WO2024126792A1

WO2024126792A1 - Cosmetic use of a composition for caring for keratin materials comprising at least indole-3-acetamide

Info

Publication number: WO2024126792A1
Application number: PCT/EP2023/086058
Authority: WO
Inventors: Amélie PREVOT-GUEGUINIAT; Magali MOREAU; Amina BOUSLIMANI; Okan ALTUNCU; Samira TAMOUTOUNOUR
Original assignee: L'oreal
Priority date: 2022-12-16
Filing date: 2023-12-15
Publication date: 2024-06-20
Also published as: FR3143324A1

Abstract

Cosmetic use of a composition for caring for keratin materials comprising at least indole-3-acetamide The present invention relates to the cosmetic use, notably topical non-therapeutic cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3- acetamide, an isomer thereof or a salt thereof, for preventing a reduction in the skin barrier function and/or reinforcing the skin barrier function in an individual, in particular an individual with dry skin The invention also relates to the non-therapeutic use of such a composition for preventing and/or treating a skin disorder of sensitive skin, in an individual, and also to the use of such a composition for preventing and/or treating pruritus and/or inflammation of the skin of an individual. Finally, the invention relates to a non- therapeutic cosmetic process for caring for keratin materials, in particular the skin, comprising the topical application of such a composition to these keratin materials.

Description

Title: Cosmetic use of a composition for caring for keratin materials comprising at least indole-3-acetamide

Technical field

The present invention relates to the use of indole-3-acetamide for improving the skin barrier function and moisturizing the skin.

More particularly, the present invention aims to propose the cosmetic use, notably topical non-therapeutic cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for preventing a reduction in the skin barrier function and/or reinforcing the skin barrier function in an individual, in particular an individual with dry skin.

The invention further relates to the cosmetic use, notably topical cosmetic use, of such a composition for preventing and/or treating atopic dermatitis or eczema.

The invention also relates to the cosmetic use, notably topical non-therapeutic cosmetic use, of such a composition for preventing and/or treating a skin disorder of sensitive skin, in an individual.

The invention additionally relates to the cosmetic use, notably topical cosmetic use, of such a composition for preventing and/or treating pruritus and/or inflammation of the skin of an individual, in particular present in a dermatological disorder, chosen from the group constituted of atopic dermatitis or eczema, psoriasis, nodular prurigo, seborrhoeic dermatitis, acne, folliculitis and rosacea.

Prior art

The skin is a tissue, the cells of which are joined together and integrally attached to each other. The skin tissue forms an outer covering comprising sebaceous or sweat glands, and hair follicles. The skin, and in particular the scalp, are epithelia which undergo continual renewal. Renewal, or desquamation, is a coordinated and finely regulated process resulting in the imperceptible and invisible removal of the superficial cells.

Human skin is constituted of two compartments, namely an upper compartment, the epidermis, and a deep compartment, the dermis. The epidermis is conventionally divided into a basal layer of keratinocytes that constitutes the germinal layer of the epidermis, a spinous layer constituted of several layers of polyhedral cells positioned on the germinal layers, one to three "granular" layers constituted of flattened cells containing distinct cytoplasmic inclusions, keratohyalin granules, and finally a set of upper layers referred to as the cornified layers (or stratum corneum), constituted of keratinocytes at the terminal stage in their differentiation, referred to as corneocytes.

Comeocytes are anucleated cells mainly constituted of a fibrous material containing cytokeratins, surrounded by a cornified envelope. New keratinocytes are constantly being produced to compensate for the continuous loss of epidermal cells at the cornified layer by a mechanism referred to as desquamation.

Nevertheless, an imbalance between the production of cells at the basal layer and the rate of desquamation may notably lead to the formation of scales on the surface of the skin. Similarly, a lack of terminal differentiation of the cells of the stratum corneum, for various reasons, can result in the formation of large, thick cell clusters which are visible to the naked eye and are referred to as "squamae", or in other situations, in a thinning of the stratum corneum.

This may lead to a weakness in the barrier properties of the epidermis, to chronic dehydration of the stratum corneum, to a loss of mechanical elasticity, to tautness, and also to a loss of radiance and transparency of the skin.

As examples of factors that promote a reduction in skin surface quality, which weakens the skin barrier, mention may be made of stress, the winter period, excess sebum or a lack of moisturization.

Thus, weakening of the skin barrier can occur in the presence of external attacking factors, notably chosen from irritants (detergents, acids, bases, oxidizing agents, reducing agents, concentrated solvents, gases or noxious fumes, pollutants), thermal or climatic imbalances (cold, drought, radiation), xenobiotics (undesirable microorganisms, allergens) or internal attacking factors such as psychological stress.

This deterioration of the skin barrier may result in skin discomfort, sensory phenomena and notably unpleasant phenomena. The individual who is affected thereby may then experience a feeling of skin discomfort, which may be manifested in particular by stinging, tautness, hotness and/or itching. These feelings of skin discomfort, of cosmetic and non-therapeutic nature, are more common in the most exposed areas of the body, namely the hands, the feet, the face and the scalp.

They may notably occur on areas subjected to certain daily or frequently repeated hygiene actions such as shaving, hair removal, cleaning with toiletry products or household products, the application of adhesives (dressings, patches, or the attachment of prostheses) or in the case of sporting or professional actions, or simply actions associated with lifestyle and with the wearing of clothing, or the use of tools or equipment that give rise to localized friction. They may also be amplified by psychological stress.

These feelings of skin discomfort affect everyone, and in particular:

- people with "fragile" or "delicate" and vulnerable skin which becomes rapidly imbalanced during large variations in temperature or relative humidity (for example in the case of babies’ skin);

- people with "weakened" skin, notably including:

(i) people whose protective hydrolipidic film composed of sweat, sebum and natural moisturizing factors becomes diminished, as is the case for people over 60 years of age and notably in the case of the elderly (at least 75 years old);

(ii) people for whom the composition of the hydrolipidic film is modified.

Mention may also be made of people with "attacked" skin, for example shaved skin.

One of the critical steps in the process of terminal differentiation of the stratum corneum is the crosslinking of the precursor proteins of the cornified envelope (CE). This phenomenon has an essential role in the development and maintenance of skin cohesion, of the physical properties of the skin such as the barrier function, and is a crucial step in the abovementioned process of terminal differentiation.

The moisturizing active ingredients conventionally used, such as humectants, moisturizing polymers or fatty substances such as liquid petroleum jelly, temporarily modify the surface properties of the skin. These active ingredients may lead to mechanical softening of the stratum corneum, to an increase in the state of moisturization thereof and/or to an improvement in the skin’s microrelief by the formation of a film at the surface of the skin. However, these effects do not necessarily last very long. Moreover, these active ingredients can be eliminated by cleansing actions. To overcome these drawbacks, it is advantageous to turn to active ingredients with a long- lasting beneficial action which is not affected by cleansing while acting on biological pathways.

Recently, Chng et al. (Microbiol 2016 Jul 11;1(9): 16106. doi: 10.1038/nmicrobiol.2016.106) have demonstrated that the tryptophan metabolic pathway, namely the aryl hydrocarbon receptor (AhR) pathway, was reduced in the skin microbiota of patients suffering from atopic dermatitis. AhR is a transcription factor involved in skin homeostasis (Di Meglio et al. Immunity. 2014 Jun 19;40(6):989-1001; Haas et al. J Invest Dermatol. 2016 Nov; 136(11), 2260-2269).

The most well-known ligands that bind to AhR include xenobiotics such as polycyclic aromatic hydrocarbons (HAPs) such as benzopyrene, polychlorinated biphenyls (PCBs) and halogenated aromatic hydrocarbons (associated with air pollution), such as dioxins. AhR is notably recognized for its action in the metabolism of these xenobiotics, and their detoxification (Furue et al. Acta Derm Venereol. 2018 Nov 5;98(10):918-923).

Certain members of the cytochrome P450 family, such as CYP1A1, and also other detoxification enzymes such as glutathione S-transferase (GST), can be induced by AhR. The metabolization products of AhR xenobiotic ligands, notably polycyclic aromatic hydrocarbons, cause dysfunction of the barrier by accelerating the terminal differentiation of keratinocytes and also by inducing the release of type 2 inflammatory cytokines (Hidaka et al. Nat Immunol. 2017 Jan;18(l):64-73). This aggravates inflammation in patients suffering from atopic dermatitis. This is because CYP1A1 activity can be harmful, as it can generate reactive oxygen species in the keratinocytes. Nonetheless, other AhR ligands can also have a beneficial antioxidant effect via activation of the transcription factor nuclear factor-erythroid 2-related factor-2 (NRF2) (Schafer et al. EMBO Mol Med. 2012 May; 4(5): 364-379).

Thus, there is a need to identify new active ingredients that make it possible to only very weakly induce the harmful biological pathway mediated by the cytochrome P450, CYP1A1, of the AhR pathway, while activating the beneficial biological detoxification pathway mediated by NRF2 within this same AhR pathway.

By identifying these new active ingredients, it is therefore sought to:

- prevent a reduction in, and/or to reinforce, the skin barrier function, in particular of dry skin; and/or - prevent and/or reduce feelings of skin discomfort, stinging, tautness, hotness and itching, in particular in people with sensitive, fragile, weakened or delicate skin (for example babies or people at least 60 years of age and in particular people at least 75 years of age), or people for whom the composition of the hydrolipidic film is modified, and/or

- prevent and/or treat atopic dermatitis or eczema and/or prolong the remission phases between acute flare-ups of this type of condition.

There is thus also a need for an active ingredient that enables the skin, in particular dry and/or sensitive and/or atopic skin, to maintain its barrier function.

There is also a need for an active ingredient for improving skin moisturization.

There is furthermore a need for active ingredients for improving the quality and/or complexion of the skin, in particular the quality and/or complexion of sensitive skin; and/or preventing and/or treating skin disorders associated with sensitive skin, in particular chosen from tautness, stinging, hotness and/or itching.

There is also a need for active ingredients that enable the prevention and/or treatment of pruritus and/or inflammation of the skin of an individual, in particular inflammation of skin affected by a dermatological disorder chosen from the group constituted of atopic dermatitis or eczema, psoriasis, nodular prurigo, seborrhoeic dermatitis, acne, folliculitis and rosacea, or by a dermatological disorder following exposure of the skin to pollutants and/or UV rays.

Disclosure of the invention

The aim of the present invention is to solve the abovementioned technical problems.

Indeed, the inventors have now discovered that, in a skin model of atopic dermatitis, indole- 3-acetamide makes it possible to significantly reduce, in particular to a greater extent than active ingredients that are already known, the production of thymic stromal lymphopoietin (TSLP) in keratinocytes. Indeed, TSLP is a key chemokine of keratinocyte communication due to its ability to induce itching by directly activating certain types of neurons (TRPA- 1+) and also the type 2 immune responses involved in atopic dermatitis. As illustrated for example in Si-Hang Wang and Ya-Gang Zuo (Front Immunol. 2021 Jun 24:12:698522) and in Zsolt Dajnoki et al. (J Invest Dermatol. 2017 May; 137(5): 1114- 1125), it is well known that there is a link between the TSLP marker and certain skin disorders, among which atopic dermatitis, psoriasis, rosacea, chronic spontaneous urticaria and systemic sclerosis. Moreover, the inventors have also observed the ability of indole- 3 -acetamide to decrease TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) production in keratinocytes of this same model. TRAIL is a protein involved in the apoptosis pathway and is produced in large amounts during the stimulation used to reproduce the atopic dermatitis model.

It is also observed that, unlike other active ingredients available in the prior art, indole-3- acetamide only very weakly induces, or does not induce, the Cyplal pathway, the activity of which can be harmful because it generates reactive oxygen species in keratinocytes, unlike indole-3-carboxaldehyde (IALD) which is a strong inducer, which is not desired, as shown in the examples below.

Finally, the inventors have demonstrated that indole-3-acetamide makes it possible to restore a control thickness of the stratum corneum of an epidermis in a skin model of atopic dermatitis, and to do so in a superior way to the compounds known from the prior art.

Summary of the invention

Thus, according to a first aspect, the present invention relates to the cosmetic use, notably topical non-therapeutic cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for preventing a reduction in the skin barrier function and/or reinforcing the skin barrier function in an individual, in particular an individual with dry skin.

An isomer of indole-3-acetamide according to the present invention may for example be 3 H-indole- 3 -acetamide .

According to a second aspect, the present invention relates to the cosmetic use, notably topical cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for preventing and/or treating atopic dermatitis or eczema.

According to a third aspect, the present invention relates to the cosmetic use, notably topical non-therapeutic cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for preventing and/or treating a skin disorder of sensitive skin, in an individual.

Such a skin disorder may notably be a feeling of discomfort, and notably tautness, stinging, hotness and/or itching. According to a fourth aspect, the present invention relates to the cosmetic use, notably topical cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for preventing and/or treating pruritus and/or inflammation of the skin of an individual.

Pruritus and/or inflammation of the skin of an individual may in particular be present:

- in a dermatological disorder chosen from the group constituted of atopic dermatitis or eczema, psoriasis, nodular prurigo, seborrhoeic dermatitis, acne, folliculitis and rosacea; or

- in a dermatological disorder following exposure of the skin to pollutants and/or UV rays. Finally, the invention also relates to a non-therapeutic cosmetic process for caring for keratin materials, in particular the skin, comprising the topical application to these keratin materials of a composition comprising, in a physiologically acceptable medium, indole-3- acetamide, an isomer thereof or a salt thereof.

A composition used according to the invention may be applied to fragile, weakened, dry, atopic and/or sensitive skin.

A composition used according to the invention may notably be suitable for topical administration.

Other characteristics, aspects and advantages of the invention will become apparent on reading the detailed description that follows.

Detailed description

Composition used according to the invention

A composition used according to the invention is preferably cosmetic.

A composition used according to the invention is preferentially suitable for topical application to keratin materials, in particular to the skin, and thus comprises a physiologically acceptable medium, i.e. a medium that is compatible with the skin.

The term “cosmetic” means a composition that is compatible with keratin materials, in particular the skin, mucous membranes and skin appendages. The composition used according to the invention is non-therapeutic.

The term “keratin materials” in particular means the skin, mucous membranes, fibres, eyelashes and skin appendages. The term "skin" means all of the skin of the body, and preferably the skin of the face, scalp, neckline, neck, arms and forearms, or more preferably still the skin of the face (in particular of the forehead, nose, cheeks and chin), of the neckline and of the neck.

A composition used according to the invention preferably comprises a cosmetically acceptable medium, i.e. one which has a pleasant colour, odour and feel and which does not cause any unacceptable discomfort, i.e. stinging or tautness, liable to discourage the user from applying this composition.

As used herein, the terms “treat” and “treatment” mean the alleviation of the symptoms associated with a specific disorder or condition and/or the elimination of said symptoms and also the complete disappearance of the disorder or condition in question.

In the context of the present invention, the terms “prevent” and “prevention” denote the reduction, to a lesser degree, of the risk or probability of occurrence of a given phenomenon.

A composition used according to the present invention thus makes it possible to confer beneficial properties on the skin, notably in a long-lasting manner, in particular: effective barrier function; moisturizing effect; elasticity and smooth texture of the skin; surface morphology with low roughness, good tissue cohesion, good thickness of the stratum corneum and an improvement in the visual appearance of the skin.

In particular, a composition used according to the invention may be used on fragile, weakened, dry, atopic and/or sensitive skin of an individual.

A recent epidemiological study in adult subjects from various countries (Haftek et al., Clin Cosmet Investig Dermatol. 2013; 6: 289-294) made it possible to establish that the concept of "fragile skin" had a specific resonance among the populations studied. "Fragile skin" can be defined as skin having an intrinsic fragility, such that it is more receptive to attacking factors of all kinds than a non-fragile skin.

In general, fragile skin has a disruption of the barrier function leading to permeability and therefore greater reactivity to environmental stresses or attacking factors compared with "normal skin" (non-fragile skin). This type of skin is therefore less resistant to stress or environmental attacking factors. In addition to the dysfunction of the barrier function, these stresses can also lead to skin inflammation. Lastly, fragile skin is also slower to recover its basal state once exposed to such conditions. Fragile skin is referred to as constitutionally fragile skin, and corresponds, for example, to baby skin, to the skin of an elderly person, or else to the skin of delicate areas of the body (eyelids, face, etc.).

Weakened skin is fragile skin referred to as "environmentally” or "pathologically” fragile skin. "Environmentally" fragile skin is notably skin which has been attacked by climatic stress (heat, cold, drought, etc.), mechanical stress (friction, etc.), physical stress (UV radiation, laser, etc.) or chemical stress (surfactants, solvents, etc.). "Pathologically" fragile skin relates to skin suffering notably from atopic dermatitis or eczema, psoriasis, nodular prurigo, seborrhoeic dermatitis, acne, folliculitis or rosacea.

The term "atopic skin" here means skin of a patient exhibiting the same physiological and molecular characteristics as skin of a patient suffering from atopic dermatitis, in particular exhibiting pruritus or inflammation, these manifestations being chronic and interspersed with periods of remission.

The expression "skin disorder" covers feelings of discomfort and also the temporary visible and unattractive cutaneous signs liable to affect this same individual.

In general, sensitive skin is defined by a particular reactivity of the skin. This skin reactivity is generally reflected by the manifestation of signs of discomfort in response to an individual coming into contact with a triggering factor, which may have diverse origins. It may be the application of a cosmetic product to the surface of sensitive skin, the consumption of food, the exposure to sudden variations in temperature, to atmospheric pollution and/or to ultraviolet or infrared rays. The appearance of these signs of discomfort, which appear within minutes of the individual coming into contact with the triggering factor, is one of the essential characteristics of sensitive skin. These are mostly dysesthetic sensations. "Dysesthetic sensations" means sensations felt in an area of the skin, such as stinging, tautness, hotness and/or itching.

These subjective signs usually exist in the absence of visible clinical signs such as redness and desquamations.

This skin type will therefore present feelings of discomfort much more quickly and frequently than other skin types.

Dry skin appears rough to the touch and appears to be covered with squamae and manifests essentially in a feeling of tautness and/or tension. Indeed, dry skin is generally accompanied by desquamation. In physiological terms, dry skin is often notably associated with a decrease in the degree of skin moisturization and with an adversely affected barrier function, measured by the insensible water loss. In sensory terms, it is notably characterized by feelings of skin tautness and/or tension.

Dry skin, also known as "xerosis", may appear at any age, and may be unrelated to a pathological condition.

A composition according to the invention thus proves to be very particularly effective for treating tautness, stinging, hotness and/or itching, notably associated with fragile, weakened, dry, atopic and/or sensitive skin, for physiologically restoring a suitable state of moisturization of the stratum corneum, for restoring an adversely affected thickness, and in particular a thinning, of the stratum corneum of the skin, for improving the comfort of fragile, weakened, dry, atopic and/or sensitive skin.

As indicated above, a composition according to the invention comprises indole-3- acetamide, an isomer thereof or a salt thereof.

Indole-3-acetamide, also referred to as lH-indole-3-acetamide, has the following formula I:

[Chem 1]

A “salt” of an indole according to the invention means a salt formed by an inorganic or organic acid or else an inorganic or organic base.

A composition used according to the invention may comprise a content of indole-3- acetamide, an isomer thereof or a salt thereof, of at least 0.0001% by weight relative to the total weight of the composition, preferably a content of between 0.0001% and 5% by weight, more preferentially a content of between 0.001% and 1% by weight, better still a content of between 0.001% and 0.01% by weight relative to the total weight of the composition.

A composition used according to the invention may further comprise at least one adjuvant chosen from the group constituted of liquid, pasty or solid fatty substances; organic solvents chosen from linear or branched Cl -C6 monoalcohols such as ethanol, isopropanol, tert-butanol; polyols such as glycerol, propylene glycol, pentylene glycol, caprylyl glycol, hexylene glycol (or 2-methyl-2,4-pentanediol) and polyethylene glycols; polyol ethers such as dipropylene glycol monomethyl ether; ionic or nonionic, hydrophilic or lipophilic, thickeners; softeners; humectants; emollients; opacifiers; stabilizers; silicones; antifoams; fragrances; preservatives; anionic, cationic, nonionic, zwitterionic or amphoteric surfactants; fillers; polymers; propellants; basifying or acidifying agents; and mixtures thereof.

Such an adjuvant may represent from 0.01% to 20% by weight, preferably from 0.1% to 10% by weight and better still from 1% to 5% by weight relative to the total weight of the composition.

Of course, those skilled in the art will take care to select this or these adjuvant(s), and/or the amount thereof, such that the advantageous properties of the indole-3 -acetamide, an isomer thereof or a salt thereof of the composition used according to the invention are not, or are not substantially, adversely affected by the envisaged addition.

Preferably, a composition used according to the invention may comprise water.

A composition used according to the invention may comprise from 1% to 95% by weight, preferably from 20% to 80% by weight of water, better still from 30% to 60% by weight relative to the total weight of the composition.

The pH of a composition used according to the invention is advantageously less than or equal to 8, preferably ranging from 4 to 7, better still ranging from 5.5 to 6.5.

Advantageously, the composition used according to the invention may comprise one or more water-miscible organic solvents.

According to the present invention, the term “water-miscible solvent” denotes a compound that is liquid at room temperature and water-miscible, notably having a miscibility with water of greater than 50% by weight at 25°C and atmospheric pressure.

The water- miscible organic solvents can be chosen from linear or branched C1-C6 monoalcohols, such as ethanol, isopropanol or tert-butanol; polyols such as glycerol, propylene glycol, pentylene glycol, caprylyl glycol, hexylene glycol (or 2-methyl-2,4- pentanediol) and polyethylene glycols; polyol ethers, for instance dipropylene glycol monomethyl ether; and mixtures thereof. These water-miscible organic solvents may be present in a composition used according to the invention in a concentration ranging from 0.01% to 20% by weight, preferably from 0.1% to 10% by weight and better still from 1% to 5% by weight, relative to the total weight of the composition.

The composition used according to the invention may also comprise at least one additional cosmetic active ingredient.

This may in particular be at least one active ingredient for caring for dry skin.

In the context of the present invention, the term “additional active ingredient” means a compound which has inherently, that is to say not requiring the intervention of an external agent in order to activate it, a biological activity which may in particular be:

- a soothing or anti-irritant activity, and/or

- a humectant activity; and/or

- an emollient activity.

The additional active ingredient which can be used in the compositions used according to the invention may in particular be chosen from humectants such as urea and/or glycerol, soothing agents, anti-irritant agents, emollients such as liquid petroleum jelly, and mixtures thereof in any proportion.

The additional active ingredient used in the composition used according to the invention may represent from 0.0001% to 20%, preferably from 0.01% to 10% and better still from 0.01% to 5% by weight relative to the total weight of the composition.

Needless to say, a person skilled in the art will take care to select this or these optional additional compound(s), and/or the amount thereof, such that the advantageous properties of the composition used according to the invention are not, or are not substantially, adversely affected by the envisioned addition.

A composition used according to the invention may in particular be in any presentation form normally used in the cosmetic field, and in particular any presentation form normally available for the selected mode of administration.

The support may be of diverse nature according to the type of composition considered.

The compositions according to the invention may be in any presentation form conventionally used for topical application and notably in the form of aqueous or aqueous- alcoholic solutions, oil-in-water (O/W), water-in-oil (W/O) or multiple (triple: W/O/W or O/W/O) emulsions, aqueous gels, or dispersions of a fatty phase in an aqueous phase using spherules, it being possible for these spherules to be lipid vesicles of ionic and/or nonionic type (liposomes, niosomes or oleosomes). These compositions are prepared according to the usual methods.

A composition used according to the invention is preferentially suitable for topical administration.

As more particularly regards compositions intended for topical administration, i.e. administration on the skin, they may be aqueous, aqueous -alcoholic or oily solutions, dispersions of the solution type or dispersions of the lotion or serum type, emulsions of liquid or semi-liquid consistency of the milk type, suspensions or emulsions of the cream type, aqueous or anhydrous gels, microemulsions, microcapsules, microparticles, or vesicular dispersions of ionic and/or nonionic type.

A composition used according to the invention may advantageously comprise at least one liquid fatty substance.

The term “liquid fatty substance” means a compound with a melting point below approximately 30-35°C, as opposed to solid fatty substances, such as waxes, which have a melting point above approximately 50°C.

As oils which may be used in the composition of the invention, mention may for example be made of:

- hydrocarbon-based oils of animal origin;

- hydrocarbon-based oils of plant origin;

- synthetic esters and ethers, notably of fatty acids, for instance oils of formulae R’COOR2 and R’OR2 in which R’ represents a fatty acid residue including from 8 to 29 carbon atoms and R2 represents a branched or unbranched hydrocarbon-based chain containing from 3 to 30 carbon atoms;

- linear or branched hydrocarbons, of mineral or synthetic origin;

- fatty alcohols containing from 8 to 26 carbon atoms;

- fluoro oils which are partially hydrocarbon-based and/or silicone -based;

- silicone oils;

- mixtures thereof.

In the list of oils mentioned above, the term “hydrocarbon-based oil” means any oil mainly including carbon and hydrogen atoms, and possibly ester, ether, fluoro, carboxylic acid and/or alcohol groups. The other fatty substances that may be present in the oily phase are, for example, fatty acids including from 8 to 30 carbon atoms, waxes, silicone resins and silicone elastomers.

These fatty substances may be chosen in a varied manner by those skilled in the art in order to prepare a composition having the desired properties, for example in terms of consistency or texture.

According to a particular embodiment of the invention, the composition according to the invention is a water-in-oil (W/O) or oil-in-water (O/W) emulsion. The proportion of the oily phase of the emulsion may range from 5% to 90% by weight and preferably from 5% to 60% by weight relative to the total weight of the composition. The emulsions generally contain at least one emulsifier chosen from amphoteric, anionic, cationic and nonionic emulsifiers, used alone or as a mixture, and optionally a coemulsifier. The emulsifiers are appropriately chosen according to the emulsion to be obtained (W/O or O/W).

The emulsifier and the coemulsifier are generally 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.

For the W/O emulsions, examples of emulsifiers that may be mentioned include dimethicone copolyols and alkyldimethicone copolyols. A crosslinked elastomeric solid organopolysiloxane including at least one oxyalkylene group may also be used as W/O emulsion surfactant.

For the O/W emulsions, examples of emulsifiers that may be mentioned are nonionic emulsifiers.

Preferentially, a composition used according to the invention differs from compositions having an essentially detergent purpose with regard to the skin, hair and/or mucous membranes, such as soaps, shampoos and shower gels for washing and/or cleansing.

More particularly, a composition used according to the invention may be intended for topical application and may preferably be in the form of an emulsion, preferably an oil-in- water emulsion. Preferably, such an emulsion is not intended to be rinsed off after application.

A composition used according to the invention may alternatively be in the form of a face and/or body care or makeup product, and may be packaged, for example, in the form of a cream in a jar or a fluid in a tube or a pump bottle or a dropper bottle. Uses and processes

As mentioned above, according to one of its aspects, the present invention relates to the cosmetic use, notably topical non-therapeutic cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3 -acetamide, an isomer thereof or a salt thereof, for preventing a reduction in the skin barrier function and/or reinforcing the skin barrier function in an individual, in particular an individual with dry skin, notably for improving skin moisturization.

The invention also relates to the cosmetic use, notably topical cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for preventing and/or treating atopic dermatitis or eczema. The present invention additionally relates to the cosmetic use, notably topical non- therapeutic cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for preventing and/or treating a skin disorder of sensitive skin, in an individual.

The invention additionally relates to a non-therapeutic cosmetic process for caring for keratin materials, in particular the skin, comprising the topical application to these keratin materials of a composition comprising, in a physiologically acceptable medium, indole-3- acetamide, an isomer thereof or a salt thereof.

The skin in particular affected by such a method, and thus the skin on which a composition used according to the invention is applied, may preferably be fragile, weakened, dry, atopic and/or sensitive skin.

In particular, the composition used in a process according to the invention may comprise a content of indole- 3 -acetamide of at least 0.0001% by weight relative to the total weight of the composition, preferably a content of between 0.0001% and 5% by weight, more preferentially a content of between 0.001% and 1% by weight, better still a content of between 0.001% and 0.01% by weight relative to the total weight of the composition.

In addition, the composition used in a process according to the invention may comprise at least one adjuvant chosen from the group constituted of fatty substances; organic solvents chosen from ethanol, isopropanol, tert-butanol, propylene glycol, hexylene glycol (or 2- methyl-2,4-pentanediol) and polyethylene glycols; polyol ethers such as dipropylene glycol monomethyl ether; ionic or nonionic, hydrophilic or lipophilic, thickeners; softeners; opacifiers; stabilizers; silicones; antifoams; fragrances; preservatives; anionic, cationic, nonionic, zwitterionic or amphoteric surfactants; fillers; polymers; propellants; basifying or acidifying agents; and mixtures thereof.

As indicated above, a composition used in a process of the present invention is preferably suitable for topical administration.

The cosmetic uses, methods and processes considered according to the invention are non- therapeutic.

The cosmetic uses and processes of the invention are preferentially performed by topically administering a composition according to the invention.

Topical administration consists of the external application to the skin of cosmetic compositions according to the usual techniques for the use of these compositions.

By way of illustration, the cosmetic use or process according to the invention may be implemented by topical, for example daily, application of at least one composition according to the invention, which may be formulated, for example, in the form of a cream, gel, serum, lotion, emulsion, or makeup-removing milk, preferably in the form of an emulsion.

The application can be repeated, for example, once to twice daily for one or more days and generally over an extended period of at least 4 weeks, or even 4 to 15 weeks, with, where appropriate, one or more periods of stoppage.

According to one embodiment, the application is daily (once a day) and generally over an extended period of at least 4 weeks, or even 4 to 15 weeks, with, where appropriate, one or more periods of stoppage.

According to one embodiment, the cosmetic treatment process according to the invention may comprise a single application.

Throughout the description, including the claims, the terms “between ... and ...”, and “ranging from ... to ...” should be understood as meaning limits included, unless otherwise specified.

The examples that follow illustrate the present invention without limiting the scope thereof. In the examples, unless otherwise specified, the temperature is room temperature (20°C) and is expressed in degrees Celsius, and the pressure is atmospheric pressure.

Examples MATERIALS AND METHODS

Stimulation of RHE with a cocktail that mimics atopic dermatitis

Use was made of a reconstructed human epidermis in which the keratinocytes exhibited reduced expression of the FLG gene. This model was notably described in “Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation”, Valerie Pendaries et al. 2014 Dec;134(12):2938-2946. The reconstructed epidermis rests on an inert non-submerged polycarbonate surface of 0.5 cm², and is cultured on cell culture medium (Episkin). In our study, the RHEs are produced using filaggrin (FLG)-deficient keratinocytes. This is because FLG is greatly reduced in patients with atopic skin. This FLG-deficient line was generated using a short hairpin RNA that targets FLG (shFLG). The use of the RHE-shFLG in a 3D RHE model has been published (see Madiedo-Podvrsan et al., Sci Rep. 2021 Mar 18;11(1):6217).

In order to produce a phenotype similar to that observed in atopic dermatitis patients in terms of chemokines produced and histology, it is necessary to stimulate the RHEs using a cocktail composed of:

- Polyinosinic-polycytidylic acid (Poly (I :C)) (Reference P9582, Sigma) at 10 pg/ml;

- Interleukin 4 (IL-4) (Reference BMS337, Invitrogen) and Interleukin 13 (IL-13) (Reference 213-ILB, R&D Systems) at 50 ng/ml; and

- TNF (Tumour necrosis factor Reference 210-TA/CF, R&D Systems) at 10 ng/ml. Simultaneous bringing into contact with the various molecules to be tested:

- IALD ref: 129445, Sigma: stock solution 10 mg/ml in DMSO diluted in the RHE (Episkin) culture medium to the final concentration of 10 pg/ml;

- FICZ ref: SML1489, Sigma: stock solution 0.5 mg/ml in DMSO diluted in the RHE (Episkin) culture medium at the final concentration of 100 ng/ml; and

- 13 A ref: 286281, Sigma: stock solution 10 mg/ml in DMSO diluted in the RHE (Episkin) culture medium to the final concentration of 10 pg/ml. the chemokines in the culture

The inflammatory cocktail as defined above, and also the various molecules to be tested (I3A, IALD and FICZ), are added simultaneously to the suitable cell culture medium, in which the RHEs are placed. The culture plates are then incubated at 37°C for 48 hours. The culture supernatant is then recovered, and the various chemokines are measured (kits in Table 1 below). The RHEs are milled using ceramic beads and the RNA is extracted according to the manufacturer’s instructions (kits in the table below). The expression of the target genes (Table 1 below) is measured by qPCR.

[Table 1]

Measuring the thicknesses of the Stratum corneum and non-viable layer

48 h after culturing the RHEs under the different stimulation conditions, the tissues are fixed in 4% paraformaldehyde (w/v), pH 6.9 (Carlo Erba Reagents, France) and kept at 4°C for 24 to 48h. The tissues are then dehydrated in successive baths of 70% and 100% ethanol, and xylene, then mounted in a paraffin block. The blocks are cut into 5 pm sections using a microtome, and the sections are collected on SuperFrost Plus slides (ThermoFisher, USA). The sections are then subjected to a deparaffinization process (successive baths of ethanol, xylene and water). H&E staining is then performed in a first haematoxylin (ThermoFisher) bath for 2 minutes, then washing for 2 min in water, and finally in a 1% eosin (ThermoFisher) bath before a final washing. The sections are dehydrated again, and mounted using Coverquick 2000 Q (VWR). The slides are scanned using a Nanozoomer S60 (Hamamatsu, Japan) and analyzed using the NDP view software. The images are analyzed with the DHisTo-Skin software (Digital Histological Tools for Skin), using the GeoEower algorithm. Statistical analysis

All experiments were performed with at least three biological replicates. The data is presented in the form of mean ± SEM. GraphPad Prism (version 7.0; GraphPad Software, La Jolla, California). The data was analysed with the one-way ANOVA test followed by Dunnett’s multi-comparison test. The results are considered to be statistically significant when p < 0.05.

Example 1: Study of the anti-pruritic and anti-inflammatory effect of indole-3- acetamide (I3A)

The anti-pruritic effect of indole-3-acetamide and of comparative products (indole-3- aldehyde (IALD) and FICZ (5,l l-dihydroindolo[3,2-b]carbazole-6-carboxaldehyde, 6- formy lindolo [3, 2-b] carbazole)) was studied on 3D models reproducing atopic dermatitis. FICZ is our anti-pruritic and anti-inflammatory positive control, based on the literature. It is also a strong inducer of the Cyplal pathway which can have deleterious effects in certain inflammatory conditions (see Deeba N Syed and Hasan Mukhtar, J Invest Dermatol. 2015 Jun; 135(6): 1478- 1481). This is because CYP1A1 activity can be harmful, as it can generate reactive oxygen species in the keratinocytes.

IALD is also a positive control. Indeed, in the study by Yu et al (J Allergy Clin Immunol, 2019 Jun;143(6):2108-2119.el2), topical application of IALD made it possible to reduce skin inflammation in a dermatitis-like mouse model. IALD is said to inhibit production of TSLP (thymic stromal lymphopoietin) in keratinocytes, and this phenomenon is said to be dependent on the aryl hydrocarbon receptor (AhR) pathway. TSLP is a a key chemokine of keratinocyte communication due to its ability to induce itching by directly activating certain types of neurons. TSLP production can lead to pruritus, one of the factors that can worsen a patient’s quality of life, and to inflammatory lesions (see S. R. Wilson et al., Cell. 2013, Oct 10, 155(2), 285-95).

The metabolites alone are unable to induce TSLP or the various chemokines measured. Stimulation of the shFLG model by the (Poly(LC), TNFa, IL- 13 , IL-4) cocktail as mentioned above results in TSLP production which is on average 10 times greater, and between 20 to 30 times greater for the other chemokines measured, than the control conditions in the culture supernatant. The results in Table 2 below are expressed as percentage difference relative to the stimulated control in the RHE shFLG model.

[Table 2]

Table 2

This Table 2 represents the percentage of the level of expression of TSLP and TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) relative to the stimulated control in the RHE culture medium 48 h after stimulation. The p-values are calculated with respect to the stimulated control.

Table 2 shows a significant reduction in TSLP production for IALD, I3A and FICZ. This reduction is slightly greater for I3A than for IALD or FICZ.

TRAIL is a protein involved in the apoptosis pathway and is produced in large amounts during the stimulation used to reproduce the atopic dermatitis model (PMID: 18813321). A reduction in TRAIL production by I3A and FICZ is observed, which is not the case for IALD.

Example 2: Study of the effect of indole-3-acetamide on the deleterious AhR pathway (mediated by CYP1A1) and on the beneficial antioxidant AhR pathway (mediated by NRF2, HMOX, and NQO1). qPCRs were performed to examine the expression of certain target genes induced in the context of the AhR pathway following stimulation with the cocktail that mimics certain phenotypes of atopic dermatitis, as defined above. FICZ is known to be a strong inducer of the Cyplal pathway, which is confirmed by the results shown in Table 3 below.

[Table 3]

Table 3 Conversely, a weaker induction of Cyplal by I3A is observed in comparison with that by FICZ. Thus, I3A induces fewer adverse effects than FICZ, or even no adverse effects, by limiting the induction of Cyplal and thus the xenobiotic pathway. Induction of the antioxidant pathway is monitored using the expression of the genes Nrf2, Hmoxl, and Nqol. Under atopic conditions, 13 A slightly induces the antioxidant pathways.

To evaluate the overall impact of the metabolites under the stimulated conditions, the morphology of the RHEs was analyzed.

Example 3: 13 A improves the quality of the epidermis

Treatment with the cocktail that mimics atopic dermatitis as defined above induces disorganization of the epidermis, which can be observed on the H&E histology images, compared to the control (Ctr) (illustrations not presented). Shrinkage of the stratum corneum and of the layers of keratinocytes in the basal layer is observed. Clumps of undifferentiated/dedifferentiated keratinocytes appear in the RHE shFLG model.

It is observed that 13 A, unlike FICA, is able to decrease the surface area and/or number of undifferentiated/dedifferentiated keratinocytes (data not presented).

The use of the software DHisTo-skin makes it possible to measure the thicknesses of the stratum corneum. The values are reported in Table 4, and represent mean thicknesses (pm) of the stratum corneum of the RHE epidermis.

[Table 4]

Table 4

Shrinkage of the stratum corneum (SC) under the stimulated condition, versus the nonstimulated control, is observed. I3A has superior ability to FICZ in restoring a control thickness of the SC.

In conclusion, all of these results demonstrate that I3A has a better ability to restore the barrier function of the epidermis compared to FICZ.

Claims

1. Cosmetic non-therapeutic use, notably topical non-therapeutic cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for preventing a reduction in the skin barrier function and/or reinforcing the skin barrier function in an individual, in particular an individual with dry skin.

2. Composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for the use thereof in the prevention and/or treatment of atopic dermatitis or eczema.

3. Cosmetic non-therapeutic use, notably topical non-therapeutic cosmetic use, of a composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for preventing and/or treating a skin disorder of sensitive skin, in an individual, the skin disorder being a feeling of discomfort, notably tautness, stinging, hotness and/or itching.

4. Composition comprising, in a physiologically acceptable medium, indole-3-acetamide, an isomer thereof or a salt thereof, for the use thereof in the prevention and/or treatment of pruritus and/or inflammation of the skin of an individual.

5. Composition for the use thereof according to Claim 4, wherein pruritus and/or inflammation of the skin of an individual is present:

- in a dermatological disorder following exposure of the skin to pollutants and/or UV rays.

6. Use according to Claim 1 or 3, or composition for the use thereof according to any one of Claims 2, 4 and 5, wherein the composition is applied to fragile, weakened, dry, atopic and/or sensitive skin.

7. Use according to Claim 1 or 3, or composition for the use thereof according to any one of Claims 2 and 4 to 6, wherein the composition comprises a content of indole-3-acetamide, an isomer thereof or a salt thereof, of at least 0.0001% by weight relative to the total weight of the composition, preferably a content of between 0.0001% and 5% by weight, more preferentially a content of between 0.001% and 1% by weight, better still a content of between 0.001% and 0.01% by weight relative to the total weight of the composition.

8. Use according to Claim 1 or 3, or composition for the use thereof according to any one of Claims 2 and 4 to 7, wherein the composition further comprises at least one adjuvant chosen from the group constituted of liquid, pasty or solid fatty substances; organic solvents chosen from linear or branched Cl -C6 monoalcohols such as ethanol, isopropanol, tert-butanol; polyols such as glycerol, propylene glycol, pentylene glycol, caprylyl glycol, hexylene glycol (or 2-methyl-2,4-pentanediol) and polyethylene glycols; polyol ethers such as dipropylene glycol monomethyl ether, ionic or nonionic, hydrophilic or lipophilic, thickeners; softeners; humectants; emollients; opacifiers; stabilizers; silicones; antifoams; fragrances; preservatives; anionic, cationic, nonionic, zwitterionic or amphoteric surfactants; fillers; polymers; propellants; basifying or acidifying agents; and mixtures thereof.

9. Use according to Claim 1 or 3, or composition for the use thereof according to any one of Claims 2 and 4 to 8, the composition being suitable for topical administration.