EP1965872A2

EP1965872A2 - Compositions including at least one retinoid compound and at least one anti-irritant compound and uses thereof

Info

Publication number: EP1965872A2
Application number: EP06842054A
Authority: EP
Inventors: Laurent Fredon; Claire Mallard; Eve Ferrara
Original assignee: Galderma Research and Development SNC
Current assignee: Galderma Research and Development SNC
Priority date: 2005-12-15
Filing date: 2006-11-28
Publication date: 2008-09-10
Also published as: FR2894820B1; WO2007071861A3; WO2007071861A8; US20090098219A1; FR2894820A1; WO2007071861A2; CA2632911A1

Abstract

The invention relates to a topical composition consisting of a physiologically acceptable medium containing at least one retinoid compound selected from all-trans retinoic acid, isotretinoin, motretinide and naphthoic acid derivatives of formula (I), salts and esters thereof, and at least one anti-irritant compound selected from allantoin, EDTA, divalent strontium salts, divalent zinc salts, monovalent sodium salts and hydrated derivatives thereof.

Description

COMPOSITIONS COMPRISING AT LEAST ONE RETINOID COMPOUND AND AT LEAST ONE ANTI-IRRITANT COMPOUND AND USES THEREOF

The present invention relates to compositions for topical application, and their uses as cosmetic or pharmaceutical products, said compositions being intended, in particular, for the treatment of acne.

Acne is a common multifactorial pathology that reaches skin rich in sebaceous glands (face, scapular region, arms and intertriginous regions). It is the most common dermatitis. The following five pathogenic factors play a determining role in the constitution of acne:

1. genetic predisposition;

2. overproduction of sebum (seborrhea);

3. androgens;

4. disorders of follicular keratinisation (comedogenesis); and

5. bacterial colonization and inflammatory factors.

There are several forms of acne, all having in common the involvement of pilosebaceous follicles. These include acne conglobata, keloid acne, drug acne, recurrent acne, acne necrotic, acne neonatorum, premenstrual acne, acne rosacea, senile acne, solar acne, and acne vulgaris.

Acne vulgaris, also called polymorphous juvenile acne, is the most common. It comprises four stages:

Stage 1 corresponds to comedonal acne characterized by a large number of open and / or closed comedones and microcysts.

Stage 2, or papulopustular acne, is of mild to moderate severity. It is characterized by the presence of open and / or closed comedones, microcysts, but also red papules and pustules. It mainly affects the face and leaves few scars. Stage 3, or papulocomedonian acne, is more serious and extends to the back, thorax and shoulders. It is accompanied by a larger number of scars.

Stage 4, or nodulocystic acne, is accompanied by numerous scars. It presents nodules as well as voluminous pustules violaceous and painful.

The different forms of acne described above can be treated with active agents such as anti-seborrhoeic agents and anti-infectious agents, for example benzoyl peroxide (in particular the product Eclaran® marketed by the company Pierre Fabre), with retinoids such as that tretinoin (in particular Retacnyl® product marketed by Galderma) or isotretinoin (Roaccutane® product marketed by Roche Laboratories), or by naphthoic acid derivatives. The naphthoic acid derivatives, such as in particular 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid), commonly known as adapalene (Differine® product marketed by Galderma), are widely described and recognized as active ingredients as effective as tretinoin for the treatment of acne.

Adapalene in particular has a proven efficacy; however, it would be beneficial and useful if its topical tolerance, although superior to that of its competitors in the same chemical class (tretinoin, tazarotene), be improved.

Now, the Applicant has surprisingly found that the combination of adapalene with certain specific anti-irritant compounds can significantly improve the tolerance of this retinoid, and thus overcome the problem of irritation. Indeed, as shown in Example 2, some anti-irritants can reduce the edema caused by adapalene up to 40%. The subject of the present invention is therefore a composition, in particular pharmaceutical, and preferably dermatological, intended in particular for a topical application, comprising, in a physiologically acceptable medium, at least one retinoid compound, preferably chosen from naphthoic acid derivatives of Formula (I) below, their salts and esters, and at least one anti-irritant compound selected from allantoin, EDTA, divalent strontium salts, divalent zinc salts, monovalent sodium salts, and derivatives thereof hydrated. Preferably, said composition does not include any depigmenting agent.

In particular, said composition does not comprise any depigmenting agent distinct from the retinoid compound, in particular adapalene.

By physiologically acceptable medium is meant a medium compatible with the skin, mucous membranes and / or integuments.

The retinoid compound according to the invention may be chosen from retinoic acid while trans (or tretinoin), isotretinoin or even motretinide.

The retinoid compound according to the invention is preferably chosen from the naphthoic acid derivatives of formula (I), their salts and esters:

(I) where R represents a hydrogen atom, a hydroxyl radical, a branched or unbranched alkyl radical having from 1 to 4 carbon atoms, an alkoxy radical having 1 to 10 carbon atoms or a substituted or unsubstituted cycloaliphatic radical.

By linear or branched alkyl radical having from 1 to 4 carbon atoms, is meant preferably the methyl, ethyl, propyl and butyl radicals.

By alkoxy radical having from 1 to 10 carbon atoms is preferably meant methoxy, ethoxy, propoxy, butoxy, hexyloxy and decyloxy radicals.

The term "cycloaliphatic radical" preferably means mono or polycyclic radicals such as the 1-methylcyclohexyl radical or the 1-adamantyl radical.

By salts of naphthoic acid derivatives is meant salts formed with a pharmaceutically acceptable base, in particular a mineral base such as sodium hydroxide, potassium hydroxide and aqueous ammonia or an organic base such as lysine, arginine, N -methyl-glucamine, but also the salts formed with fatty amines such as dioctylamine, aminomethyl propanol and stearylamine.

By esters of naphthoic acid derivatives is meant esters formed with pharmaceutically acceptable alcohols.

Preferably, among the naphthoic acid derivatives which may be used in the compositions according to the invention, 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid (adapalene) will be chosen. , 6- [3- (1-adamantyl) -4-hydroxyphenyl] -2-naphthoic acid, 6- [3- (1-adamantyl) -4-decyloxyphenyl] -2-naphthoic acid or acid 6- [3- (1-adamantyl) -4-hexyloxyphenyl] -2-naphthoic acid.

Even more preferentially, the retinoid compound which can be used according to the invention is chosen from adapalene (6- [3- (1 -adamantyl) -4-methoxyphenyl] -2-naphthoic acid), its salts and its esters.

By adapalene salts is meant in particular salts formed with a pharmaceutically acceptable base, in particular mineral bases such as sodium hydroxide, potash and ammonia or organic bases such as lysine, arginine,

N-methyl-glucamine.

Adapalene salts are also understood to mean salts formed with fatty amines such as dioctylamine, aminomethylpropanol and stearylamine.

Preferably, the retinoid compound is adapalene.

The anti-irritants that can be used according to the present invention are chosen from allantoin, EDTA, divalent strontium salts, divalent zinc salts, monovalent sodium salts, and their hydrated derivatives. The use of these specific anti-irritants reduces the irritation caused by retinoids, including adapalene.

By divalent salts of strontium is meant in particular strontium nitrate, strontium chloride, strontium sulphide, strontium carbonate and strontium bromide. Preferably, the divalent salts of strontium are strontium nitrate and strontium chloride hexahydrate.

By divalent salts of zinc is meant in particular zinc sulphate, zinc chloride, zinc carbonate and zinc citrate. Preferably, the divalent zinc salt is zinc sulfate.

Monovalent sodium salt is preferably sodium cholate.

By hydrated derivatives is meant in particular the anti-irritant compounds mentioned above hydrated by one or more water molecules. Preferably, the hydrated derivatives are strontium chloride hexahydrate or strontium bromide hexahydrate. Preferably, the anti-irritant compounds are selected from strontium nitrate, allantoin, zinc sulfate, sodium cholate, strontium chloride hexahydrate, and EDTA.

Preferably, the anti-irritant is allantoin or strontium nitrate.

In the compositions according to the invention, the concentration of retinoid compound is between 0.001% and 10%, preferably between 0.01% and 5% and, more preferably, between 0.05% and 2% by weight of the total weight of the composition. Throughout this text, unless otherwise specified, it is understood that when concentration ranges are given, they include the upper and lower limits of said range.

Preferably, the retinoid compound concentration is 0.1%. Alternatively, the concentration of retinoid compound is preferably 0.3%.

The concentration of anti-irritant compound is between 0.01% and 10%, preferably between 0.1% and 7%.

The compositions according to the present invention may be in any of the galenical forms normally used for topical application, especially in the form of aqueous, aqueous-alcoholic or oily dispersions, lotion-type dispersions, aqueous, anhydrous or lipophilic gels, liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O), or suspensions or emulsions of soft, semi-liquid or solid consistency cream type, gel-cream, mousse or ointment or microemulsions, micro capsules, micro particles or vesicular dispersions of ionic and / or nonionic type, or in the form of sprays.

Preferably, the compositions are in the form of a gel. Those skilled in the art will take care to choose the excipients constituting the compositions according to the invention as a function of the desired dosage form and so that the advantageous properties of the composition according to the invention are respected.

The composition according to the invention may furthermore in particular comprise one or more of the following ingredients: a) one or more gelling agents or suspending agents, b) one or more chelating agents distinct from EDTA, c) one or more wetting agents , d) one or more preservatives.

By way of non-limiting example of gelling agents or suspending agents that can be used in the compositions according to the invention, mention may be made of the carbomers sold under the generic name of Carbopol®, carbomers known as non-sensitive to electrolytes, sold under the name of Ultrez 10® or Carbopol ETD® by the company BF Goodrich, polysaccharides with, by way of nonlimiting examples, xanthan gum such as Keltrol T® sold by Kelco, guar gum, chitosans, cellulose and its derivatives such as hydroxyethylcellulose, in particular the product sold under the name Natrosol HHX 250® by the company Aqualon, and the copolymer of sodium acrylamide and acrylamino-2-methylpropane sulphonate in a 40% dispersion in isohexadecane and polysorbate 80 sold under the name Simulgel 600® by the company Seppic.

As a preferred gelling agent, mention may be made of hydroxyethylcellulose sold in particular under the name Natrosol HHX 250®.

Among the chelating agents, mention may be made, by way of non-limiting examples, of diethylene triamine pentaacetic acid (DTPA), ethylene diamine di (O-hydroxyphenyl acetic acid) (EDDHA) and hydroxy-2-ethylene acid. triacetic diamine (HEDTA), ethyldiamine-di (O-hydroxy-p-methyl phenyl) acetic acid (EDDHMA) and ethylene diamine-di (5-carboxy-2-hydroxyphenyl) acetic acid (EDDCHA). Among the wetting agents whose function is to reduce the surface tension and to allow a greater spreading of the liquid, it is preferable to use, without this list being limiting, compounds such as propylene glycol, dipropylene glycol and propylene glycol dipelargonate. , lauroglycol and ethoxydiglycol, alone or in admixture. Compounds, also known for their role as emulsifiers, such as the Tween 80, Glyceryl Monostearate & POE Stearate type sold under the name Arlacel 165FL® by the company Uniquema, Polyoxyethylene (21) Stearyl Ether sold under the name Brij721 ® by Uniquema or synperonics with Synperonic PE / L62 (Poloxamer 182) or Synperonic PE / L44 (Poloxamer 124).

As a preferred wetting agent, mention may be made of propylene glycol, Synperonic PE / L62 (Poloxamer 182) or Synperonic PE / L44 (Poloxamer 124).

Among the preserving agents, mention may be made, by way of non-limiting examples, of benzoic acid and its derivatives with benzyl alcohol, benzalkonium chloride, sodium benzoate, bronopol, chlorhexidine, chlorocresol and its derivatives, ethyl alcohol, phenethyl alcohol, phenoxyethanol, potassium sorbate, diazolidinyl urea, parabens such as propyl paraben or methyl paraben, alone or in mixtures.

As a preferred preservative, mention may be made of parabens and phenoxyethanol or benzalkonium chloride alone or as a mixture.

The composition according to the invention may also comprise one or more emulsifiers.

The surfactant emulsifiers are amphiphilic compounds which have a hydrophobic part having an affinity for the oil and a hydrophilic part having an affinity for water thus creating a link between the two phases. Emulsifiers Ionic or nonionic agents thus stabilize the oil / water emulsions by adsorbing at the interface and forming lamellar layers of liquid crystals.

As preferred emulsifiers, mention may be made of the emulsifiers previously mentioned for their wetting agent property or lipophilic emulsifiers of the Glucate SS and Glucamate SSE type.

The compositions of the invention may furthermore comprise any additive usually used in the cosmetic or pharmaceutical field, such as neutralizers, sunscreens, antioxidants, fillers, electrolytes, dyes, conventional or inorganic or organic bases or acids. , perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA, soothing and protective agents for the skin, penetrating agents, or a mixture of these. Of course, those skilled in the art will take care to choose this or these optional additional compounds, and / or their amount, such that the advantageous properties of the composition according to the invention are not, or not substantially impaired.

These additives may be present in the composition in a proportion of 0.001% to 20% by weight relative to the total weight of the composition.

The present invention also relates to the composition as described above as a medicament.

In particular, the invention relates to the use of a composition as described above for the preparation of a medicament for the treatment and / or prevention of dermatological disorders related to a keratinization disorder relating to differentiation. and on cell proliferation, especially to treat vulgar, comedonal, papulopustular, papulocomedonous, nodulocystic acne, conglobata acne, keloid neck acne, relapsing acne acne, necrotic acne, acne neonatorum, occupational acne, rosacea, senile acnes, solar acnes and medicated acnes.

Preferably, the invention relates to the use of a composition as described above for the preparation of a medicament for preventing and / or treating acne vulgaris.

Preferably, said compositions according to the invention are administered topically.

In addition, the invention also relates to the cosmetic use of a composition according to the invention for the treatment of acne-prone skin, to combat the oily appearance of the skin or hair.

The present invention will now be illustrated by means of the following examples, which can not limit the scope of the present invention.

Example 1: Anti-irritant solutions

The anti-irritants used are formulated unless otherwise indicated in an ethanol / water vehicle (50:50) at the concentrations indicated in the table below. The latter also indicates, for each anti-irritant, the group treated in Example 2.

Groups 4 and 6 are used as negative controls in the following studies. Indeed, as shown by the following studies, although known as anti-irritants, the compounds used in these two groups (enoxolone and disodium potassium salt of beta-glycyrrhizic acid) have no effect on the irritation due to retinoids.

EXAMPLE 2 Evaluation of the Effect of Different Anti-Irritants as Preventive Treatment Before Topical Application of Differin® αel in BALB / c Mice: Tolerance Study

The present study aims to compare the irritancy of a reference gel with 0.1% of adapalene when this treatment is preceded or not by treatment with an anti-irritant.

The treatment consists of a daily topical application (20 μl) of anti-irritant formulated in a hydro-alcoholic vehicle (50% ethanol and 50% water by volume) on the inside of the right mouse ear. BALB / c divided into fifteen groups (female mice approximately 9 weeks old), followed by topical application (20 μl) of Differin® gel (0.1% reference gel of adapalene), one application of each formulation per day for 6 days.

The products to be tested are: Group 1: Untreated (controls) Group 2: Differin® gel (reference gel)

Group 3: Ethanol / Water solution (hydro-alcoholic vehicle of anti-irritants) then Différine® gel

Group 4: Enoxolone then Différine® gel Group 5: Zinc sulphate then Différine® gel

Group 6: Disodium potassium salt of beta-glycyrrhizic acid and then Différine® gel Group 7: Sodium chololeate then Différine® gel Group 8: Strontium nitrate then Différine® gel

Group 9: Allantoin then Différine® gel

Group 10: 3.3% Strontium Chloride Hexahydrate and then Differin® Gel

Group 11: 6.6% Strontium Chloride Hexahydrate and then Differin® Gel

Group 12: EDTA at 3% then Différine® gel

Group 13: EDTA at 1% then Différine® gel

The evaluation is done by measurements of the thickness of the ear using the Oditest and by clinical observation of the animals from the 2nd to the 19th day.

The results are shown in the table below and in Figures 1 to 3 where:

- Figure 1 represents the kinetics of the average thickness of the ears of mice between the 2nd and 19th days for groups 1 to 3 (references) and 4 to 6.

These kinetics show that the Differér® gel formulation alone is irritating; adding the hydro-alcoholic vehicle to this formulation does not change the degree of irritation (group 3).

In addition, a decrease in the irritation of the formulation is observed with zinc sulphate. In contrast, enoxolone and potassium disodium salt of beta-glycyrrhizic acid have virtually no effect on the decrease of irritation caused by Differine gel.

FIG. 2 represents the kinetics of the mean thickness of the mouse ears between the 2nd and 19th days for groups 1 to 3 (references) and 7 to 9.

These kinetics show, for group 7, that sodium cholate slightly reduces the irritation due to Différine® gel

Strontium nitrate and allantoin surprisingly decrease the irritation due to Differer® gel, in proportions of 37% and 40%, respectively.

FIG. 3 represents the kinetics of the mean thickness of the mouse ears between the 2nd and 19th days for groups 1 to 3 (references) and 10 to 13. These kinetics, very similar for groups 10 to 13, show that strontium chloride hexahydrate and EDTA reduce the irritation due to Differer® gel by at least 10%.

Table summarizing the results of the areas under the curve (AUC) of the kinetics of ear thicknesses (cf Figure 4 for histograms)

% inhibition t-test

AUC edema D2-D19 AUC P values Student

Mean Sem vs Differin vs Differin

Not treated

Difference 158.6 24.4

Ethanol / water + Differin 147.6 12.8 7.0 0.6989 NS enoxolone + Differin 159.0 23.8 -0.3 0.9909 NS

Zinc Sulfate + Differin 118.1 24.5 25.5 0.2755 NS

Potassium disodium salt of beta-glycyrrhizic acid + Differin 149.7 17.1 5.6 0.7727 NS

Sodium Choleate + Differin 144.1 15.7 9.1 0.6307 NS

Strontium Nitrate + Differin 99.8 26.1 37.1 0.1379 NS Allantoin + Differin 95.2 18.5 40.0 0.0720 NS

Strontium chloride hexahydrate 3.3% + Differin 127.8 24.9 19.4 0.4029 NS

Strontium chloride hexahydrate 6.6% + Differin 125.6 21.6 20.8 0.3407 NS

EDTA 3% + Differin 141, 3 19.0 10.9 0.5909 NS

EDTA 1% + Differin 116.8 26.1 26.4 0.2759 NS

NS≈No Significant

The results of the study show that after repeated topical applications of 20 μl of an anti-irritant solution and then 20 μl Différine® gel from J1 to J6 on the ear of BALB / c mice:

- Differér® gel formulation is irritating;

The anti-irritants tested enoxolone and sodium potassium disodium beta- glycyrrhizic have no effect on the irritation caused by Differin gel;

- The anti-irritants tested zinc sulphate, sodium cholate, strontium chloride hexahydrate and EDTA reduce the edema by 25%, 9%, 20% and 10% respectively; Strontium nitrate and allantoin anti-irritants significantly lessen (at least 37%) the edema.

This example demonstrates that the anti-irritants do not all have the same effect vis-à-vis the edema caused by Differin® gel, and that only zinc sulfate, sodium cholate, hexahydrate chloride strontium, EDTA, strontium nitrate and allantoin are effective in decreasing the irritation due to adapalene.

It should also be noted that no weight loss is noted during the study.

Example 3 Evaluation of the Comedolytic Activity of Differin® Gel Only Compared to Differin® Gel Associated with a Placebo Comprising an Anti-Irritant in the Rhino Mouse

The purpose of this study is to compare the comedolytic activity of Différine® gel (reference gel with 0.1% of adapalene) when this treatment is preceded or not by treatment with an anti-irritant.

The treatment consists of a daily topical application of a hydro-alcoholic vehicle (ethanol / water 50:50) comprising an anti-irritant (strontium nitrate or allantoin), followed 30 minutes later by an application of Différine® gel, on the back of mouse RHINO FVB / N RJ-hr ^rh (Rhino) for 18 days.

The products to be tested are: Group 1: Differin® gel alone

Group 2: Hydro-alcoholic vehicle then placebo Différine® gel Group 3: Hydro-alcoholic vehicle then Différine® gel Group 4: Strontium nitrate and then Différine® gel Group 5: Allantoin then Différine® gel. Figure 5 shows the results of counting the number of comedones per centimeter (cm) on the back of Rhino mice after 18 days of topical treatment for the 5 groups mentioned above.

The results of this study show that skins treated with placebos (group 2) have a high number of comedones per centimeter, ranging between 51 and 60. Skins treated with Differine® gel alone or preceded by a placebo (groups 1 and 3) have a comparable and low number of comedones per centimeter, between 3 and 5.

Skins previously treated with an anti-irritant (allantoin or strontium nitrate) have a statistically lower number of comedones per centimeter than groups 1 and 3 (number of comedones between 1 and 2). However, given the abnormally high comedolytic activity of group 1, this significant difference is not considered biologically relevant.

It thus appears from FIG. 5 that the combination of an allantoin anti-irritant or strontium nitrate with Differin® gel in dissociated treatment does not reduce the comedolytic activity of Differin® gel alone.

Finally, after 18 days of topical treatment, it should be noted that the animals do not show weight loss.

This global study demonstrates that the application of a specific anti-irritant prior to Differér® gel treatment does not decrease the comedolytic activity of adapalene.

Example 4 αel Formulations Comprising Adapalene at 0.1% and Antiirritants

Example 5: Tolerability Study of the Formulations of Example 4

A tolerance study is conducted according to the protocol of Example 2 with the formulations of Example 4. However, it is here, unlike Example 2, an undissociated treatment, since adapalene and the anti-irritant are present in the same formulation.

The results of the areas under the curve (AUC) of ear thickness kinetics between days 2 and 19 are given in the following table:

Conclusions of the study:

Differin® Gel 0.1% increases the area under the curve by 45% compared to the placebo gel.

Anti-irritant formulations increase the area under the curve compared to the placebo gel in the following order: Formula A> Formula B.

Compared to Differin® Gel 0.1%, formula B is less irritating by 20%.

Strontium nitrate (Formula B) appears to be the most effective anti-irritant. These results confirm those of Example 2 in which the anti-irritants were evaluated in dissociated treatment, that is to say before application of Differin® Gel 0.1%.

Allantoin (Formula A) formed in a gel may be of limited effectiveness in reducing the irritation due to adapalene.

Claims

claims

1. A composition comprising, in a physiologically acceptable medium, at least one retinoid compound chosen from all-trans retinoic acid, isotretinoin, motretinide and naphthoic acid derivatives of formula (I), their salts and esters:

where R represents a hydrogen atom, a hydroxyl radical, a branched or unbranched alkyl radical having from 1 to 4 carbon atoms, an alkoxy radical having from 1 to 10 carbon atoms or a substituted or unsubstituted cycloaliphatic radical,

and at least one anti-irritant compound selected from allantoin, divalent strontium salts, divalent zinc salts, monovalent sodium salts, and hydrated derivatives thereof, said composition comprising no depigmenting agent distinct from the retinoid compound.

2. Composition according to claim 1, characterized in that the alkyl radical in formula (I) is methyl, ethyl, propyl or butyl.

3. Composition according to claim 1 or 2, characterized in that the alkoxy radical in the formula (I) is methoxy, ethoxy, propoxy, butoxy, hexyloxy or decyloxy.

4. Composition according to one of claims 1 to 3, characterized in that the cycloaliphatic radical in the formula (I) is 1-methylcyclohexyl radical or 1-adamantyl radical.

5. Composition according to one of claims 1 to 4, characterized in that the retinoid compound is chosen from adapalene, 6- [3- (1-adamantyl) -4-hydroxyphenyl] -2-naphthoic acid, 6- [3- (1-adamantyl) -4-decyloxyphenyl] -2-naphthoic acid and 6- [3- (1-adamantyl) -4-hexyloxyphenyl] -2-naphthoic acid.

6. Composition according to claim 5, characterized in that the retinoid compound is adapalene.

7. Composition according to one of claims 1 to 6, characterized in that the divalent salts of strontium are selected from strontium nitrate, strontium chloride.

8. Composition according to one of claims 1 to 7, characterized in that the hydrated derivatives are selected from strontium chloride hexahydrate and strontium bromide hexahydrate.

9. Composition according to one of claims 1 to 8, characterized in that the anti-irritant compounds are selected from strontium nitrate, allantoin, zinc sulfate, sodium cholate, and chloride hexahydrate strontium.

10. Composition according to one of claims 1 to 9, characterized in that it is topical application.

11. Composition according to one of claims 1 to 10, characterized in that it is in the form of a gel.

12. Composition according to one of claims 1 to 11, characterized in that the concentration of retinoid compound is between 0.001% and 10%, preferably between 0.01% and 5% and, more preferably, between 0.05%. and 2% by weight of the total weight of the composition.

13. Composition according to claim 12, characterized in that the concentration of retinoid compound is equal to 0.1%.

14. Composition according to claim 12, characterized in that the concentration of retinoid compound is equal to 0.3%.

15. Composition according to one of claims 1 to 14, characterized in that the concentration of anti-irritant compound is between 0.01% and 10%, preferably between 0.1% and 7%.

16. A composition according to any one of the preceding claims as a medicament.

17. Use of a composition according to one of claims 1 to 15 for the preparation of a medicament for the treatment and / or prevention of dermatological disorders related to a disorder of keratinization on differentiation and proliferation cell especially to treat acne vulgaris, comedoniennes, papulopustuleuse, papulocomédoniennes, nodulocystic, acnes conglobata, keloid acne necrosis, recurrent miliatic acne, necrotic acne, neonatorum acne, occupational acne, rosacea, senile acne, solar acne and medicinal acne.

18. Use of a composition according to one of claims 1 to 15 for the preparation of a pharmaceutical composition for preventing and / or treating acne vulgaris.

19. Cosmetic use of a composition according to any one of claims 1 to 15 for the treatment of acne-prone skin or to combat the oily appearance of the skin or hair.