;

- devices dedicated to contributing heat and/or cold, thus modifying the electrical signals at certain receptors, such as, for example, the Derm-Ice^® device; and

- devices dedicated to contributing light, activating or inhibiting certain enzymatic systems. In the last two alternatives, the device contributes to stimulating the effectiveness of the active agent according to the invention at the administration site under consideration.

Thus, the present invention is also targeted at a kit comprising at least one container containing a composition comprising steviol, a steviol glycoside derivative or one of their isomers and at least one device appropriate for the administration of said composition to an individual, in particular as described above.

The present invention relates to a cosmetic method for stimulating, restoring or regulating the metabolism of melanocytes, in particular elderly melanocytes, of the skin or semimucous membranes, comprising at least one stage of administration, to an individual having need thereof, of steviol, of steviol glycoside derivative or of one of their isomers.

A cosmetic method according to the invention can be carried out daily, for example at the rate of a single administration per day or of an administration split up into two or three times per day, for example once in the morning and once in the evening.

Throughout the description, including the claims, the expression "comprising a" should be understood as being synonymous with "comprising at least one", unless otherwise specified.

The expressions "between ... and ..." and "ranging from ... to ..." should be understood as meaning limits included, unless otherwise specified.

The examples and figures which follow are presented by way of illustration and without implied limitation of the invention. The percentages are expressed by weight of starting materials. The compounds are, as the case may be, mentioned as chemical names or as CTFA (International Cosmetic Ingredient Dictionary and Handbook) names.

FIGURE

Figure 1 : The viability of the melanocytes and the reduction in the production of melanin by melanocytes in the presence of increasing concentrations of rebaudioside A are illustrated in this figure.

EXAMPLE 1

Influence of rebaudioside A on depigmentation

The active agent tested is a Stevia extract comprising 99% of rebaudioside A sold by Blue California under the name Good'n sweet™.

The modulating effect on melanogenesis of the compounds of formula (I) was measured according to the method described in application EP 0 993 826, filed by the Applicant Company, and in the paper by R. Schmidt, P. Krien and M. Regnier, Anal. Biochem., 235(2), 113-18, (1996).

As shown in figure 1, rebaudioside A brings about a dose-dependent decrease in the synthesis of melanin, thus resulting in a depigmentation (lower curve in the figure). This effect is observed, of course, at noncytotoxic doses (upper curve in the figure) and at an active agent concentration of greater than 0,08 mg/ml.

These results reveal the properties of regulating the metabolism of the melanocytes by rebaudioside A and the advantage of the use of steviol, of its glycoside derivatives or of the isomers of these for regulating this metabolism and thus for preventing or treating detrimental changes in the complexion of the skin.

EXAMPLE 2

Emulsion for the face

This cream, of pH = 5, is used to improve the uniformity of the complexion.

EXAMPLE 3

Localized anti-blemish face care product

INCI name % by weight

Disodium EDTA 0.05

Dimethicone/vinyl dimethicone crosslinked

1.2

polymer

Nylon- 12 5

Sodium styrene/MA copolymer 0.8

Stevia extract comprising 99% of rebaudioside

A, sold by Blue California under the name 2.0

Good'n sweet™.

Octanoylsalicylic acid 0.5

Octyldodecanol 2.00

Cyclopentasiloxane 17.3

Glycerol 23

Propylene glycol 6

Dimethicone 3.8

PEG/PPG- 18/18 dimethicone 2.4

Vegetable oil 3

Phenyl trimethicone 4

Silica 3

Water q.s. for 100

Preservatives 0.9 EXAMPLE 4

Complexion restoring cream

INCI name % by weight

Myristyl alcohol 0.025

Stearyl alcohol 1.025

Phenoxyethanol 0.8

Potassium hydroxide 0.5

Glyceryl stearate 1.25

Cetyl alcohol 0.95

Stevia extract comprising 99% of rebaudioside 3.0 A, sold by Blue California under the name

Good'n sweet™.

Octanoylsalicylic acid 0.2

Isopropyl lauroyl sarcosinate 3.00

Hydro xypropyl tetrahy dropyrantrio 1 9.00

Cyclopentasiloxane 15

Glycerol 5

Hydrogenated polyisobutene 5

Water q.s. for 100

Carbomer 0.6

PEG-50 stearate 2.5

PEG- 100 stearate 1.25

EXAMPLE 5

Anti-blemish complexion-perfecting fluid care gel

INCI name % by weight

Potassium hydroxide 1.00

Disodium EDTA 0.15

Sodium citrate 0.70

Phenoxyethanol 0.4

Caprylic acid/capric acid triglyceride 2.00

Xanthan gum 0.2

Carbomer 0.3

Polyacrylamide (and) Ci3_i₄ isoparaffin (and) 2.00 laureth-7

Dimethicone 1.00

Glycerol 5.00

Stearic acid 1.00

Glyceryl stearate (and) PEG- 100 stearate 1.00

Stevia extract comprising 99% of rebaudioside 5.00 A, sold by Blue California under the name

Good'n sweet™.

Salicylic acid 0.20

Water q.s. for 100 EXAMPLE 6

Care powder for lightening the skin

Claims

1. A cosmetic use by topical route of steviol, of a steviol glycoside derivative or of one of their isomers to stimulate, restore or regulate the metabolism of melanocytes of the skin and semimucous membranes.

2. A cosmetic use by topical route of steviol, of a steviol glycoside derivative or of one of their isomers to prevent, reduce and/or treat a detrimental change in the complexion of the skin or in the complexion of the semimucous membranes.

3. The use as claimed in claim 1 or 2, to reduce the melanin synthesis.

4. The use as claimed in claim 1 or 2, for decreasing pigmentation of the skin and/or promoting depigmentation of the skin.

5. The use as claimed in claim 1 or 2, to prevent, reduce and/or treat a defect of pigmentation of the skin.

6. The use as claimed in the preceding claim, wherein the defect of pigmentation of the skin is chosen from melasma, chloasma, lentigines, liver spots, vitiligo, postinflammatory hyperpigmentations due to an abrasion and/or a burn and/or a scar, genetically-determined hyperpigmentations, hyperpigmentations of metabolic or drug origin, or any other pigmentation lesions.

7. The use as claimed in any one of the preceding claims, to lighten the skin.

8. The use as claimed in any one of the preceding claims, to prevent, reduce and/or treat a detrimental change in the complexion of the skin chosen from a detrimental change in the radiance of the complexion of the skin, a muddy skin complexion, a lifeless skin complexion, a nonuniform skin complexion, spots, dry patches, dyschromias and/or blackheads.

9. The use as claimed in any one of the preceding claims, wherein the skin is aged skin.

10. The use as claimed in any one of the preceding claims, wherein the steviol glycoside derivative is represented by the formula (II):

in which Rl and R2 represent, independently of one another, a hydrogen atom or a cyclized or noncyclized, linear or branched, sugar residue.

11. The use as claimed in the preceding claim, wherein Rl and R2, which are identical or different and preferably different, represent a sugar residue comprising one or more glucose and/or rhamnose entities.

12. The use as claimed in claim 10 or 11, wherein Rl represents a glucose unit and R2 represents a branched triholoside.

13. The use as claimed in any one of the preceding claims, wherein the the steviol glycoside derivative is chosen from stevioside, rebaudioside A, rebaudioside C, dulcoside A, rebaudioside B, rebaudioside D, rebaudioside E, rebaudioside F, steviolbioside, rubusoside, and their mixtures, preferably from stevioside, rebaudioside A, rebaudioside C, dulcoside A, and their mixtures, and better still is rebaudioside A.

14. The use as claimed in any one of the preceding claims, wherein the steviol, the steviol glycoside derivative or one of their isomers is employed in a composition in the form of at least one extract of at least one plant of the Stevia genus.

15. The use as claimed in the preceding claim, wherein the extract is obtained from the leaves of a plant of the Stevia genus and in particular from a plant of the species Stevia rebaudiana.

16. The use as claimed in claim 14 or 15, wherein the extract is employed in a composition in a proportion of from 0.00001% to 50% by weight, preferably from 0.0001% to 10% by weight and better still from 0.01% to 4% by weight, with respect to the total weight of said composition.

17. Steviol, a steviol glycoside derivative or one of their isomers as agent for stimulating, restoring or regulating by topical route the metabolism of the melanocytes of the skin and/or semimucous membranes.

18. Steviol, a steviol glycoside derivative or one of their isomers as agent for preventing, reducing and/or treating by topical route a detrimental change in the complexion of the skin or in the complexion of the semimucous membranes.

19. A cosmetic or dermatological topic composition comprising an effective amount of steviol, of a steviol glycoside derivative or of one of their isomers, in combination with at least one additional active agent chosen from polyols, vitamins, keratolytic and/or desquamating agents, soothing agents and their mixtures.

20. The composition as claimed in the preceding claim, wherein the steviol, the steviol glycoside derivative or one of their isomers is defined as claimed in any one of claims 8 to 14.

21. A kit comprising at least one container containing a composition comprising steviol, a steviol glycoside derivative or one of their isomers and at least one device arranged in order to make possible the administration by topical route of said composition to an individual, and/or to increase the effectiveness of said composition for an individual, and/or to promote the topical penetration for an individual of said composition.

22. A cosmetic method for stimulating, restoring or regulating the metabolism of the melanocytes of the skin, comprising at least one stage of administration by topical route, to an individual having need thereof, of steviol, of steviol glycoside derivative or of one of their isomers.

23. A cosmetic method for preventing, reducing and/or treating a detrimental change in the complexion of the skin, comprising at least one stage of administration by topical route, to an individual having need thereof, of steviol, of steviol glycoside derivative or of one of their isomers.

24. A cosmetic method for lightening the skin, comprising at least one stage of administration by topical route, to an individual having need thereof, of steviol, of steviol glycoside derivative or of one of their isomers.