(12) Patent Application Publication (10) Pub. No.: US 2010/0160439 A1 MALLARD (43) Pub

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US 2010.0160439A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0160439 A1 MALLARD (43) Pub. Date: Jun. 24, 2010

(54) DERMATOLOGICAL COMPOSITIONS A6IP 7/2 (2006.01) COMPRISING AT LEAST ONE RETNOID A61O 19/00 (2006.01) COMPOUND, AN ANTI-IRRITANT (52) U.S. Cl...... 514/569 COMPOUND AND BENZOYL PEROXDE (57) ABSTRACT (75) Inventor: Claire MALLARD, Mougins (FR) Dermatological compositions contain, formulated into a Correspondence Address: physiologically acceptable medium, at least one retinoid BUCHANAN, INGERSOLL & ROONEY PC compound selected from among all-trans retinoic acid, isotre POST OFFICE BOX 1404 tinoin, motretinide, and naphthoic acid compounds of for ALEXANDRIA, VA 22313-1404 (US) mula (I), and salts and esters thereof: (73) Assignee: GALDERMARESEARCH & (I) DEVELOPMENT, BIOT (FR) O (21) Appl. No.: 12/635,866 (22) Filed: Dec. 11, 2009 CO OH Related U.S. Application Data (63) Continuation of application No. PCT/EP08/05731, R filed on Jun. 11, 2008. (60) Provisional application No. 60/929.205, filed on Jun. 18, 2007. (30) Foreign Application Priority Data 19 Jun. 11, 2007 (FR) ...... O755658 wherein R is a hydrogenatom, a hydroxyl radical, a branched or unbranched alkyl radical having from 1 to 4 carbon atoms, Publication Classification an alkoxy radical having from 1 to 10 carbon atoms, or a (51) Int. Cl. cycloaliphatic radical which is substituted or unsubstituted, A6 IK3I/92 (2006.01) and benzoyl peroxide, and also at least one anti-irritant com A6 IK 8/368 (2006.01) pound selected from among 183-glycyrrhetinic acid, and its A6IP 7/10 (2006.01) salts and derivatives thereof. US 2010/0160439 A1 Jun. 24, 2010

DERMATOLOGICAL COMPOSITIONS the product Eclaran R) marketed by Pierre Fabre), with retin COMPRISING AT LEAST ONE RETNOD oids such as tretinoin (in particular, the product Retacnyl(R) COMPOUND, AN ANTI-IRRITANT marketed by Galderma) or isotretinoin (the product Roaccu COMPOUND AND BENZOYL PEROXDE tane(R) marketed by Laboratories Roche), or else with naph thoic acid derivatives. Naphthoic acid derivatives such as, in CROSS-REFERENCE TO particular, 6-3-(1-adamantyl)-4-methoxyphenyl-2-naph PRIORITYAPROVISIONAL APPLICATIONS thoic acid, which is commonly called adapalene (the product 0001. This application claims priority under 35 U.S.C. Differine(R) marketed by Galderma), are widely described and S119 of FR 0755658, filed Jun. 11, 2007, S120 of U.S. Pro recognized as active ingredients that are just as effective as visional Application No. 60/929.205, filed Jun. 18, 2007, and tretinoin for the treatment of acne. is a continuation/national phase of PCT/EP 2008/057310, 0018. However, to increase the effectiveness of treat filed Jun. 11, 2008 and designating the United States (pub ments, especially treatments for dermatological disorders, lished in the English language on Dec. 18, 2008 as WO and in particular, for acne, and to reduce the toxicity of the 2008/152064 A1), each hereby expressly incorporated by active ingredients (Cunliffe W. J. J. Dermatol. Treat., 2000, reference in its entirety and each assigned to the assignee 1I (suppl2), S13-S14), several categories of active ingredients hereof. are commonly administered. 0019. An article by Korkut and Piskin, J. Dermatology, 2005, 32: 169-173, reports the results of a study comparing a BACKGROUND OF THE INVENTION treatment combining application of adapalene in the evening 0002. 2. Technical Field of the Invention and application of BPO in the morning, relative to an appli 0003. The present invention relates to compositions for cation of each of the active principles alone. The authors do topical application, and to the administration thereofas cos not observe any superiority of the combined treatment over a metic or pharmaceutical products, said compositions being period of 11 weeks of treatment. useful in the treatment of dermatological disorders, and in 0020 Since the multiple application of various dermato particular, in the treatment of acne. logical products is quite laborious and demanding for the 0004 2. Description of Background and/or Related and/or patient, the value of a novel treatment which is effective on Prior Art dermatological conditions, in particular, acne, in a stable 0005 Acne is a common multi-factor pathology that composition which offers good cosmeticity, which signifi attacks skin rich in sebaceous glands (face, shoulder area, cantly improves tolerance and which makes it possible to arms and intertriginal areas). It is the most commonly occur increase patient compliance, is therefore apparent. ring form of dermatosis. The following five pathogenic fac 0021 Combinations of active agents are now beginning to tors play a determining role in the formation of acne: appear. Exemplary is the DUAC combination comprising 0006 1. genetic predisposition; clindamycin and benzoyl peroxide or combinations of anti 0007 2. Overproduction of sebum (seborrhea); biotics. Among these, also exemplary is a gel comprising at 0008. 3. androgens; least one retinoid and benzoyl peroxide as described in WO 0009 4. follicular keratinization disorders (comedogen O3/55472. esis); and 0022. However, the formulation of such a composition 0010) 5. bacterial colonization and inflammatory factors. comprising several active agents, including benzoyl peroX 0011. There are several forms of acne, the common factor ide, presents several problems. of all being attack of the pilosebaceous follicles. Exemplary 0023 First, the effectiveness of the benzoyl peroxide is are in particular, of acne conglobata, cheloid acne of the nape linked to its decomposition when it is brought into contact of the neck, acne medicamentosa, recurrent miliary acne, with the skin. It is the oxidizing properties of the free radicals necrotic acne, neonatal acne, premenstrual acne, occupa produced during this decomposition which produces the tional acne, acne rosacea, senile acne, Solar acne and common desired effect. Thus, to maintain optimum effectiveness for aCC. the benzoyl peroxide, it is important to prevent its decompo 0012 Common acne, also known as polymorphic juvenile sition before use, i.e., during storage. acne, is the most common. It comprises four stages: 0024 Now, benzoyl peroxide is a chemical compound that 0013 stage 1 corresponds to comedonic acne character is unstable, which makes it difficult to formulate in finished ized by a large number of open and/or closed comedones and products. of microcysts; 0025. The solubility and the stability of benzoyl peroxide 0014 stage 2, or papulopustular acne, is of mild to mod have been studied in ethanol, propylene glycol and various erate seriousness. It is characterized by the presence of open mixtures of polyethylene glycol 400 (PEG 400) and water and/or closed comedones, of microcysts, but also of red pap (Chellquist E. M. and Gorman W. G., Pharm. Res., 1992, Vol. ules and pustules. It mainly affects the face and leaves few 9: 1341-1346). The authors thus note that benzoyl peroxide in SCarS. Solution degrades more or less rapidly in all the solvents 0.015 stage 3, or papulocomedonic acne, is more serious studied, depending on the type of solvent and on its concen and extends to the back, the chest and the shoulders. It is tration. accompanied by a large number of Scars; 0026. The benzoyl peroxide degradation times observed 0016 stage 4, or nodulocystic acne, is accompanied by are so short that they do not make it possible to formulate a numerous Scars. It exhibits nodules and also painful Volumi product that is intended to be marketed. nous crimson pustules. 0027. It is known, moreover, that benzoyl peroxide is more 0017. The various forms of acne described above can be stable in water and in propylene glycol when it is in Suspen treated with active agents such as anti-seborrheic agents and sion (i.e., in disperse form), since it is not degraded after 90 anti-infectives, for example, benzoyl peroxide (in particular, days of storage in these solvents. US 2010/0160439 A1 Jun. 24, 2010

0028. Thus, to limit the problem of rapid instability of benzoyl peroxide in solution, it has been found to be advan tageous to formulate benzoyl peroxide in dispersed form. (I) 0029. Another difficulty to be overcome in the formulation of a composition comprising both a retinoid, an anti-irritant and benzoyl peroxide is that most retinoids are particularly OH sensitive to natural oxidation, to visible light and to ultraviolet radiation. Since benzoyl peroxide is a strong oxidizing agent, the chemical compatibility of these compounds in the same formulation presents many problems of stability from the physical and chemical point of view. 0030. In addition, it has been reported that benzoyl perox ide can sometimes induce dryness of the skin and on certain occasions irritation of the skin. 0031. Among the retinoids commonly employed, ada palene in particular, exhibits a unanimously proven effective ness. However, it would be advantageous and useful to reduce the irritation caused by retinoids applied topically, including wherein R is a hydrogenatom, a hydroxyl radical, a branched adapalene, although its tolerance is greater than that of its or unbranched alkyl radical having from 1 to 4 carbon atoms, competitors belonging to the same chemical category (tretin an alkoxy radical having from 1 to 10 carbon atoms or a oin, tazarotene). cycloaliphatic radical which is substituted or unsubstituted, at 0032. The term “irritation” means, in particular, the symp least one anti-irritant compound selected from among 186 toms or the conditions linked to the application to the skin of glycyrrhetinic acid (enoXolone), its salts and its derivatives, chemical products of natural or synthetic origin, used in cos and benzoyl peroxide. metics or dermatology, and which can be characterized in particular, by an inflammation, an erythema, an oedema, red DETAILED DESCRIPTION OF BEST MODE ness, itching, pain, burning, a sting, or else tingling. AND SPECIFICAPREFERRED EMBODIMENTS OF THE INVENTION SUMMARY OF THE INVENTION 0038. In one particular embodiment of the invention, the retinoid compound is a naphthoic acid compound of formula 0033. The present invention solves the above problems by (I), and salts and esters thereof. providing stable topical compositions that are barely irritant 0039. In a specific embodiment, the naphtoic acid of for or not at all, comprising, in a pharmaceutically acceptable mula (I) is such that the alkyl radical is the methyl, ethyl, medium, a retinoid, benzoyl peroxide and an anti-irritant, propyl or butyl radical; the alkoxy radical is the methoxy, useful for the treatment of dermatological disorders, and in ethoxy, propoxy, butoxy, hexyloxy or decyloxy radical; and particular, for the treatment of acne. the cycloaliphatic radical is the 1-methylcyclohexyl radical or 0034. The presence of an anti-irritant makes it possible to the 1-adamantyl radical. significantly improve the tolerance of the Subject composi 0040. In a preferred embodiment, the retinoid compound tions comprising a retinoid and benzoyl peroxide, and there is selected from among 6-3-(1-adamantyl)-4-methoxyphe fore to overcome the problem of irritation. Advantageously, nyl-2-naphthoic acid (adapalene), 6-3-(1-adamantyl)-4-hy Such compositions according to the invention make it pos droxyphenyl-2-naphthoic acid, 6-3-(1-adamantyl)-4-decy sible to increase the concentrations of the active ingredients loxyphenyl-2-naphthoic acid and 6-3-(1-adamantyl)-4- while at the same time limiting their side effects. In addition, hexyloxyphenyl-2-naphthoic acid and salts and esters when said compositions are in the form of a gel, a cream-gel thereof. More preferably, the retinoid compound is 6-3-(1- or an emulsion, same provide emollience and avoids in par adamantyl)-4-methoxyphenyl-2-naphthoic acid (adapalene) ticular, leaving too greasy a feel on the skin. and salts and esters thereof. 0035. In addition, the pharmaceutical or cosmetic compo 0041. In a specific embodiment, the concentration of ret sitions according to the invention conserve, throughout their inoid compound ranges from 0.001% to 10%, preferentially shelf life, precise physicochemical criteria for guaranteeing from 0.01% to 5%, preferably from 0.01% to 1%, more pref their pharmaceutical or cosmetic quality. Among these crite erentially from 0.01% to 0.5%, and preferentially still from ria, it is necessary for the rheological properties to be con 0.1% to 0.3% by weight of the total weight of the composi served. These rheological properties define the behavior and tion. More preferred, the concentration of retinoid compound the texture of the composition during application, but also the is equal to 0.1% or equal to 0.3%. properties of release of the active ingredients. 0042. In a preferred embodiment of invention, the anti 0036. Thus, novel compositions have now been developed irritant compound is selected from among the potassium salt which meet the above needs, while at the same time overcom of 18f3-glycyrrhetinic acid, the sodium salt of 18f3-glycyrrhe ing the problem of irritation. tinic acid, the monoammonium salt of 183-glycyrrhetinic 0037. The present invention thus features compositions acid, the disodium Succinate salt of 183-glycyrrhetinic acid, comprising, formulated into a physiologically acceptable the dipotassium salt of 18f3-glycyrrhetinic acid and the medium, at least one retinoid compound selected from among monoester of 183-glycyrrhetinic acid. all-trans retinoic acid, isotretinoin, motretinide, and naph 0043 Preferably, the concentration of anti-irritant com thoic acid compounds of formula (I), and salts and esters pound ranges from 0.01% to 10%, preferentially from 0.1% thereof: to 7%. US 2010/0160439 A1 Jun. 24, 2010

0044. In a specific embodiment of the invention, the ben 0.052 Herein unless otherwise specified, it is understood Zoyl peroxide is in dispersed form in the composition. Alter that, when concentration ranges are given, they include the natively, the benzoyl peroxide is in encapsulated or free form. upper and lower limits of said range. Similarly, unless other Preferably, the composition comprises from 0.0001% to 20% wise indicated, the proportions of the various constituents of of benzoyl peroxide, preferentially from 0.025% to 10%, the composition are expressed as percentage by weight (m/m) even more preferentially from 2.5% to 5%. of the total weight of said composition. 0045. The compositions are for topical application. Pref 0053 According to the invention, the subject composi erably, the composition is in the form of aqueous, aqueous tions comprise, in a physiologically acceptable medium, at alcoholic or oily dispersions, dispersions of the lotion type, least one compound of retinoid type, at least one anti-irritant aqueous, anhydrous or lipophilic gels, emulsions of liquid or compound and benzoyl peroxide. semi-liquid consistency of the milk type, obtained by disper 0054 The term “physiologically acceptable medium’ sion of a fatty phase in an aqueous phase (O/W) or vice versa means a medium compatible with the skin, the mucous mem (W/O), or Suspensions or emulsions of soft, semi-liquid or branes and/or the appendages. Solid consistency of the cream, gel, cream-gel, foam or oint 0055. The retinoid compound according to the invention ment type, or microemulsions, microcapsules, microparticles may be selected from among all-trans retinoic acid (or tret or vesicular dispersions of ionic and/or nonionic type, in the inoin), isotretinoin or else motretinide. form of sprays, or else in the form of dermal devices Such as 0056. The retinoid compound according to the invention is patches. preferably selected from among naphthoic acid derivatives of 0046 More preferably, the composition is in the form of a formula (I), and salts and esters thereof: gel, a cream-gel or an emulsion. 0047 Most preferred, said composition is a medicament. 0048. The present invention also features administration, (I) whether regime or regimen of at least one retinoid compound, benzoyl peroxide and at least one anti-irritant compound selected from among 183-glycyrrhetinic acid (enoXolone), its OH salts and its derivatives, or composition comprised thereof for the treatment and/or prevention of dermatological conditions linked to a keratinization disorder relating to cell differentia tion and proliferation, in particular, for treating common acne, comedonic acne, papulopustular acne, papulocome donic acne, nodulocystic acne, acne conglobata, cheloid acne of the nape of the neck, recurrent miliary acne, necrotic acne, neonatal acne, occupational acne, acne rosacea, senile acne, Solar acne and acne medicamentosa. Preferably, the Subject pharmaceutical compositions are useful for preventing, inhibiting or treating common acne. 0049. The present invention also features a method for wherein R is a hydrogenatom, a hydroxyl radical, a branched formulating a Subject composition by mixing at least one or unbranched alkyl radical having from 1 to 4 carbon atoms, retinoid compound with benzoyl peroxide and with at least an alkoxy radical having from 1 to 10 carbon atoms, or a one anti-irritant compound and in particular, in the form of a cycloaliphatic radical which is substituted or unsubstituted. gel, and also a method for preparing a composition in the form 0057 The expression “linear or branched alkyl radical of a cream-geland/or a method for preparing a composition in having from 1 to 4 carbon atoms” means, preferably, methyl, the form of an emulsion. ethyl, propyl and butyl radicals. 0050. This invention also provides a regime or regimen for 0058. The expression “alkoxy radical having from 1 to 10 treating and/or preventing and/or inhibiting dermatological carbonatoms” means, preferably, methoxy, ethoxy, propoxy, conditions linked to a keratinization disorder relating to cell butoxy, hexyloxy and decyloxy radicals. differentiation and proliferation, in particular, for treating 0059. The term “cycloaliphatic radical means, prefer common acne, comedonic acne, papulopustular acne, papu ably, monocyclic or polycyclic radicals, such as the 1-meth locomedonic acne, nodulocystic acne, acne conglobata, che ylcyclohexyl radical or the 1-adamantyl radical. loid acne of the nape and/or the neck, recurrent miliary acne, 0060. The term "salts of the naphthoic acid derivatives' necrotic acne, neonatal acne, occupational acne, acne rosa means salts formed with a pharmaceutically acceptable base, cea, senile acne, Solar acne and acne medicamentosa, com in particular, an inorganic base Such as sodium hydroxide, prising administering to an individual in need thereof, a thera potassium hydroxide oraqueous ammonia, oran organic base peutical effective amount of composition defined previously. Such as lysine, arginine or N-methylglucamine, but also the 0051 Finally, the present invention features a non-thera salts formed with fatty amines such as dioctylamine, ami peutic cosmetic treatment process for embellishing the skin nomethyl propanol and Stearylamine. or its surface appearance, in which a composition comprising, 0061 The term “esters of the naphthoic acid derivatives' formulated into a physiologically acceptable medium, a ret means esters formed with pharmaceutically acceptable alco inoid, an anti-irritant selected from among 183-glycyrrhe hols. tinic acid (enoXolone), its salts and its derivatives and benzoyl 0062 Preferably, among the naphthoic acid derivatives peroxide is topically applied to the skin and/or its integument that may comprise the compositions according to the inven annexes. In a preferred embodiment, the treatment of skin is tion, 6-3-(1-adamantyl)-4-methoxyphenyl-2-naphthoic for skin with an acneic tendency or for combating the greasy acid (adapalene), 6-3-(1-adamantyl)-4-hydroxyphenyl-2- appearance of the skin or the hair. naphthoic acid, 6-3-(1-adamantyl)-4-decyloxyphenyl-2- US 2010/0160439 A1 Jun. 24, 2010 naphthoic acid or 6-3-(1-adamantyl)-4-hexyloxyphenyl-2- 0078. The expression "derivatives of the 18 B-glycyrrhe naphthoic acid will be selected. tinic acid salts' means, in particular, the monoester of 18B 0063 Even more preferably, the retinoid compound that glycyrrhetinic acid. can be administered according to the invention is selected 0079 Preferably, the anti-irritant is the potassium salt of from among adapalene (6-3-(1-adamantyl)-4-methoxyphe 18B-glycyrrhetinic acid. nyl-2-naphthoic acid), salts thereof and esters thereof. 0080. The anti-irritant according to the invention may be 0064. The term “adapalene salts' means, in particular, the of natural or synthetic origin. salts formed with a pharmaceutically acceptable base, in par I0081. The term “natural origin” means an anti-irritant in ticular, inorganic bases such as sodium hydroxide, potassium the pure state or in solution irrespective of its concentration in hydroxide or aqueous ammonia, or organic bases such as said solution, obtained, by various methods, from a natural lysine, arginine or N-methylglucamine. element. 0065. The term “adapalene salts' also means the salts I0082. The term “synthetic origin” means an anti-irritant in formed with fatty amines such as dioctylamine, aminomethyl the pure state or in Solution, irrespective of its concentration propanol and Stearylamine. in said solution, obtained by chemical synthesis. I0083. The concentration of anti-irritant compound 0066 Preferably, the retinoid compound according to the according to the invention is, for its part, from 0.01% to 10%, invention is adapalene. preferentially from 0.1% to 7%. 0067. Advantageously, the compositions according to the I0084. The composition according to the invention also invention do not comprise any depigmenting agent distinct comprises benzoyl peroxide. from the retinoid compound, in particular, adapalene. I0085 Preferably, the benzoyl peroxide according to the 0068 According to a specific embodiment of the inven invention is in dispersed form. tion, the adapalene is in dispersed form in the composition. I0086. The benzoyl peroxide that can be formulated 0069. In the compositions according to the invention, the according to the invention can equally be used in free form or concentration of retinoid compound ranges from 0.0001% to else in an encapsulated form, for example, in a form adsorbed 10%, in particular, from 0.01% to 5%, preferably from 0.01% onto, or absorbed into, any porous Support. It may, for to 1%, more preferentially from 0.01% to 0.5%, and prefer example, be benzoyl peroxide encapsulated in a polymeric entially from 0.1% to 0.3% by weight of the total weight of system consisting of porous microspheres, for instance the composition. microSponges marketed under the trademark MicroSponges 0070. Even more preferentially, the concentration of ret P009A Benzoyl PeroxideTM by Amcol. inoid compound is equal to 0.1%. Alternatively, the concen I0087 Advantageously, the particle size of the benzoyl tration of retinoid compound is preferably equal to 0.3%. peroxide is such that at least 80% by number of the particles, 0071. According to the invention, the term “anti-irritant” preferably at least 90% by number of the particles, have a means an active agent that modulates the manifestations of diameter of less than 25um and at least 99% by number of the sensitive skin, i.e., the manifestations of skin irritation, Such particles have a diameter of less than 100 um. as stinging, tight skin, burning sensation and redness. I0088. The concentration of benzoyl peroxide in the com 0072 The expression “sensitive skin' covers both irritable positions according to the invention ranges from 0.0001% to and/or reactive skin and intolerant skin. 20%, preferentially from 0.025% to 10%, even more prefer 0073. Irritable and/or reactive skin is skin which reacts entially from 0.5% to 5% to more preferred 2.5% to 5%. through pruritis, i.e., through itching or through stinging, to I0089. The composition according to the invention may various factors such as the environment, emotions, foods, also, in particular, comprise at least one propenetrating agent. wind, friction, shaving, Soap, Surfactants, hard water with a 0090 The concentration of propenetrating agents in the high calcium content, temperature variations or wool. Ingen compositions according to the invention ranges from eral, these signs are associated with dry skin with or without OOOO1% to 20%. dry patches, or with skin that exhibits erythema. 0091. The propenetrating agents should generally not solubilize the active agents at the percentage used, not cause 0074 Intolerant skin is skin which reacts through sensa exothermic reactions harmful to the benzoyl peroxide, aid tions of burning, tightening, stinging and/or redness, to Vari good dispersion of the active agents and have anti-foam prop ous factors such as the environment, emotions, foods and erties. certain cosmetic products. In general, these signs are associ 0092. The compositions according to the invention may ated with hyperseborrheic or acneic skin with or without dry also, in particular, comprise at least one pH-independent gel patches and associated with erythema. ling agent. 0075. The use of these specific anti-irritants makes it pos 0093. The term “pH-independent gelling agent’ means a sible to reduce the irritation caused by the active ingredients, gelling agent capable of conferring a Sufficient viscosity on in particular, the retinoids. the composition so as to maintain both the retinoid, the anti 0076. The anti-irritants that can be formulated according irritant and the benzoyl peroxide in Suspension, even under to the present invention are selected from among 183-glycyr the influence of a variation in pH due to the release of benzoic rhetinic acid (enoXolone), its salts and its derivatives. acid by the benzoyl peroxide. The gelling agent according to 0077. The term “18B-glycyrrhetinic acid salts' means, in the invention also has good physical stability, i.e., no decrease particular, the potassium salt of 183-glycyrrhetinic acid, the in viscosity is observed over time at temperatures from 4 to sodium salt of 18 B-glycyrrhetinic acid, the zinc salt of 18B 40° C., maintaining good chemical stability of the active glycyrrhetinic acid, the monoammonium salt of 183-glycyr agents, i.e., no degradation of the active agents is observed rhetinic acid (ammonium glycyrrhetinate), the disodium suc over time and attemperatures from 4 to 40°C. cinate salt of 183-glycyrrhetinic acid, or else the dipotassium 0094. Non-limiting examples of gelling agents and/or Sus salt of 18 B-glycyrrhetinic acid. pending agents and/or pH-independent agents that comprise US 2010/0160439 A1 Jun. 24, 2010 the compositions according to the invention include microc iting, of compounds Such as those of the poloxamers and/or rystalline cellulose et sodium carboxymethyl cellulose (such glycols families and more particularly Synperonic PE/L44 as this marketed as Avicel CL-611 or RC/CL by FMC and/or Symperonic PE/L62 and/or compounds such as propy Biopolymer), the “electrolyte-insensitive' carbomers mar lene glycol, dipropylene glycol, propylene glycol dipelargo keted under the trademark Ultrez 20TM, Carbopol 1382TM, nate, lauroglycol, ethoxydiglycol. Pemulen TR1, Pemulen TR2 or Carbopol ETD2020TM by 0101 By way of preferred wetting agents, exemplary are Noveon; polysaccharides, non-limiting examples of which propylene glycol or symperonic PE/L44 (Poloxamer 124TM). include xanthan gum, such as Xantural 180TM marketed by 0102 The concentration of wetting agents in the compo Kelco, guar gum, chitosans, carrageenans, cellulose and its sitions according to the invention ranges from 0.0001% to derivatives such as hydroxypropylmethylcellulose, in par 20%, preferentially from 0.1% to 10% to more preferably ticular, the product marketed under the trademark Methocel from 2 and 7% in weight with regards to the total composition E4 PremiumTM by Dow Chemical or hydroxyethylcellulose, weight. in particular, the product marketed under the trademark 0103) The compositions according to the invention may Natrosol HHX 250TM by Aqualon, the family of magnesium also in particular, comprise at least one emulsifier. aluminum silicates such as Veegum KTM marketed by Vander 0104 Preferably, the emulsifier used is different from the bilt, the family of carrageenans in particular, those in the four Wetting agents. following subfamilies: k, ), B, () such as Viscarin R) or Gel 0105. The term "emulsifiers’ means amphiphilic com carins(R) marketed by IMCD, the family of acrylic polymers pounds having a hydrophobic part which has an affinity for oil coupled to hydrophobic chains, such as the PEG-150/decyl/ and a hydrophilic part which has an affinity for water, thus SMDI copolymer marketed under the trademark Aculyn 44TM creating a link from the two phases. Ionic or nonionic emul (polycondensate comprising at least, as elements, a polyeth sifiers thereforestabilize emulsions (O/W) by adsorbing them ylene glycol comprising 150 or 180 mol of ethylene oxide, into one another at the interface and forming lamellar layers decyl alcohol and methylenebis(4-cyclohexylisocyanate) of liquid crystals. (SMDI), at 35% by weight in a mixture of propylene glycol 0106 The emulsifying capacity of nonionic emulsifiers is (39%) and water (26%)), the family of modified starches such closely linked to the polarity of the molecule. This polarity is as the modified potato starch marketed under the trademark defined by the HLB (hydrophilic/lipophilic balance). Structure SolanaceTM, or else mixtures thereof, and the gel 0107. A high HLB indicates that the hydrophilic fraction ling agents of the polyacrylamide family, Such as the Sodium is predominant and, conversely, a low HLB indicates that the acryloyldimethyltaurate copolymer/isohexadecane/polysor lipophilic part is predominant. For example, HLB values of bate 80 mixture marketed under the trademark Simulgel greater than approximately 10 correspond to hydrophilic Sur 600PHATM by Seppic, or the polyacrylamidefisoparaffin factants. C13-14/laureth-7 mixture such as, for example, that marketed 0108. The emulsifiers may be categorized, according to under the trademark Sepigel 305TM by Seppic. their structure, under the generic terms “ionic' (anionic, cat 0095. The preferred gelling agents are derived from the ionic, amphoteric) or “nonionic'. The nonionic emulsifiers polyacrylamide family, such as Simulgel 600PHATM or Sepi are emulsifiers which do not dissociate to ions in water and gel 305TM; “electrolyte-insensitive' carbomers such as Car are therefore insensitive to variations in pH. bopol 1382TM; polysaccharides such as xanthan gum; cellu 0109 The nonionic emulsifiers are particularly suitable lose derivatives such as hydroxypropylmethylcellulose or for the preparation of oil-in-water type emulsions. Thus, the hydroxyethylcellulose; and magnesium aluminum silicates, emulsifying system comprises at least one nonionic emulsi alone or as a mixture. fier, with a predominant hydrophilic fraction, i.e., having a 0096. The pH-independent gelling agent as described high HLB, of greater than approximately 10. above can be included at the preferential concentrations rang 0110. Non-limiting examples of nonionic emulsifiers hav ing from 0.001% to 15% to more preferentially from 0.15% to ing a high HLB, sorbitan esters such as the POE (20) sorbitan 5%. monooleate marketed under the trademark Tween 80TM 0097. The compositions according to the invention may (HLB=15), or the POE (20) sorbitan monostearate marketed also, in particular, comprise at least one wetting agent. under the trademark Tween 60TM (HLB=14.9), fatty alcohol 0098. The wetting capacity is the tendency of a liquid to ethers such as the POE (21) stearyl ether (HLB=15.5), or the spread out over a surface. ceteareth 20 marketed under the trademark Eumulgin B2TM 0099 Preferably, they are wetting agents which have an by Cognis (HLB of 15.5) polyoxyethylene glycol esters such HLB (hydrophilic/lipophilic balance) of 7 to 18, or nonionic as glyceryl Stearate and PEG 100 stearate marketed under the wetting agents of polyoxyethylenated and/or polyoxypropy trademark Arlacel 165 FL(R) (HLB=11) by Uniqema, PEG 6 lenated copolymer type. Non-limiting examples of wetting Stearate and PEG 32 stearate marketed under the trademark agents include Poloxamers and more particularly the product TEFOSE 1500 (HLB=10) by Gatefossé, sucroesters with as known as Symperonic PE/L44 (Polyethylene-polypropy high HLB such as PEG 20 methyl glucose sesquistearate lene glycol; Polyoxyethylene-Polyoxypropylene Block marketed under the trademark glucamate SSE20 (HLB=15) Copolymer) and/or Symperonic PE/L62 marketed by by Amerchol and sucrose laurate marketed under the trade Uniqema, glycols such as those known as propylene glycol, mark Surfhope C-1216(R) (HLB=16) and sucrose stearate dipropylene glycol, lauroglycol, propylene glycol dipelargo marketed under the trademark Surfhope C-1811(R) (HLB=11) nate, ethoxydiglycol. They should be liquid so as to incorpo by Gattefossé. rate readily into the composition without it being necessary to 0111 Preferably, said nonionic emulsifiers with a high heat it. HLB have an HLB of from 10 and 18. 0100 Among the wetting agents whose role it is to reduce 0112 Examples of nonionic emulsifiers with a low HLB the Surface tension and to allow greater spreading of the (lipophilic) are Sorbitan esters such as Sorbitan monostearate liquid, use is preferentially made, without this list being lim (HLB-47) (marketed under the trademark Span 60TM by US 2010/0160439 A1 Jun. 24, 2010

Uniqema company), glycerol esters such as glycerol I0123. By way of preferred preservative, exemplary are monostearate (marketed under the trademark Cutina GMS parabens and phenoxyethanol or benzalkonium chloride, VPHTM by Cognis company) such as glyceryl monostearate taken alone or as a mixture. (Cutina GMSTM (HLB-3.8) from Cognis company), polyeth 0.124. The compositions of the invention may also, in par ylene glycol esters such as PEG-6 isostearate marketed with the trademark Olépal isostearic (HLB=8) by Gattefossé, ticular, comprise any additive normally used in the cosmetics sucroesters with low HLB such as methyl glucose ses or pharmaceutical field, such as neutralizers or pH adjusters quistearate marketed under the trademark Glucate SS Such as well known mineral or organic bases or acids, such as (HLB-6) by Amerchol and sucrose dilaurate marketed under example triethanolamine, NaOH 10% solution, sodium suc the trademark Surfhope C-1205 (HLB-5) and sucrose cinic acid/succinate buffer, sodium citric acid/citrate buffer, tristearate marketed under the trademark Surfhope C-1803 humectants and/or emollients, Sunscreens, antioxidants, fill (HLB-3) by Gattefossé. ers, electrolytes, dyes, customary inorganic or organic bases 0113 Preferably, said nonionic emulsifiers with a low or acids, fragrances, essential oils, active cosmetic agents, HLB have an HLB of less than 10. moisturizers, vitamins, essential fatty acids, sphingolipids, 0114. The nonionic emulsifiers may be used alone or as a self-tanning compounds Such as DHA, and agents for calm mixture of two or more of them so as to form the emulsifying ing and protecting the skin optionally one stabilizer of ben system. Zoyl peroxide (Such as non-limited example sodium docusate, 0115 Preferably, one or more “nonionic emulsifier with a sodium C14-16 olefin sulfonate). high HLB/“nonionic emulsifier with a low HLB' pairs will 0.125. Of course, one skilled in the art will take care to be used as emulsifying system; it may in particular, be a select this or these possible additional compound(s), and/or nonionic emulsifying system comprising at least one non the amount thereof, in Such a way that the advantageous ionic emulsifier having an HLB of greater than approximately properties of the composition according to the invention are 10 and at least one nonionic Surfactant having an HLB of less not, or not substantially, impaired. than approximately 10. 0116. The ratio of each of the two emulsifiers forming the 0.126 The concentrations of said additives of the compo abovementioned pair is most commonly determined by cal sition are from 0.001% to 20% by weight, relative to the total culating the required HLB of the fatty phase used. weight of the composition. 0117. By way of preferred emulsifiers, exemplary are I0127. The compositions according to the present inven hydrophilic emulsifiers of the type glyceryl Stearate & PEG tion may be in any of the galenical forms normally employed 100 Stearate marketed under the trademark Arlacel 165FLTM for topical application, in particular, in the form of aqueous, by Uniqema; the PEG 6 stearate and PEG 32 stearate mar aqueous-alcoholic or oily dispersions, dispersions of the keted under the trademark Tefose 1500TM by Gattefosse, lipo lotion type, aqueous, anhydrous or lipophilic gels, emulsions philic emulsifiers of Sucrose ester type, such as the glucate of liquid consistency (in particular, compatible with a presen SSTM (methyl glucose sesquistearate) and glucamate SSE tation form of impregnated wipe type) or semi-liquid consis 20TM (PEG 20 methyl glucose sesquistearate) marketed by tency of the milk type, obtained by dispersion of a fatty phase Amerchol, the polyoxyethylene (21) stearyl ether marketed in an aqueous phase, oil-in-water (O/W), or vice versa water under the trademark Brij721TM by Uniqema, and the ceteareth in-oil (W/O), or Suspensions or emulsions of soft, semi-liquid 20 marketed under the trademark Eumulgin B2PHTM by Cog or Solid consistency, of the cream, cream-gel, foam or oint 1S. ment type, or microemulsions, microcapsules, microparticles 0118. According to the invention, the preferred concentra or vesicular dispersions of ionic and/or nonionic type, in the tions of emulsifiers are from 0.001% to 20%. More prefer form of sprays, or else in the form of dermal devices Such as ably, the concentration ranges from 1% to 15%, and prefer patches. ably from 3% to 11% by weight, relative to the total weight of the composition. I0128. The term “topical application” means application to 0119 The compositions according to the invention may the skin or the mucous membranes. also, in particular, comprise at least one chelating agent and/ I0129. Preferably, the compositions according to the inven or at least one preservative. tion are in the form of a gel or a cream-gel of semi-liquid 0120 Among the chelating agents, exemplary are dieth consistency of the milk type to Solid consistency of the cream ylenetriaminepentaacetic acid (DTPA), ethylenediamine-di type, obtained by dispersion of a fatty phase in an aqueous (O-hydroxyphenylacetic) acid (EDDHA), 2-hydroxyethyl phase (O/W). enediaminetriacetic acid (HEDTA), ethylenediamine-di-(O- 0.130 Preferably, the compositions according to the inven hydroxy-p-methylphenyl)acetic acid (EDDHMA), ethylenediaminetetraacetic acid (EDTA) and ethylenedi tion are in the form of an emulsion, preferably a light emul amine-di-(5-carboxy-2-hydroxyphenyl)acetic acid (ED sion in the form of an (O/W) emulsion. DCHA). I0131 The term “light emulsion” means an emulsion con 0121 A preferred chelating agent is ethylene diamine tet taining a low proportion of fatty phase, the aqueous phase raacetic acid (EDTA). remaining predominant. 0122 Among the preservatives, exemplary are benzoic 0.132. The term "emulsion” means a liquid system com acid and its derivatives such as benzyl alcohol, benzalkonium prising two fluids that are insoluble or relatively insoluble in chloride, sodium benzoate, bronopol, chlorhexidine, chloro one another, and in which one of the fluids disperses in the cresol and its derivatives, ethyl alcohol, phenethyl alcohol, other in microscopic particles. Preferably, the emulsions used phenoxyethanol, potassium Sorbate, diazolidinylurea, and comprise at least one emulsifier, a polar hydrophilic, prefer parabens Such as propylparaben or methylparaben, taken ably aqueous, phase and a non-polar fatty phase. Preferably, alone or as mixtures. they are in the form of emulsions (O/W or W/O). US 2010/0160439 A1 Jun. 24, 2010

0133. To obtain this essential stabilization, an emulsifier 0146 In particular, the present invention relates to the use which reduces the surface tension from the two phases is of at least one retinoid compound, benzoyl peroxide and at introduced. The emulsions have an important role in derma least one anti-irritant compound described above, or of a tological and cosmetic products because said emulsions cor composition as described above, for treatment and/or preven respond to the physiological needs of the skin, and make it tion of dermatological conditions linked to a keratinization possible to bring about uniform penetration of both water disorder relating to cell differentiation and proliferation, in soluble Substances and oil-soluble Substances. particular, for treating common acne, comedonic acne, papu 0134. Those skilled in the art will take care to select the lopustular acne, papulocomedonic acne, nodulocystic acne, excipients constituting the compositions according to the acne conglobata, cheloid acne of the nape of the neck, recur invention according to the galenical form desired, and in Such a way that the advantageous properties of the composition rent miliary acne, necrotic acne, neonatal acne, occupational according to the invention are respected. acne, acne rosacea, senile acne, Solar acne and acne medica 0135 The fatty phase of the composition according to the mentOSa. invention may comprise, for example, plant, mineral, animal 0147 Preferably, this invention features formulating at or synthetic oils, silicone oils, and mixtures thereof. least one retinoid compound, benzoyl peroxide and at least 0.136 Exemplary mineral oils include liquid paraffins of one anti-irritant compound described above, or of a compo various viscosities, such as Primol 352(R), Marcol 82R and sition as described above, into medicaments useful for pre Marcol 152(R) marketed by Esso. venting and/or treating common acne. 0.137 As plant oils, exemplary are sweet almond oil, palm 0.148. In addition, this invention also features the cosmetic oil, soybean oil, sesame oil and Sunflower oil. use of a composition according to the invention, for the treat 0138 AS animal oils, exemplary are lanolin, squalene, fish ment of skin with an acneic tendency, for combating the oil, and mink oil, with, as a derivative, the squalane marketed greasy appearance of the skin or the hair. under the trademark CosbiolR by Laserson. 014.9 The present invention also features a method for 0.139. As synthetic oils, exemplary are an ester such as formulating a composition as described above. Such a cetearyl isononanoate, for instance the product marketed method comprises a step of mixing at least one retinoid com under the trademark Cetiol SNPHR) by Cognis France, diiso pound as defined above, preferably present in a physiologi propyl adipate, for instance the product marketed under the cally acceptable medium, with benzoyl peroxide and with at trademark Crodamol DAR) by Croda, isopropyl palmitate, for least one anti-irritant compound, said retinoid compounds instance the product marketed under the trademark Crodamol and benzoyl peroxide preferably being in a dispersed form in IPPR) by Croda, triglycerides such as caprylic/capric triglyc said composition. eride, for instance Miglyol 812 marketed by Hills/Univar, polymers such as hydrogenated polyisobutene and deriva 0150. The introduction of the other optional excipients tives. and additives will be carried out according to the chemical 0140. As volatile or non-volatile silicone oils, exemplary nature of the compounds and the galenical form selected. are dimethicones, for instance the products marketed under 0151. For more clarity in the following descriptions of the trademark Dow Corning 200 Fluid R or Q7-9120 silicone processes, by lipophilic compound, is meanta Substance hav fluid with a viscosity from 20 cstand 12500cst or the product ing an affinity for, tending to combine with, or capable of marketed under the trademark ST-Cyclomethicone-5NF by dissolving in lipids, fat or oils. Dow corning. 0152. By hydrophilic ingredients, it is meant a substance 0141 Solid fatty substances such as natural or synthetic having a strong affinity for water, tending to dissolve in, mix waxes, fatty acids such as Stearic acid, fatty alcohols such as with, or be wetted by water. Speziol C18 Pharma marketed by Cognis and texture agents 0153. The formulation of a composition according to the such as tribehenate, for example, Compritol 888 marketed by invention is carried out according to a general process as Gattefossé or hydrogenated castor oils such as Cutina HR follows: marketed by Cognis may also be introduced. In this case, one skilled in the art will adjust the heating temperature for the 0154) a) the retinoid compound is mixed with at least one preparation according to the presence or absence of these wetting agent in water, until said retinoid compound is com Solids. pletely dispersed, to obtain the active phase 1: 0142 For the compositions according to the invention, 0155 b) the benzoyl peroxide is mixed with at least one synthetic and/or silicone oils, and more particularly Marcol wetting agent in water, until said benzoyl peroxide is com 152(R) et la ST-5cyclomethicone-5NF, are preferred. pletely dispersed, to obtain the active phase 2; 0143. The hydrophilic phase of the emulsions according to 0156 c) an aqueous phase comprising water, at least one the invention is preferably aqueous and may therefore com anti-irritant, at least one hydrophilic ingredients is prepared, prise water. This water may, in particular, be a floral water optionally, add the gelling agent; Such as cornflower water, or a natural mineral water or spring 0157 d) optionally, for obtaining an emulsion, mix, if water, for example, selected from among Vittel water, water necessary heat at least one emulsifier, at least one lipophilic from the Vichy basin, Uriage water, La Roche Posay water, compound and optionally solid fatty Substances until homog Avéne water or Aix-les-Bains water. enization, to obtain the fatty phase; 0144 Said aqueous phase may be present at a content of 0158 e) Optionally, for obtaining a gel-cream, mix if nec from 10% to 90% by weight, relative to the total weight of the essary heat at least one oil and/or solid fatty Substance until composition, preferably from 20% to 80% by weight. homogenization, to obtain the fatty phase; 0145 The present invention also features the composi 0159 f) the two active phases obtained respectively in a) tions as described above, as medicaments. and b) are mixed to obtain one unique active phase; US 2010/0160439 A1 Jun. 24, 2010

0160 g) in case of gel or gel-cream, mix the unique active 0183 Steps c), d), f), g), h), i) of the previously described phase obtained in stepf) with aqueous phase obtained in step process remain unchanged accordingly. c); 0184. According to another embodiment, the method for 0161 h) optionally, add the gelling agent preparing the compositions according to the invention in the 0162 i) in case of emulsion, said fatty phase obtained in form of a cream-gel, comprises successively the following step d) is mixed with the aqueous active phase obtained in step steps of: c) to obtain an emulsion; 0185 a) mixing at least one retinoid with water and, at 0163 ) optionally in case of emulsion, the unique active least one wetting agent, until complete dispersion, to obtain phase obtained in step e) is mixed with emulsion obtained in the active phase 1: step i); 0186 b) mixing the benzoyl peroxide with water and, et 0164 k) optionally, in case of gel-cream, the unique ingre least one a wetting agent, until complete dispersion, to obtain dient of fatty phase or the fatty phase obtained in step e) is the active phase 2; mixed with the phase obtained in step g) or Steph); 0187 c) preparing an aqueous phase comprising water, at 0.165. 1) if necessary, heat sensitive additives are added: least one anti-irritant and, at least one hydrophilic agent, 0166 m) if necessary, a pH adjuster is introduced into the optionally, add the gelling agent; emulsion obtained in Step) or into the gel obtained in step g) 0188 d) optionally, mixing at least two lipophilic com or in Steph) or into gel-cream obtained in step k) to obtain the pounds to obtain the fatty phase; desired pH; 0189 e) the active phases 1 and 2 respectively obtained in 0167 n) if necessary, water is added to make up the Stepa) and step b) are mixed together to obtain a unique active remainder. phase; 0168 According to alternative embodiment, the composi 0.190 f) the unique active phase obtained in step d) is tion according to the present invention is prepared as follows: mixed with the aqueous phase obtained in c) 0169 a') stepsa) and b) of the general process as described 0191 g) optionally, add the gelling agent; previously are merged to obtained a unique step a') which is 0.192 h) add the unique ingredient offatty phase or option the mix of at least the retinoid, the benzoyl peroxide and at ally the fatty phase obtained in step d) in the gel obtained in least one wetting agent with water until complete dispersion step f) or in step g) to obtain a gel-cream; 0193 i) if necessary, heat sensitive additives are added: of ingredients to obtain a unique active phase. 0194 j) if necessary, a pH adjuster is introducedgel-cream 0170 Steps c), d), e), g), h), i), j), k), 1), m) et n) of the obtained in Steph) or in step i); previously described process remain unchanged accordingly. 0.195 k) if necessary, water is added to make up the 0171 More specifically, a first embodiment of the present remainder. invention is the method or the process for preparing a com 0196. More specifically, according to a particular embodi position according to the invention in the form of a gel. ment of the invention, one aspect is an alternative process of comprising the following steps: preparation of the instant invention in a form of a gel-cream, 0172 a) mixing at least one retinoid with water and, at comprising the following steps: least a wetting agent until complete dispersion, to obtain the 0197) a) steps a) and b) of the general process as described active phase 1: previously are merged to obtained a unique step a') which is 0173 b) mixing the benzoyl peroxide with water and, at the mix of at least the retinoid, the benzoyl peroxide and at least a wetting agent, until complete dispersion, to obtain the least one wetting agent with water until complete dispersion active phase 2; of ingredients to obtain a unique active phase. 0174 c) preparing an aqueous phase comprising water, at 0198 Steps c), d), e), f), g), h), i) j), k) of the previously least one anti-irritant, at least one hydrophilic agent, option described process remain unchanged accordingly. ally, add the gelling agent; 0199 According to a third embodiment, the method for 0175 d) the active phases 1 and 2 respectively obtained in preparing the compositions according to the invention in the step a) and step b) are mixed to obtain a unique active phase; form of an emulsion comprises successively the following 0176 e) the unique active phase obtained in step d) is steps of: mixed with the aqueous phase obtained in step c) and stirring 0200 a) mixing at least one retinoid with water and, at until complete homogenization; least one wetting agent, until complete dispersion, to obtain 0177 f) optionally, add the gelling agent; the active phase 1: 0.178 g) if necessary, heat sensitive additives are added: 0201 b) mixing the benzoyl peroxide with water and, at 0179 h) if necessary, a pH adjuster is introduced into the least one wetting agent, until complete dispersion, to obtain phase obtained in Step d) or in step e) or in stepf) to obtain the the active phase 2; desired pH; 0202 c) preparing an aqueous phase comprising water, at 0180 i) if necessary, water is added to make up the remain least one anti-irritant and, at least one hydrophilic agent; der. 0203 d) the active phases 1 and 2 respectively obtained in 0181 More specifically, according to a particular embodi Stepa) and step b) are mixed together to obtain a unique active ment of the invention, an alternative process of preparation of phase; the instant composition in a form of a gel, comprises the 0204 e) mixing at least one emulsifier with at least one following steps: lipophilic compound to obtain the fatty phase; 0182 a') stepsa) and b) of the general process as described 0205 f) the fatty phase obtained in step e) is mixed with previously are merged to obtained a unique step a') which is the aqueous phase obtained in step c) to obtain an emulsion. the mix of at least the retinoid, the benzoyl peroxide and at 0206 g) the unique active phase obtained in step d) is least one wetting agent with water until complete dispersion mixed with the emulsion obtained in step f) of ingredients to obtain a unique active phase. 0207 h) optionally, add the gelling agent; US 2010/0160439 A1 Jun. 24, 2010 9

0208 i) if necessary, heat sensitive additives are added: Example 2 (0209 j) f necessary, a pH adjuster is introduced in emul- Formulation of Cream Type Comprising 0.3% Ada sion obtained in Steph); palene, 5% Benzoyl Peroxide and Sodium Salt of 0210 k) if necessary, water is added to make up the 18B-Glycyrrhetinic Acid as Anti-Irritant remainder. 0218. The formula is prepared according to above detailed 0211 More specifically, according to a particular embodi- process of preparation: ment of the invention, one aspect is an alternative process of preparation of the instant invention in a form of an emulsion, comprising the following steps: 0212 a') stepsa) and b) of the general process as described Constituents Content (% milm) previously are merged to obtained a unique step a') which is Benzoyl Peroxide S.OO the mix of at least the retinoid, the benzoyl peroxide and at Adapalene O.30 least one wetting agent with water until complete dispersion S.al is Glynleins Acid 3. of ingredients to obtain a unique active phase. Symperonic PEL44 0.20 0213 Steps c), d), e), f), g), h), i) j), k) of the previously Glycerine 7.00 described process remain unchanged accordingly. MOS PH t 0214. The methods for formulating the compositions Arlace 165FL 3.00 according to the invention presented above are exemplary Speziol C18 Pharma 2.00 only. Mygliol 812 N 7.00 ST-Cyclomethine 5 NF 6.OO 0215 Finally, the present invention also features the non- Simulgel 600 PHA 2.50 therapeutic cosmetic treatment process for embellishing the Purified Water qsp 100% skin or its Surface appearance, in which a subject composition Sodium Hydroxyde qsp pH 5.5 + 0.5 comprising, in a physiologically acceptable medium, a retin oid, an anti-irritant selected from among 18R-glycyrrhetinic acid (enoXolone), its salts and its derivatives and benzoyl Example 3 peroxide, is topically applied to the skin and/or its append- Formulation of Lotion Type Comprising 0.3% Ada ageS. palene, 1% Benzoyl Peroxide and the Sel Dipotas 0216) To further illustrate the present invention and the sium Salt of 18 B-Glycyrrhetinic Acid as Anti-Irritant advantages thereof, the following specific examples are given, it being understood that same are intended only as 0219. The formula is prepared according to above detailed illustrative and in nowise imitative. In said examples to fol process of preparation: low, all parts and percentages are given by weight, unless otherwise indicated. Constituents Content (% milm) Benzoyl Peroxide 1.00 EXAMPLES Adapalene O.30 Dipotassium salt of 18f3-Glycyrrhetinic Acid 1...SO Example 1 Avice CL-611 1...SO Dipropylene glycol 3.00 Formulation of Cream Type Comprising 0.1% Ada- RS.E.L44 9. palene, 2.5% Benzoyl Peroxide and EnoXolone as Brij 721 3.00 Anti-Irritant Arlace 165FL 3.00 Propyl Paraben O.OS 0217. The formula is prepared according to above detailed CetoPerhydrosqualene SNPH S.OO process of preparation: Simulgel 600PHA 1...SO Purified Water qsp 100% Triethanolamine qsp pH 5.5 +/- 0.5

Constituents Content (% milm) Benzoyl Peroxide 2.50 Example 4 Adapalene 1...SO Enoxolone 1...SO Formulation of Gel Type Comprising 0.1% Ada Symperonic PEL44 O.2O palene, 2.5% Benzoyl Peroxide and Potassium Salt Sodium Docusate O.OS of 18f3-Glycyrrhetinic Acid as Anti-Irritant Propylene glycol 6.OO EDTA O.10 0220. The formula is prepared according to above detailed Carbopol Ultrez 20 O4O rocess of preparation: Glycerine 3.00 p prep Glucamate SSE20 3.SO Glucate SS 3.SO Cosbiol 6.OO ST-Cyclomethicone 5 NF 13.00 Constituents Content (% milm) Purified water qsp 100% Triethanolamine qsp pH 5.5 + 0.5 Benzoyl Peroxide 2.50 Adapalene O.10 US 2010/0160439 A1 Jun. 24, 2010

Example 7 -continued Formulation of Gel Type Comprising 0.3% Ada palene, 5% Benzoyl Peroxide and the Disodium Suc Constituents Content (% milm) cinate Salt of 18 B-Glycyrrhetinic Acid as Anti-Irri tant Potassium Salt of 18B-Glycyrrhetinic Acid 1...SO 0223) The formula is prepared according to above detailed Propylene Glycol 4.OO process of preparation: Symperonic PEL44 O.20 EDTA O.10 Glycerine 4.OO Constituents Content (% milm) Sodium Docusate O.OS Adapalene O.30 Simulgel 600PHA 4.OO Disodium Succinate salt of 18 B-Glycyrrhetinic Acid 1...SO Purified Water qsp 100% Benzoyl Peroxide S.OO Titriplex III O.2O Natrosol 250 HHX Pharm 2.OO Propylene Glycol 4.OO Symperonic PE/L.62 O.2O Example 5 Phenoxyethanol 1.OO Purified Water qs 100 Formulation of Gel-Cream Type Comprising 0.1% Adapalene, 2.5% Benzoyl Peroxide And Potassium E le 8 Salt of 18f3-Glycyrrhétinicw & 8 Acid as Anti-Irritantr Xa p Formulation of Emulsion Type Comprising 0.1% 0221) The formula is prepared according to above detailed Adapalene, 2.5% Benzoyl Peroxide and the Dipotas process of preparation: sium Salt of 18 B-Glycyrrhetinic Acid as Anti-Irritant 0224. The formula is prepared according to above detailed process of preparation: Constituents Content (% milm) Benzoyl Peroxide 2.50 Adapalene O.10 Constituents Content (% milm) Potassium Salt of 18B-Glycyrrhetinic Acid 1...SO Propylene Glycol 6.OO Benzoyl Peroxide 2.50 Symperonic PEL44 O.20 Adapalene O.10 Glycerine S.OO Dipotassium Salt of 18 B-Glycyrrhetinic Acid 1...SO ST-Cyclomethicone 5NF 7.00 Propylene Glycol 2.OO Simulgel 6OOPHA 4.OO Symperonic PEL62 O.2O Purified Water qsp 100% HEDTA O.10 Nilpagin M (optional) O.2O Carbopol Ultrez 20 O.15 Veegum K O.30 Glycerol 3.00 Example 6 Phenoxyethanol 1.OO Nipasol M (optional) O.2O Formulation of Gel Type Comprising 0.3%O Ada GlucateGlucamate SS SSE20 S.OO1.OO palene, 2.5% Benzoyl Peroxide and the Monoammo- Miglyol 812 N 9.OO nium Salt of 18f3-Glycyrrhetinic Acid as Anti-Irritant Q7-9120 silicone Fluid 20 cst 1.OO Purified Water qs 100 Sodium Hydroxide 10% mi?m qs pH 5.5 + 0.5 0222. The formula is prepared according to above detailed process of preparation: Example 9 Constituent Content (% m Formulation of Emulsion Type Comprising 0.3% OSCS ontent (% milm) Adapalene, 2.5% Benzoyl Peroxide and the Potas Adapalene O.30 sium Salt of 18 B-Glycyrrhetinic Acid as Anti-Irritant Monoammonium Salt of 18f3-Glycyrrhetinic Acid 1...SO Benzoyl Peroxide 2.50 0225. The formula is prepared according to above detailed Titriplex III O.20 process of preparation: Simulgel 600 2.00 Propylene Glycol 4.OO Symperonic PE/L.62 O.20 Phenoxyethanol 1.00 Purified Water qs 100 Constituents Content (% milm) Sodium Hydroxide 10% mi?m qspH 5.5 + 0.5 Benzoyl Peroxide 2.50 Adapalene O.30 US 2010/0160439 A1 Jun. 24, 2010

-continued -continued Constituents Content (% milm) Constituents Content (% milm) Potassium Salt of 18B-Glycyrrhetinic Acid 1...SO Simulgel 600 3.00 Propylene Glycol 2.00 Phenoxyethanol 1.00 Symperonic PE/L.62 O.20 Nipasol M (optional) O.10 HEDTA O.10 Miglyol 812 7.00 Nilpagin M (optional) O.20 Purified Water qs 100 Carbopol Ultrez 20 O.15 Sodium Hydroxide 10% mi?m qs pH 5.5 + 0.5 Veegum K O.30 Glycerol 3.00 Phenoxyethanol 1.00 0228. Each patent, patent application, publication, text Nipasol M (optional) O.20 and literature article/report cited or indicated herein is hereby GlucateGlucamate SS SSE20 S.OO1.00 expresslylvi incorporated ted bby referencef in itits enurely.tiret Miglyol 812 N 9.00 0229 While the invention has been described in terms of Q7-9120 silicone Fluid 20 cst 1.00 various specific and preferred embodiments, the skilled arti Purified Water qs 100 san will appreciate that various modifications, Substitutions, Sodium Hydroxide 10% milm qspH 5.5 + 0.5 omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the Example 10 following claims, including equivalents thereof. Formulation of Emulsion Type Comprising 0.1% What is claimed is: Adapalene, 2.5%- - - - Benzoyl- - Peroxide and 18B-Glycyrr 1. A topically applicable, non-irritating, emollient and rhetinic Acid Disodium Succinate as Anti-Irritant rheologically stable dermatological composition comprising: 0226. The formula is prepared according to above detailed at least one retinoid compound selected from among all process of preparation: trans retinoic acid, isotretinoin, motretinide, and naph thoic acid compounds of formula (I), and salts and esters thereof:

Constituents Content (% milm) I Benzoyl Peroxide 2.50 O (I) Adapalene O.10 18B-Glycyrrhetinic Acid Disodium Succinate 1...SO Propylene Glycol 4.OO OH Symperonic PEL44 O.2O HEDTA O.10 Nilpagin M (optional) O.2O Carbopol ETD2020 O.2O Stearyl Alcohol 1.OO Phenoxyethanol 1.OO R Nipasol M (optional) O.10 Tefose 1500 S.OO Miglyol 812 N 7.OO Purified Water qs 100 Sodium Hydroxide 10% milm qs pH 5.5 + 0.5

Example 11 r wherein R is a hydrogenatom, a hydroxyl radical, a branched Formulation of Cream-Gel Type Comprising 0.3% or unbranched alkyl radical having from 1 to 4 carbon atoms, Adapalene, 5% Benzoyl Peroxide and Enoxolone as an alkoxy radical having from 1 to 10 carbon atoms, or a Anti-Irritant cycloaliphatic radical which is substituted or unsubstituted, benzoyl peroxide, and 0227. The formula is prepared according to above detailed at least one anti-irritant compound selected from among process of preparation: 18B-glycyrrhetinic acid, its salts and its derivatives thereof, formulated into a topically applicable, physiologically Constituents Content (% milm) acceptable medium therefor. 2. The dermatological composition as defined by claim 1, AdapaleneBenzoyl Peroxide S.OOO.30 wherein the at least one retinoid compound comprises a naph Enoxolone 2.00 thoic acid compound of formula (I), or salt or ester thereof. Propylene Glycol 7.00 3. The dermatological composition as defined by claim 2, SynperonicHEDTA PEL44 O.20O.10 said compound of formula (I) comprising an alkyl radical Nilpagin M (optional) 0.20 selected from among the methyl, ethyl, propyl or butyl radi Glycerol S.OO cal; an alkoxy radical selected from among the methoxy, ethoxy, propoxy, butoxy, hexyloxy or decyloxy radical; or a US 2010/0160439 A1 Jun. 24, 2010 cycloaliphatic radical selected from the 1-methylcyclohexyl drous or lipophilic gels, emulsions of liquid or semi-liquid radical or the 1-adamantyl radical. consistency of the milk type, obtained by dispersion of a fatty 4. The dermatological composition as defined by claim 2, phase in an aqueous phase (O/W) or vice versa (W/O), or wherein said at least one retinoid compound is selected from Suspensions or emulsions of soft, semi-liquid or Solid consis among 6-3-(1-adamantyl)-4-methoxyphenyl-2-naphthoic tency of the cream, cream-gel, foam or ointment type, or acid (adapalene), 6-3-(1-adamantyl)-4-hydroxyphenyl-2- microemulsions, microcapsules, microparticles or vesicular naphthoic acid, 6-3-(1-adamantyl)-4-decyloxyphenyl-2- dispersions of ionic and/or nonionic type, in the form of naphthoic acid and 6-3-(1-adamantyl)-4-hexyloxyphenyl sprays, or in the form of dermal devices and patches. 15. The dermatological composition as defined by claim 2-naphthoic acid, and the salts and esters thereof. 14, in the form of a gel, a cream-gel or an emulsion. 5. The dermatological composition as defined by claim 4. 16. A regime or regimen for the treatment and/or preven wherein the at least one retinoid compound comprises ada tion of dermatological conditions linked to a keratinization palene, or salt or ester thereof. disorder relating to cell differentiation and proliferation, for 6. The dermatological composition as defined by claim 1, treating common acne, comedonic acne, papulopustular wherein the concentration of retinoid compound ranges from acne, papulocomedonic acne, nodulocystic acne, acne con 0.001% to 10% by weight of the total weight of the compo globata, cheloid acne of the nape of the neck, recurrent mil sition. iary acne, necrotic acne, neonatal acne, occupational acne, 7. The dermatological composition as defined by claim 6, acne rosacea, senile acne, Solar acne and acne medicamen wherein the concentration of retinoid compound is 0.1%. tosa, comprising topically applying onto the skin of an indi 8. The dermatological composition as defined by claim 6, vidual in need of such treatment, a thus effective amount of a wherein the concentration of retinoid compound is 0.3%. dermatological composition as defined by claim 1. 9. The dermatological composition as defined by claim 1, 17. A regime or regimen as defined by claim 16, for pre wherein the at least one anti-irritant compound is selected venting or treating common acne. from among the potassium salt of 183-glycyrrhetinic acid, the 18. A regime or regimen for the treatment of skin with an Sodium salt of 183-glycyrrhetinic acid, the monoammonium acneic tendency or for combating the greasy appearance of salt of 183-glycyrrhetinic acid, the disodium Succinate salt of the skin or the hair, comprising topically applying onto the 183-glycyrrhetinic acid, the dipotassium salt of 183-glycyr skin or hair of an individual in need of Such treatment, a thus rhetinic acid and the monoester of 18f3-glycyrrhetinic acid. effective amount of a dermatological composition as defined 10. The dermatological composition as defined by claim 1, by claim 1. wherein the concentration of at least one anti-irritant com 19. A method for formulating a composition as defined by pound ranges from 0.01% to 10%. claim 1, comprising a step of mixing at least one retinoid 11. The dermatological composition as defined by claim 1, compound with benzoyl peroxide and with at least one anti wherein the benzoyl peroxide is in dispersed form. irritant compound. 12. The dermatological composition as defined by claim 1, 20. A non-therapeutic cosmetic regime or regimen for wherein the benzoyl peroxide is in encapsulated or free form. embellishing the skin or its Surface appearance, comprising 13. The dermatological composition as defined by claim 1, topically applying onto the skin and/or it integuments of an comprising from 0.0001% to 20% of benzoyl peroxide. individual in need of such treatment, a thus effective amount 14. The dermatological composition as defined by claim 1, of a dermatological composition as defined by claim 1. formulated in the form of aqueous, aqueous-alcoholic or oily dispersions, dispersions of the lotion type, aqueous, anhy c c c c c