AU2006290364B2

AU2006290364B2 - Composition comprising at least one naphthoic acid derivative and at least one compound of polyurethane polymer type or derivatives thereof, preparation processes therefor and uses thereof

Info

Publication number: AU2006290364B2
Application number: AU2006290364A
Authority: AU
Inventors: Eve Ferrara; Claire Mallard
Original assignee: Galderma Research and Development SNC
Current assignee: Galderma Research and Development SNC
Priority date: 2005-09-16
Filing date: 2006-09-15
Publication date: 2012-07-05
Anticipated expiration: 2026-09-15
Also published as: AU2006290364A1; JP5074401B2; JP2009508843A; RU2421216C2; EP1933827A2; JP2012184258A; WO2007031883A2; MX2008003422A; CA2622468A1; RU2008114840A; WO2007031883A3

Abstract

The invention relates to a composition for topical application comprising, in a physiologically acceptable medium, at least one naphthoic acid derivative and at least one compound of polyurethane polymer type or derivatives thereof . The invention is characterized in that the said naphthoic acid derivative is in a form dispersed in the said composition. The invention applies in particular to human pharmacy or cosmetics.

Description

WO 2007/031883 PCT/IB2006/003852 COMPOSITIONS COMPRISING AT LEAST ONE NAPHTHOIC ACID DERIVATIVE AND AT LEAST ONE COMPOUND OF POLYURETHANE POLYMER TYPE OR DERIVATIVES THEREOF, PREPARATION PROCESSES THEREFOR AND USES THEREOF 5 The present invention relates to compositions for topical application, to processes for preparing such compositions and to their uses as cosmetic or pharmaceutical products, the said compositions being 10 intended in particular for treating acne. Acne is a common multi-factor pathology that attacks skin rich in sebaceous glands (face, shoulder area, arms and intertriginal areas). It is the most commonly 15 occurring form of dermatosis. The following five pathogenic factors play a determining role in the formation of acne: 1. genetic predisposition; 20 2. overproduction of sebum (seborrhoea); 3. androgens; 4. follicular keratinization disorders (comedogenesis); and 5. bacterial colonization and inflammatory factors. 25 There are several forms of acne, the common factor of all being attack of the pilosebaceous follicles. Mention may be made especially of acne conglobata, cheloid acne of the nape of the neck, medication 30 related acne, recurrent miliary acne, necrotic acne, neonatal acne, premenstrual acne, occupational acne, acne rosacea, senile acne, solar acne and simple acne. Simple acne, also known as polymorphic juvenile acne, 35 is the most common. It comprises four stages, but passage through all the stages is not obligatory: - stage 1 corresponds to comedonic acne characterized by a large number of open and/or WO 2007/031883 PCT/IB2006/003852 -2 closed comedones and of microcysts; - stage 2, or papulopustular acne, is of mild to moderate seriousness. It is characterized by the 5 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 papulocomedonic acne, is more serious 10 and extends to the back, the chest and the shoulders. It is accompanied by a larger number of scars; - stage 4, or nodulocystic acne, is accompanied by 15 many scars. It presents nodules and also painful voluminous crimson pustules. The various forms of acne described above may be treated with active agents such as anti-seborrhoeic 20 agents and anti-infectious agents, for example benzoyl peroxide (especially the product Eclaran@ sold by the company Pierre Fabre), with retinoids such as tretinoin (especially the product Retacnyl@ sold by the company Galderma) or isotretinoin (the product Roaccutane@ sold 25 by Laboratoires Roche), or with naphthoic acid derivatives. Naphthoic acid derivatives such as, especially, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2 naphthoic acid, which is commonly known as adapalene (the product Differine@ sold by the company Galderma), 30 are widely described and acknowledged as active principles that are just as effective as tretinoin for the treatment of acne. Adapalene also has the advantage of causing fewer side effects, such as phenomena of irritation, dryness of the skin or intolerance, than 35 the other active agents described above, which makes it a product of choice. Needless to say, it has been sought to develop compositions for increasing the topical penetration of WO 2007/031883 PCT/IB2006/003852 -3 certain active agents by including, in compositions, compounds of polyurethane polymer type or derivatives thereof (patent EP 0 299 758). The product Avita@, sold by the company Bertek Pharmaceuticals Inc., is an 5 example thereof. It especially contains 0.025% by weight, relative to the total weight of the composition, of tretinoin dissolved in compositions of cream or gel type and containing polyurethane polymers (type-2 polyolprepolymers sold by the company Bertek 10 Pharmaceuticals Inc.) to limit desquamation, irritation and dryness of the skin. The patent application US2002/01555180 describes a composition comprising as active principle an Extract of Saw Palmetto Berries (SPBE), and in which adapalene 15 is used as an agent for improving the penetration of the active principle SPBE into the follicles and the sebaceous gland. It turns out that the Applicant has demonstrated, 20 surprisingly, that polyurethane polymers, which are known to increase the topical penetration of only certain dissolved active agents (absence of crystals of these active agents when observed by microscope), can also promote the topical penetration of insoluble 25 compounds, dispersed or suspended in pharmaceutical compositions, especially such as naphthoic acid derivatives. However, there was nothing in the prior art to suggest 30 that the anti-irritant effect of polyurethane polymers could be obtained with an active agent in dispersed and undissolved form. Taking the foregoing into account, a problem that the 35 invention proposes to solve is that of preparing stable compositions that are less irritant than those of the prior art, comprising at least one naphthoic acid derivative in dispersed form and at least one compound -4 of polyurethane polymer type or derivatives thereof, and also a process for preparing such a composition; the said composition needing to promote the topical penetration of the active principle in dispersed form. 5 Thus, a first subject of the invention is a composition comprising, in a physiologically acceptable medium, at least one naphthoic acid derivative and at least one compound of polyurethane polymer type or derivatives 10 thereof, the said naphthoic acid derivative being in dispersed form in the said composition, the said composition not comprising any extract of saw palmetto berries. 15 According to the invention, the term "active agent in dispersed form" means an active principle in the form of solid particles, suspended in a given vehicle. Such particles are especially greater than 10 pm in size. 20 A second subject of the invention is a process for preparing a composition as described above, wherein it comprises the step of mixing a physiologically acceptable vehicle comprising at least one naphthoic acid derivative with at least one compound of 25 polyurethane polymer type or derivatives thereof, the said naphthoic acid derivative being in a form dispersed in the said composition. The term "physiologically acceptable vehicle" means a vehicle that is compatible with the skin, mucous membranes 30 and/or the integuments. Finally, a third subject of the invention is the use of a composition as described above for the preparation of a pharmaceutical composition for treating and/or 35 preventing dermatological complaints associated with a keratinization disorder that has a bearing on cell differentiation and proliferation, especially for treating comedonic acne, simple acne, papulocomedonic WO 2007/031883 PCT/IB2006/003852 -5 acne, nodulocystic acne, polymorphic acne, acne rosacea, acne conglobata, senile acne, and secondary acnes such as solar acne, medication-related acne or occupational acne. 5 When a composition comprises, in a physiologically acceptable medium, at least one naphthoic acid derivative and at least one compound of polyurethane polymer type or derivatives thereof, the said naphthoic 10 acid derivative being in a form dispersed in the said composition, it shows good chemical stability, high anti-comedolytic efficacy and also good tolerance. The invention will be understood more clearly on 15 reading the non-limiting description that follows, which has been written with regard to the attached drawings, in which: - Figures 1 to 4 show the results of a study aimed 20 at comparing the irritant power of a reference gel containing 0.1% adapalene with that of three 0.1% adapalene formulations in gel form comprising a polyurethane polymer at various concentrations, and also placebos thereof, on the skin of BALB/c 25 mouse ear after repeated topical applications for 6 days; - Figures 5 to 8 show the results of a study aimed at evaluating the comedolytic activity of a 30 reference gel containing 0.1% adapalene and of two 0.1% adapalene formulations in gel form with a polyurethane polymer at various concentrations, and also placebos thereof, on dorsal skin of RHINO FVB/N RJ-hrrh mice (Rhino) after repeated topical 35 applications for 18 days. The composition according to the invention comprises at least one naphthoic acid derivative and at least one compound of polyurethane polymer type or derivatives WO 2007/031883 PCT/IB2006/003852 -6 thereof. Naphthoic acid is a compound of formula: HO 0 5 The term "naphthoic acid derivative" means the compounds of formula (I): O OH R (I) 10 in which R represents a hydrogen atom, a hydroxyl radical, a branched or unbranched alkyl radical containing from 1 to 4 carbon atoms, an alkoxy radical 15 containing from 1 to 10 carbon atoms or a substituted or unsubstituted cycloaliphatic radical. The term "linear or branched alkyl radical containing from 1 to 4 carbon atoms" preferably means methyl, 20 ethyl, propyl and butyl radicals. The term "alkoxy radical containing from 1 to 10 carbon atoms" preferably means methoxy, ethoxy, propoxy, butoxy, hexyloxy and decyloxy radicals.

WO 2007/031883 PCT/IB2006/003852 7 The term "cycloaliphatic radical" preferably means monocyclic or polycyclic radicals such as the 1-methyl cyclohexyl radical or the 1-adamantyl radical. 5 Among the naphthoic acid derivatives that may be included in the compositions according to the invention, 6- [3- (1-adamantyl) -4-methoxyphenyl] -2 naphthoic acid (adapalene), 6-[3-(1-adamantyl)-4 10 hydroxyphenyl]-2-naphthoic acid, 6-[3-(1-adamantyl)-4 decyloxyphenyl]-2-naphthoic acid and 6-[3-(1 adamantyl)-4-hexyloxyphenyll-2-naphthoic acid will advantageously be chosen. 15 The abovementioned naphthoic acid derivatives are generally in a form dispersed in the composition according to the invention. The insoluble naphthoic acid derivatives are thus uniformly distributed in the composition according to the invention. 20 In the compositions according to the invention, the naphthoic acid derivatives are used at concentrations of less than or equal to 10% by weight relative to the total weight of the composition, and preferably between 25 0.001% and 10% by weight relative to the total weight of the composition, preferentially between 0.01% and 5%, more preferentially between 0.05% and 2% and most preferentially from 0.1% to 0.3% by weight relative to the total weight of the composition. Throughout the 30 present text, unless otherwise specified, it is understood that when ranges of concentrations are given, the upper and lower limits of the said range are included. 35 Advantageously, the naphthoic acid derivative used in the compositions according to the invention is adapalene. The adapalene concentration used in the composition according to the invention is then between 0.01% and 0.5%, and preferentially equal to 0.03%, more - 8 preferentially between 0.1% and 0.3% and in particular at a concentration of 0.1% and at a concentration of 0.3%. 5 Preferably, the naphthoic acid derivative(s) is (are) the only active principle(s) present in the composition according to the invention. Preferentially adapalene is the only active principle of the composition. 10 The composition according to the invention also comprises compounds of polyurethane polymer type or derivatives thereot. The term "polyirethane polymers" means a polymer prepared by reacting two moles of a hydroxyl- or hydroxyl/alkoxy-terminated linear 15 polyalkylene glycol or polyether with one mole of a monomeric organic diisocyanate as described in patent EP 0 299 758, and sold by the company Bertek Pharmaceuticals Inc. The polyurethane polymers according to the invention have unique properties that 20 give them advantageous properties for applications in cosmetics and pharmaceuticals. Specifically, polyurethane polymers significantly influence the deposition of certain agents onto and into the skin, by virtue of their high molecular weight. Moreover, 25 polyurethane polymers preferentially remain in the upper layers of the skin. Among the polyurethane polymers that may be included in the compositions according to the invention, mention 30 may be made of the polyurethane polymers of general formula: R O HO CH-CH 2 -0 NHCH2 NH- C O-CH 2 CH )-O--H 35 in which: - 8a R is CH3 or H; n is an integer chosen such that the polyurethane polymer has a molecular mass at least equal to WO 2007/031883 PCT/IB2006/003852 -9 1000, and n is advantageously between 5 and 55; and m is a number between 1 and 6 inclusive. As non-limiting examples of polyurethane polymers that 5 may be included in the compositions according to the invention, mention may be made of polyolprepolymer-2 (PP-2) and polyolprepolymer-14 (PP-14) (named poly[oxy (methyl-1, 2-ethanediyl) ], a-hydro-o-hydroxy-, polymer with 1,1'-methylenebis[ 4 -isocyanatocyclo 10 hexane]), and polyolprepolymer-15 (PP-15) (named poly(oxy-1,2-ethanediyl), a-hydro-o-hydroxy-, polymer with 1,1'-methylenebis[ 4 -isocyanatocyclohexane]), taken alone or as a mixture. These three polymers are sold by the company Bertek Pharmaceuticals Inc., and correspond 15 to the general formula above with m ranging from 1 to 4 and for which, respectively, n = 12 for PP-2, n = 51 for PP-14 and n = 8 for PP-15. Among the polyurethane polymers that may be included in 20 the compositions according to the invention, polyolprepolymer-2 (PP-2) will advantageously be chosen. In the compositions according to the invention, the 25 compounds of polyurethane polymer type or derivatives thereof are used at concentrations of 'less than or equal to 20% and preferably between 0.5% and 20% by weight, more preferentially between 1% and 10% by weight and in particular 1%, 3%, 7% or 10% by weight 30 relative to the total weight of the composition, and preferentially at a concentration lower than or equal to 7%. Such low concentrations of polyurethane polymers advantageously make it possible to reduce the toxicity and the general irritation of the composition according 35 to the invention. The presence of polyurethane polymers in the composition according to the invention, which are deposited in the stratum corneum, allows the formation WO 2007/031883 PCT/IB2006/003852 - 10 of a reservoir in the upper part of the skin. This reservoir allows the naphthoic acid derivatives to be released gradually into the deeper layers of the epidermis. In addition, it has been noted, 5 surprisingly, that the polyurethane polymers contained in the compositions according to the invention have anti-irritant and moisturizing properties that may be particularly advantageous in the case of adapalene formulations. The reason for this is that naphthoic 10 acid derivatives may be irritant and have a dehydrating action on the skin. It is thus advantageous to reduce the irritation induced in order to be able to increase the doses. 15 The compositions of the present invention may be in any galenical form normally used for topical application, especially in the form of aqueous, aqueous-alcoholic or oily dispersions, dispersions of the lotion type, aqueous, anhydrous or lipophilic gels, emulsions of 20 liquid or semi-liquid consistency of the milk type, obtained by dispersing a fatty phase in an aqueous phase (O/W) or vice versa (W/0), or suspensions or emulsions of soft, semi-liquid or solid consistency of the cream, cream-gel or pomade type, or alternatively 25 microemulsions, microcapsules, microparticles or vesicular dispersions of ionic and/or nonionic type. Preferably, the compositions according to the invention are in the form of lotions, cream-gels, gels or creams. 30 A person skilled in the art will take care to select the excipients constituting the compositions according to the invention as a function of the desired galenical form and such that the advantageous properties of the 35 composition according to the invention are respected. The composition according to the invention may also especially comprise one or more of the following ingredients: WO 2007/031883 PCT/IB2006/003852 - 11 a) one or more gelling agents or suspending agents, b) one or more chelating agents, c) one or more wetting agents, 5 d) one or more preserving agents. As non-limiting examples of gelling agents or suspending agents that may be included in the compositions according to the invention, mention may be 10 made of the carbomers sold under the generic name Carbopol@, the "electrolyte-insensitive" carbomers sold under the name Ultrez 10@ or Carbopol ETD@ by the company BF Goodrich, polysaccharides, non-limiting examples of which include xanthan gum such as Keltrol 15 T@ sold by the company Kelco, guar gum, chitosans, cellulose and derivatives thereof such as hydroxyethyl cellulose, in particular the product sold under the name Natrosol HHX 250@ by the company Aqualon, and the copolymer of acrylamide and of sodium acrylamino-2 20 methylpropanesulfonate as a 40% dispersion in isohexadecane and polysorbate 80 sold under the name Simulgel 600@ by the company SEPPIC. Preferred gelling agents that may be mentioned are the 25 carbomers sold especially under the names Carbopol 974P NF and Carbopol 980 NF. Among the chelating agents, non-limiting examples that may be mentioned include ethylenediaminetetraacetic 30 acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylenediaminebis (0-hydroxyphenylacetic acid) (EDBHA), hydroxy-2-ethylenediaminetriacetic acid (HEDTA), ethyldiaminebis(O-hydroxy-p-methylphenyl)acetic acid (EDBHMA) and ethylenediaminebis (5-carboxy-2 35 hydroxyphenyl)acetic acid (EDBCHA). A preferred chelating agent that may be mentioned is ethylenediaminetetraacetic acid (EDTA) sold especially under the name Titriplex III@.

WO 2007/031883 PCT/IB2006/003852 - 12 Among the wetting agents, the role of which is to reduce the surface tension and to allow greater spreading of the liquid, compounds such as propylene 5 glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol and ethoxydiglycol, alone or as a mixture, are preferentially used, without this list being limiting. 10 A preferred wetting agent that may be mentioned is propylene glycol. Among the preserving agents, non-limiting examples that may be mentioned include benzoic acid and derivatives 15 thereof with benzyl alcohol, benzalkonium chloride, sodium benzoate, bronopol, chlorhexidine, chlorocresol and derivatives thereof, ethyl alcohol, phenethyl alcohol, phenoxyethanol, potassium sorbate, diazolidinylurea, parabens such as propyl paraben or 20 methyl paraben, taken alone or as mixtures. Preferred preserving agents that may be mentioned include parabens and phenoxyethanol or benzalkonium chloride, alone or as a mixture. 25 The composition according to the invention may comprise one or more emulsifiers. Surfactant emulsifiers are amphiphilic compounds 30 containing a hydrophobic portion with affinity for oil and a hydrophilic portion with affinity for water, thus creating a bond between the two phases. Ionic or nonionic emulsifiers thus stabilize oil/water emulsions by becoming adsorbed at the interface and by forming 35 lamellar liquid crystal layers. The emulsifying power of nonionic surfactants is closely linked to the polarity of the molecule. This polarity is defined by the HLB (hydrophilic/lipophilic WO 2007/031883 PCT/IB2006/003852 - 13 balance) A high HLB indicates that the hydrophilic fraction is predominant and, conversely, a low HLB indicates that 5 the lipophilic portion is predominant. For example, HLB values of greater than about 10 correspond to hydrophilic surfactants. Surfactants may be classified, according to their 10 structure, under the generic terms "ionic" (anionic, cationic or amphoteric) or "1nonionic". Nonionic surfactants are surfactants that do not dissociate into ions in water and are thus insensitive to pH variations. 15 Nonionic surfactants are particularly suitable for preparing emulsions of oil-in-water type, which are the subject of the present invention. Thus, the emulsifying system of which the emulsion of the invention is 20 composed comprises at least one nonionic surfactant, with a hydrophilic predominant fraction, i.e. with a high HLB value, of greater than about 10. Examples of nonionic surfactants with a high HLB value 25 that may be mentioned include sorbitan esters such as POE(20) sorbitan monooleate, sold under the name "Tween 80" (HLB=15); POE(20) sorbitan monostearate sold under the name "Tween 60" (HLB=14.9); fatty alcohol ethers such as POE(21) stearyl ether (HLB=15.5) or ceteareth 30 20 sold under the name "Eumulgin B2" by Cognis (HLB=15.5); polyoxyethylene-polyoxypropylene block copolymers such as Synperonic PE/L44. Preferably, the said high-HLB nonionic surfactants have 35 an HLB of between 10 and 18. Examples of low-HLB *(lipophilic) nonionic surfactants that will be mentioned include sorbitan esters, such as sorbitan monostearate (sold under the name Span 60 by WO 2007/031883 PCT/IB2006/003852 - 14 Unichema), glycerol esters (sold under the name Cutina GMSVPH by Cognis) such as glyceryl monostearate (Cutina GMS from Cognis), Speziol C18 pharma, olipal isostearic (from gatefosse) and low-HLB sucrose esters, for 5 instance sucrose distearate. Preferably, the said low-HLB nonionic surfactants have an HLB of less than 10. 10 The nonionic surfactants may be used alone or as a mixture of two or more of them to form the emulsifying system of which the emulsion of the invention is composed. 15 Preferably, one or more high-HLB nonionic surfactant/low-HLB nonionic surfactant pairs will be used as emulsifying system: it may in particular be a nonionic emulsifying system comprising at least one nonionic surfactant with an HLB of greater than about 20 10 and at least one nonionic surfactant with an HLB of less than about 10. The ratio of each of the two surfactants forming the abovementioned pair is usually determined by 25 calculating the required HLB of the fatty phase used. Preferred emulsifiers that may be mentioned include hydrophilic emulsifiers such as Tween 80, glyceryl stearate & PEG-100 stearate sold under the name Arlacel 30 165FL@ by the company Uniqema; PEG 6 stearate and PEG 32 stearate sold under the name Tefose 1500 by Gattefosse, lipophilic emulsifiers such as Glucate SS (methyl glucose sesquistearate) and Glucamate SSE 20 (PEG 20 methyl glucose sesquistearate) sold by 35 Amerchol, polyoxyethylene (21) stearyl ether sold under the name Brij721@ by the company Uniqema, Eumulgin B2PH, and acrylates/C10-30 alkyl acrylate crosspolymer sold under the name Pemulen TR1 by Noveon.

WO 2007/031883 PCT/IB2006/003852 - 15 The composition according to the invention may also comprise a fatty phase. This fatty phase may comprise, for example, plant oils, mineral oils, animal oils, synthetic oils or silicone oils, and mixtures thereof. 5 Examples of mineral oils that may be mentioned include liquid paraffins of various viscosities such as Primol 352@, Marcol 82@ and Marcol 152@ sold by the company Esso. 10 Plant oils that may be mentioned include sweet almond oil, palm oil, soybean oil, sesame seed oil and sunflower oil. 15 Animal oils that may be mentioned include lanolin, squalene, fish oil, mink oil with, as a derivative, squalane sold under the name Cosbiol@ by the company Laserson. 20 Synthetic oils that may be mentioned include esters such as cetearyl isononanoate, for instance the product sold under the name Cetiol SN@ by the company Cognis France, diisopropyl adipate, for instance the product sold under the name Ceraphyl 230@ by the company ISF, 25 isopropyl palmitate, for instance the product sold under the name Crodamol IPP@ by the company Croda, isopropyl adipate, for instance the product sold under the name Crodamol DA by the company Croda and caprylic/capric triglyceride such as Miglyol 812@ sold 30 by the company Huls/Lambert Riviere. Silicone oils that - may be mentioned include a dimethicone, for instance the product sold under the name Dow Corning 200 Fluid@, a cyclomethicone, for 35 instance the product sold under the name Dow Corning 244 Fluid@ by the company Dow Corning or the product sold under the name Mirasil CM5@ by the company SACI

CFPA.

WO 2007/031883 PCT/IB2006/003852 - 16 Solid fatty substances such as natural or synthetic waxes may also be used. In this case, the person skilled in the art will adapt the heating temperature of the preparation as a function of the presence or 5 absence of these solids. For the composition according to the invention, liquid paraffins and more particularly Marcol 152@ and Miglyol 812@ are preferred. 10 The compositions of the invention may also comprise any additive usually used in cosmetics or pharmaceuticals, such as surfactants, neutralizers, sunscreens, antioxidants, fillers, electrolytes, dyes, common 15 mineral or organic acids or bases, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, sphingolipids, self-tanning compounds such as DHA, calmatives and skin-protecting agents such as allantoin, and pro-penetrating agents, or a mixture 20 thereof. In particular, the composition according to the invention does not comprise any of the following active agents: glycolic acid, salicylic acid, retinol, tretinoin, retinaldehyde, azelaic acid and tazarotene. Needless to say, a person skilled in the art will take 25 care to select this or these optional additional compound(s), and/or the amount thereof, such that the advantageous properties of the composition according to the invention are not, or are not substantially, adversely affected. 30 These additives may be present in the composition in a proportion of from 0.001% to 20% by weight relative to the total weight of the composition. 35 In one particular embodiment of the invention, the composition is in the form of an oil-in-water (O/W) emulsion of lotion, cream or cream-gel type and comprises: - from 0.1% to 0.3% of a naphthoic acid derivative; WO 2007/031883 PCT/IB2006/003852 - 17 - from 1% to 10% of one or more polyurethane polymers or derivatives; - from 0.1% to 3% of gelling agents or suspending agents; 5 - from 0.01% to 1.5% of chelating agents; - from 0.1% to 10% of a wetting agent; - from 0.1% to 20% of an emollient; - from 0.1% to 30% of fatty phase; - from 0.01% to 3% of preserving agents; 10 - from 0 to 10% of emulsifiers. In one particular embodiment of the invention, the composition is in gel form and comprises: - from 0.1% to 0.3% of a naphthoic acid derivative; 15 - from 1% to 10% of one or more polyurethane polymers or derivatives; - from 0.1% to 3% of gelling agents; - from 0.01% to 1.5% of chelating agents; - from 1% to 10% of a wetting agent; 20 - from 0.01% to 3% of preserving agents. In another particular embodiment of the invention, the composition is in lotion form and comprises in water: - from 0,1% to 0,3% of a naphtoic acid 25 derivative ; - 3% of one or more polyurethane polymers or derivatives, preferentially the polyolprepolymer of type 2; - 0,2% of gelling agents or suspending agents ; 30 - 0,1% of chelating agents ; - from 2% to 6% and preferentailly 4% of a wetting agent ; - from 0,1% to 20% of an emollient ; - 7% of fatty phase ; 35 - from 1% to 1,5% of preserving agents ; - from 4% to 6% of emulsifiers.

WO 2007/031883 PCT/IB2006/003852 - 18 A subject of the present invention is also the composition as described above, as medicament. A subject of the invention is also a process for 5 preparing a composition as described above. Such a process is characterized in that it comprises the step of mixing a physiologically acceptable vehicle comprising at least one naphthoic acid derivative with at least one compound of polyurethane polymer type or 10 derivatives thereof, the said naphthoic acid derivative being in a form dispersed in the said composition. The other possible excipients and additives will be introduced as a function of the chemical nature of the 15 compounds and of the chosen galenical form. The preparation of a composition according to the invention is performed in 2 or 4 steps according to the chosen galenical form, the 2 additional steps being 20 performed solely for the preparation of forms of emulsion type such as creams, lotions or cream-gels. The introduction of the polyolprepolymer into one or other of the steps is dependent on the lipophilic or 25 hydrophilic nature of the polyolprepolymer. Thus, the polyolprepolymer of the type PP-2 of lipophilic nature is introduced into the fatty phase for the emulsions and after the neutralization step for the gels. The polyolprepolymer of the type PP-15, which is 30 hydrophilic, is introduced into the active aqueous phase after dispersing of the gelling agent(s). The preparation of a composition according to the invention is thus performed according to the following 35 process: a) the naphthoic acid derivative is mixed with at least one wetting agent, at least one chelating agent, at least one gelling agent, optionally hydrophilic WO 2007/031883 PCT/IB2006/003852 - 19 emulsifiers and emollients, in water, until the said naphthoic acid derivative is fully dispersed, in order to obtain the aqueous active phase; 5 b) optionally, to produce an emulsion, at least lipophilic emulsifiers, oils and/or solid fatty substances are mixed with preserving agents, in order to obtain the fatty phase; 10 c) optionally, the said fatty phase obtained in b) is introduced into the aqueous active phase obtained in a) in order to obtain an emulsion; d) if necessary, a gelling-agent neutralizer is 15 introduced into the emulsion obtained in c) or into the aqueous phase obtained in a) in order to obtain the desired pH, and the remaining amount of water is added; the compound of polyurethane polymer type or derivatives thereof being introduced into the aqueous 20 active phase obtained in a) or into the fatty phase obtained in step b) or during step d) as a function of its lipophilic or hydrophilic nature. More specifically, the process for preparing the 25 composition according to the invention comprises the following steps: Step a: preparation of the aqueous active phase: 30 Purified water, the active principle (adapalene), optionally the hydrophilic emulsifiers (such as Arlacel 165FL or Tween 80) in the case of preparing an oil-in water emulsion, the emollients (such as glycerol or propylene glycol), the wetting agents (such as 35 Synperonic PE/L62 or Synperonic PE/L44), the chelating agent (such as EDTA), the gelling agent(s) (such as Carbopol, Pemulen TRl, Xantural, Methocel or Simulgel 600) are introduced with stirring using a deflocculator into a beaker that will serve as the receiver for the WO 2007/031883 PCT/IB2006/003852 - 20 finished product. The mixture is stirred without heating until fully dispersed. When the mixture is homogeneous, the aqueous phase is brought to 60 0 C on a water bath and the preserving agent (such as methyl 5 paraben) is introduced. Step b (optional): Preparation of the fatty phase: The lipophilic emulsifiers (such as Glucate SS, 10 Glucamate SSE 20 or Brij 721, Tefose 1500, Eumulgin B2 PH), the oily compounds (such as isostearic olepal, Cetiol SN, Crodamol DA, Speziol C18, Miglyol 812 or Cosbiol) and the preserving agents (such as phenoxyethanol and propyl paraben) are introduced with 15 stirring using a deflocculator into an additional beaker. The mixture is brought to 60 0 C on a water bath and, after homogenization, the volatile silicone, if present, is introduced into the composition. 20 Step c (optional) : Emulsification: The fatty phase is introduced gently into the aqueous phase at a temperature of 60 0 C and with stirring using a deflocculator, in order to perform the 25 emulsification. Heating is maintained for 5 minutes and the hotplate is then removed to allow the product to cool gently. The stirring is adjusted as a function of the viscosity. 30 Steps 2 and 3 are optional and are performed solely for the preparation of forms of emulsion type such as creams, lotions or cream-gels. Step d: Neutralization: 35 The gelling-agent neutralizer (such as triethanolamine or 10% sodium hydroxide solution) is introduced, if necessary, at 400C, up to a pH of 5.5 ± 0.5. The product then has a thicker consistency. At the end of WO 2007/031883 PCT/IB2006/003852 - 21 the manufacture, the pH is again checked. If it is within the norms, the sufficient quantity of water is added. The product is homogenized a final time in order to ensure good dispersion of the adapalene active 5 principle (observation by microscope revealing a uniform dispersion free of aggregates), and the product is then packaged. The compound of polyurethane polymer type is preferably 10 a polyolprepolymer that is introduced during step a) (for the gel or emulsion formulations comprising a hydrophilic polymer) or during step b) (for the emulsion formulations comprising a lipophilic polymer), or during step d) (for the gel formulations comprising 15 a lipophilic polymer) as a function of its lipophilic or hydrophilic nature. The invention also relates to the use of the novel composition as described above in cosmetics and 20 dermatology. In particular, the invention relates to the use of a composition as described above for the preparation of a pharmaceutical composition for treating and/or 25 preventing dermatological complaints associated with a keratinization disorder that has a bearing on cell differentiation and proliferation, especially for treating simple acne, comedonic acne, papulopustular acne, papulocomedonic acne, nodulocystic acne, acne 30 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 medication-related acne. 35 More particularly, the invention relates to the use of a composition as described above for the preparation of a pharmaceutical composition for preventing or treating simple acne.

- 22 The said compositions according to the invention are preferentially administered topically. In addition, the invention also relates to the cosmetic 5 use of a composition according to the invention for the treatment of acne-prone skin, for combating the greasy appearance of the skin or the hair, in the protection against the harmful aspects of sunlight or in the treatment of physiologically greasy skin, or for 10 preventing and/or combating light-induced or chronological ageing. The invention also relates to a method of treating and/or preventing dermatological complaints associated 15 with a keratinization disorder that has a bearing on cell differentiation and proliferation, especially for treating simple acne, comedonic acne, papulopustular acne, papulocomedonic acne, nodulocystic acne, acne conglobata, cheloid acne of the nape of the neck, 20 recurrent miliary acne, necrotic acne, neonatal acne, occupational acne, acne rosacea, senile acne, solar acne and medication-related acne; which comprises administering a therapeutically effective amount of the composition as described above, to a subject in need 25 thereof. The present invention will now be illustrated by means of the following examples: 30 Example 1: Manufacture of a formulation of gel type containing adapalene and polyurethane polymer The manufacture is performed in 4 steps: 35 Step 1, preparation of the aqueous phase: Purified water, EDTA and methyl paraben are introduced into a beaker. The beaker is then placed on a water bath (or on a hotplate) in order to bring the solution - 22a to 80 0 C ± 50C, allowing dissolution of the paraben. Next, the beaker is stirred with a Rayneri blender equipped with a deflocculating paddle until totally dispersed. Carbopol 980 NF is then added as a shower 5 and the mixture is stirred until fully dispersed. Step 2, preparation of the active phase: Propylene glycol and Synperonic PE/L62 are introduced 10 into an additional beaker. Adapalene is then introduced and the beaker is stirred using an Ultra-Turrax blender (paddle: 540 rpm; turbomixer 20 500 rpm) . When the adapalene is fully dispersed (observation by microscope revealing a uniform dispersion free of aggregates), the 15 WO 2007/031883 PCT/IB2006/003852 - 23 phase is then added to the rest of the formulation. Step 3: Neutralization: a sufficient amount of aqueous 10% (m/m) sodium hydroxide solution is added to the 5 formula phase in order to bring the formulation to pH 5.5 ± 0.5. Step 4: The polyurethane polymer (polyolprepolymer-2) is introduced. 10 The mixture is made up to the required volume with a sufficient quantity of water. Example 2: Formulation of gel type containing 0.1% 15 adapalene and polyolprepolymer-2: The formula is prepared according to the procedure described in Example 1. Constituents Content (% m/m) Purified water 80.00 Na2 EDTA 0.10 Methyl paraben 0.10 Carbopol 980 NF 1.00 Propylene glycol 4.00 Synperonic PE/L62 0.20 Adapalene 0.10 Polyolprepolymer-2 1.00 10% sodium hydroxide solution qs pH 5.5 ± 0.5 Purified water qs 100 20 Example 3: Formulation of gel type containing 0.1% adapalene and polyolprepolymer-2: The formula is prepared according to the procedure 25 described in Example 1. Constituents Content (%. m/m) Purified water 80.00 WO 2007/031883 PCT/IB2006/003852 - 24 Na2 EDTA 0.10 Methyl paraben 0.10 Carbopol 980 NF 1.00 Propylene glycol 4.00 Synperonic PE/L62 0.20 Adapalene 0.10 Polyolprepolymer-2 3.00 10% sodium hydroxide solution qs pH 5.5 ± 0.5 Purified water qs 100 Example 4: Formulation of gel type containing 0.1% adapalene and polyolprepolymer-2: 5 The formula is prepared according to the procedure described in Example 1. Constituents Content (% m/m) Purified water 80.00 Na2 EDTA 0.10 Methyl paraben 0.10 Carbopol 980 NF 1.00 Propylene glycol 4.00 Synperonic PE/L62 0.20 Adapalene 0.10 Polyolprepolymer-2 10.00 10% sodium hydroxide solution qs pH 5.5 ± 0.5 Purified water qs 100 Example 5: Chemical stability of the formulation 10 according to Example 2: T zero T 1 month T 2 months T 3 months T 6 months 0.9999 mg/g 1.008 mg/g 0.9913 mg/g 0.9852 mg/g 1.000 mg/g ± 0.3% + 0.3% ± 0.5% ± 0.6% + 0% (100.0%) (100.8%) (99.1%) (98.5%) (100.0%) The chemical stability of the gel formulation described in Example 2 is measured by HPLC over 6 months at room 15 temperature (RT) . The results show that this WO 2007/031883 PCT/IB2006/003852 - 25 composition is chemically stable for 6 months at room temperature. Example 6: Chemical stability of the formulation 5 according to Example 3: T zero T 1 month T 2 months T 3 months T 6 months 1.0052 mg/g 1.008 mg/g 0.9972 mg/g 0.9863 mg/g 0.9872 mg/g ± 0.3% ± 0.7% i 0.2% ± 0.1% ± 0.6% (100.5%) (100.8%) (99.7%) (98.6%) (98.7%) The chemical stability of the gel formulation described in Example 3 is measured by HPLC over 6 months at room 10 temperature (RT). The results show that this composition is chemically stable for 6 months at room temperature, and at constant pH. Moreover, the pH of the compositions was measured and 15 shows good stability. Example 7: General process for manufacturing an oil-in water emulsion formulation of cream-gel, cream or lotion type according to the invention 20 The manufacture is performed in 4 steps: Step 1, preparation of the aqueous active phase: 25 Purified water, the active principle (adapalene), the hydrophilic emulsifiers such as Arlacel 165FL and Tween 80, the emollients such as glycerol and propylene glycol, the wetting agents such as Synperonic PE/L44, the chelating agent such as EDTA and the gelling 30 agent(s) such as Carbopol, Pemulen TR1, Xantural, Methocel or Simulgel 600 are introduced with stirring using a deflocculator into a beaker that will serve as receiver for the finished product. The mixture is stirred without heating until fully dispersed. When the 35 mixture is homogeneous, the aqueous phase is brought to WO 2007/031883 PCT/IB2006/003852 - 26 600C on a water bath and the methyl paraben is introduced. Step 2: Preparation of the fatty phase: 5 The lypophilic emulsifiers such as Glucate SS/Glucamate SSE 20 or Brij 721, Tefose 1500, Eumulgin B2 PH, the oily compounds such as isostearic olepal, Cetiol SN, Crodamol DA, Speziol C18, Miglyol 812 or Cosbiol and 10 the preserving agents such as phenoxyethanol and propyl paraben are introduced with stirring using a deflocculator into an additional beaker. The mixture is brought to 600C on a water bath and, after homogenization, the volatile silicone, if present, is 15 introduced into the composition. Step 3: Introduction of the polyolprepolymer: If it is the polyolprepolymer-2, which is lipophilic, 20 it will be introduced into the fatty phase, from the start of weighing out. On the other hand, if it is the polyolprepolymer-15, which is hydrophilic, it will be introduced into the aqueous phase, after dispersion of the gelling agent(s). 25 Step 4: Emulsification: The fatty phase is introduced gently into the aqueous phase at a temperature of 600C and with stirring using 30 a deflocculator, to perform the emulsification. Heating is maintained for 5 minutes and the hotplate is then removed to allow the product to cool gently. 35 The stirring is regulated as a function of the viscosity. At 400C, the gelling-agent neutralizer (such as triethanolamine or 10% sodium hydroxide solution) is introduced, if necessary, up to a pH of 5.5 ± 0.5. The product then has a much thicker consistency. At the end WO 2007/031883 PCT/IB2006/003852 - 27 of manufacture, the pH is again checked. If it is within the norms, the sufficient quantity of water is added. The product is homogenized a final time in order to ensure good dispersion of the active principle 5 adapalene (observation by microscope revealing a uniform dispersion free of aggregates) and the product is then packaged. Example 8: Formulation of cream type containing 0.1% 10 adapalene and polyolprepolymer-2 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.10 Glucamate SSE 20 3.50 Glucate SS 3.50 Propyl paraben 0.10 Phenoxyethanol 0.50 Cosbiol 6.00 Polyolprepolymer-2 3.00 Mirasil CM5 13.00 Na2 EDTA 0.10 Carbopol 974P NF 0.40 Glycerol 3.00 Methyl paraben 0.10 Triethanolamine qs pH 5.5 0.5 Purified water qs 100 15 Example 9: Formulation of cream type containing 0.1% adapalene and polyolprepolymer-2 20 The formula is prepared according to the procedure described in Example 7. Constituents Content (% r/m) WO 2007/031883 PCT/IB2006/003852 - 28 Adapalene 0.10 Glucamate SSE 20 3.50 Glucate SS 3.50 Propyl paraben 0.10 Phenoxyethanol 0.50 Cosbiol 6.00 Polyolprepolymer-2 10.00 Mirasil CM5 13.00 Na2 EDTA 0.10 Carbopol 974P NF 0.40 Glycerol 3.00 Methyl paraben 0.10 Triethanolamine qs pH 5.5 ± 0.5 Purified water qs 100 Example 10: Formulation of cream type containing 0.1% adapalene and polyolprepolymer-15 5 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.10 Glucamate SSE 20 3.50 Glucate SS 3.50 Propyl paraben 0.10 Phenoxyethanol 0.50 Cosbiol 6.00 Polyolprepolymer-15 3.00 Mirasil CM5 13.00 Na2 EDTA 0.10 Carbopol 974P NF 0.40 Glycerol 3.00 Methyl paraben 0.10 Triethanolamine qs pH 5.5 0.5 Purified water qs 100 Example 11: Formulation of cream type containing 0.1% 10 adapalene and polyolprepolymer-15 WO 2007/031883 PCT/IB2006/003852 - 29 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0~.10 Glucamate SSE 20 3.50 Glucate SS 3.50 Propyl paraben 0.10 Phenoxyethanol 0.50 Cosbiol 6.00 Polyolprepolymer-15 10.00 Mirasil CM5 13.00 Na2 EDTA 0.10 Carbopol 974P NF 0.40 Glycerol 3.00 Methyl paraben 0.10 Triethanolamine qs pH 5.5 i 0.5 Purified water qs 100 5 Example 12: Formulation of lotion type containing 0.1% adapalene and polyolprepolymer-2 The formula is prepared according to the procedure 10 described in Example 7. Constituents Content (% m/m) Adapalene 0.10 Methyl paraben 0.15 Na2 EDTA 0.10 Methocel E4M Premium 0.10 Pemulen TR1 0.30 Isostearic olepal 2.00 Cosbiol 8.00 Polyolprepolymer-2 3.00 Cetiol SN PH 8.00 Propyl paraben 0.05 10 m/m% sodium hydroxide qs pH 5.5 i 0.5 Purified water qs 100 WO 2007/031883 PCT/IB2006/003852 - 30 Example 13: Formulation of lotion type containing 0.1% adapalene and polyolprepolymer-2 5 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.10 Methyl paraben 0.15 Na2 EDTA 0.10 Methocel E4M Premium 0.10 Pemulen TRI 0.30 Isostearic olepal 2.00 Cosbiol 8.00 Polyolprepolymer-2 5.00 Cetiol SN PH 8.00 Propyl paraben 0.05 10 m/m% sodium hydroxide qs pH 5.5 0.5 Purified water qs 100 Example 14: Formulation of lotion type containing 0.1% 10 adapalene and polyolprepolymer-2 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.10 Methyl paraben 0.15 Na2 EDTA 0.10 Methocel E4M Premium 0.10 Pemulen TR1 0.30 Isostearic olepal 2.00 Cosbiol 8.00 Polyolprepolymer-2 7.00 Cetiol SN PH 8.00 Propyl paraben 0.05 10 m/m% sodium hydroxide qs pH 5.5 i 0.5 WO 2007/031883 PCT/IB2006/003852 - 31 Purified water qs 100 Example 15: Formulation of lotion type containing 0.1% adapalene and polyolprepolymer-2 5 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.10 Methyl paraben 0.15 Simulgel 600 PHA 1.00 Brij 721 3.00 Arlacel 165FL 3.00 Na2 EDTA 0.10 Propyl paraben 0.05 Polyolprepolymer-2 3.00 Cosbiol 5.00 Cetiol SN PH 5.00 10 m/m% sodium hydroxide qs pH 5.5 i 0.5 Purified water qs 100 Example 16: Formulation of lotion type containing 0.1% 10 adapalene and polyolprepolymer-2 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.10 Methyl paraben 0.15 Simulgel 600 PHA 1.00 Brij 721 3.00 Arlacel 165FL 3.00 Na2 EDTA 0.10 Propyl paraben 0.05 Polyolprepolymer-2 5.00 Cosbiol 5.00 Cetiol SN PH 5.00 WO 2007/031883 PCT/IB2006/003852 - 32 10 m/m% sodium hydroxide qs pH 5.5 ± 0.5 Purified water qs 100 Example 17: Formulation of lotion type containing 0.1% adapalene and polyolprepolymer-2 5 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.10 Methyl paraben 0.15 Simulgel 600 PHA 1.00 Brij 721 3.00 Arlacel 165FL 3.00 Na2 EDTA 0.10 Propyl paraben 0.05 Polyolprepolymer-2 7.00 Cosbiol 5.00 Cetiol SN PH 5.00 10 m/m% sodium hydroxide qs pH 5.5 ± 0.5 Purified water qs 100 Example 18: Formulation of lotion type containing 0.3% 10 adapalene and polyolprepolymer-2 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.30 Glycerol 7.00 Methyl paraben 0.20 Na2 EDTA 0.10 Carbopol 981NF 0.15 Propyl paraben 0.10 Eumulgin B2 PH 3.00 Arlacel 165FL 3.00 Speziol C18 Pharma 2.00 WO 2007/031883 PCT/IB2006/003852 - 33 Mygliol 812 N 7.00 Polyolprepolymer-2 3.00 Mirasil CM5 6.00 Synperonic PE/L44 0.20 Propylene glycol 4.00 Simulgel 600 PHA 0.80 10 m/m% sodium hydroxide qs pH 5.5 ± 0.5 Purified water qs 100 Example 19: Formulation of cream-gel type containing 0.3% adapalene and polyolprepolymer-2 5 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.30 Na2 EDTA 0.10 Methyl paraben 0.20 Xantural 180 0.10 Glycerol 5.00 Pemulen TRl 0.35 Propyl paraben 0.10 Miglyol 812 7.00 Polyolprepolymer-2 3.00 Tween 80V Pharma 1.00 Synperonic PE/L44 0.20 Propylene glycol 5.00 10 m/m% sodium hydroxide qs pH 5.5 0.5 Purified water qs 100 Example 20: Formulation of cream-gel type containing 10 0.3% adapalene and polyolprepolymer-2 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.30 WO 2007/031883 PCT/IB2006/003852 - 34 Na2 EDTA 0.10 Methyl paraben 0.20 Glycerol 5.00 Propyl paraben 0.10 Miglyol 812 7.00 Polyolprepolymer-2 3.00 Synperonic PE/L44 0.20 Propylene glycol 5.00 Simulgel 600 PHA 2.20 Purified water qs 100 Example 21: Formulation of cream-gel type containing 0.3% adapalene and polyolprepolymer-2 5 The formula is prepared according to the procedure described in Example 7. Constituents Content (% m/m) Adapalene 0.30 Na2 EDTA 0.10 Methyl paraben 0.20 Pemulen TR1 0.30 Glycerol 5.00 Carbopol 981 NF 0.20 Propyl paraben 0.10 Miglyol 812 7.00 Polyolprepolymer-2 3.00 Tween 80V Pharma 1.00 Propylene glycol 5.00 Synperonic PE/L44 0.20 10 m/m% sodium hydroxide qs pH 5,5±0.5 Purified water qs 100 Example 22: Formulation of lotion type containing 0.1% 10 adapalene and 3% PP-2 The formula is prepared according to the procedure described in Example 7 .

WO 2007/031883 PCT/IB2006/003852 - 35 constituents Content (% m/m) Titriplex IT 0.1 Nipagin M 0.2 Carbopol 981 0.2 Phenoxetol 1.0 Nipasol M 0.1 Speziol C18 Pharma 2.0 Tefose 1500 5.0 Miglyol 812N 7.0 Polyolprepolymer-2 3.0 Adapalene 0.1 Synperonic PE/L44 0.2 Propylene glycol USP/EP 4.0 10 m/m% sodium hydroxide qs pH 5,5±0.5 Purified water qs 100 Example 23: Formulation of lotion type containing 0.3% adapalene and 3% PP-2 5 The formula is prepared according to the procedure described in Example 7 constituents Content (% m/m) Titriplex III 0.1 Nipagin M 0.2 Carbopol 981 0.2 Phenoxetol 1.0 Nipasol M 0.1 Speziol C18 Pharma 2.0 Tefose 1500 5.0 Miglyol 812N 7.0 Polyolprepolymer-2 3.0 Adapalene 0.3 Synperonic PE/L44 0.2 Propylene glycol USP/EP 4.0 10 m/m% sodium hydroxide qs pH 5,5±0.5 Purified water qs 100 WO 2007/031883 PCT/IB2006/003852 - 36 Specifications at time zero: Macroscopic appearance Very fluid glossy white milk pH at T=24 hours 5.4 globules 2.5 to 12.5 pm.. Adapalene well distributed as Microscopic appearance 10 to 25 pm lumps. Viscosity: u (4s-1) flow threshold in Pa.s~1 12 Analytical assay at TO 99.6% 5 The physical and chemical stabilities of this composition were measured. The results are given below: TI month T2 months T3 months Viscosity: ' 13 12 12 (4s-1) flow threshold in Pa.s- 1 Macroscopic Compliance Compliance Compliance RT appearance pH 5.4 5.4 / Microscopic Compliance Compliance Compliance appearance Analytical 99.-7% 98.6% 98.8% assay Macroscopic Compliance Compliance Compliance appearance 4 0 C Microscopic Compliance Compliance Compliance appearance Macroscopic Compliance Compliance Compliance appearance 40 0 C Microscopic Compliance Compliance Compliance appearance Analytical 98.9% 96.5% 98.7% assay WO 2007/031883 PCT/IB2006/003852 - 37 The composition is thus chemically and physically stable. 5 Example 24: Formulation of the lotion type cream gel containing 0.3% adapalene and 3% PP-2 The formula is prepared according to the procedure described in Example 7. 10 Composition Content (% m/m) Titriplex III 0.1 Nipagin M 0.2 Glycerol 7.0 Carbopol 981 NF 0.15 Benzalkonium chloride 0.05 Nipasol M 0.1 Eumulgin B2 PH 3.0 Speziol C18 Pharma 2.0 Miglyol 812 N 7.0 Polyolprepolymer-2 3.0 Arlacel 165 FL 3.0 Mirasil CM5 6.0 Synperonic PE/L44 0.2 Propylene glycol USP/EP 4.0 Adapalene 0.3 Simulgel 600 0.8 10 m/m% sodium hydroxide qs pH 5,5±0.5 Purified water qs 100 Specifications at time zero: Macroscopic appearance Glossy thick white milk pH at T24 hours 5.7 Globules 2.5 t and up to 10 pt Microscopic appearance Adapalene well dispersed as lumps 2.5 pim to 10 WO 2007/031883 PCT/IB2006/003852 - 38 . Pm Viscosity: r (4s-1) in Pa.s 1 44 Analytical assay at TO 98.2% The physical and chemical stabilities of this composition were measured. The results are given below: Ti month T2 months Viscosity: T 42 NR (4s-1) flow threshold in Pa.s-1 Macroscopic Compliance Compliance RT appearance pH 5.76 NR Microscopic Compliance Compliance appearance Analytical 98C.2% 98C. 3 assay Macroscopic Compliance Compliance appearance 40C Microscopic Compliance Compliance appearance Macroscopic Compliance Compliance appearance 40*C Microscopic Compliance Complianc appearance Analytical 98.3% 104.8 assay 5 The composition is thus physically and chemically stable. Example 25: Formulation of the type lotion 10 containing 0.3% adapalene and 3% PP-2 The formula is prepared according to the procedure WO 2007/031883 PCT/IB2006/003852 - 39 described in Example 7. Composition Content (% m/m) Titriplex IIT 0.1 Nipagin M 0.2 Carbopol 980 NF 0.15 Carbopol 981 NF 0.3 Glycerol 3.0 Phenoxetol 1.0 Nipasol M 0.2 Glucate SS 1.0 Glucamate SSE20 5.0 Miglyol 812 N 6.0 Polyolprepolymer-2 3.0 Q7-9120 silicone 1.0 fluid 20 cSt Synperonic PE/L44 0.2 Propylene glycol USP/EP 4 Adapalene 0.3 10 m/m% sodium hydroxide qs pH 5,5±0. 5 Purified water qs 100 Specifications at time zero: 5 Macroscopic appearance Glossy white milk pH at T=24 hours 5.4 globules 2.5 pm Adapalene distributed in Mi-croscopic appearance globules from 2.5 to 20 pm. Viscosity: V (4s-1) in Pa.s- 37 Analytical assay at TO 102.0% The physical and chemical stabilities of this composition were measured. The results are given below: T1 month T2 months T3 months WO 2007/031883 PCT/IB2006/003852 - 40 Viscosity: T 40 42 NR (4s-1) in Pa.s- 1 Macroscopic Compliance Compliance Compliance appearance RT pH 5.4 5.4 5.4 Microscopic Compliance Compliance Compliance appearance Analytical 101.4% 102.0 102.7 assay Macroscopic Compliance Compliance Compliance appearance 4 0 C Microscopic Compliance Compliance Compliance appearance Macroscopic Compliance Compliance Compliance appearance 40 0 C Microscopic Compliance Compliance Compliance appearance Analytical 102.8% 102.0 104.8 assay The composition is thus chemically and physically stable. 5 Example 26: Formulation of the type cream-gel containing 0.3% adapalene and 3% PP-2 The formula is prepared according to the procedure described in Example 7. 10 Composition Content (% m/m) Titriplex III 0.1 Nipagin M 0.2 Propylene glycol 3.0 Glycerol 5.0 Nipabutyl 0.2 Nipasol M 0.1 Miglyol 812 N 7.0 WO 2007/031883 PCT/IB2006/003852 - 41 Polyolprepolymer-2 3. 0 Benzyl alcohol 1.0 Synperonic PE/L44 0.2 Propylene glycol USP/EP 4.0 Simulgel 600 PHA 2.0 Adapalene 0.3 Purified water qs 100 Specifications at time zero: Macroscopic appearance Quite fluid glossy white milk pH at T=24 hours 5.2 Globules 5 2.5 pm to 12.5 pm. Adapalene distributed in Microscopic appearance globules from 2.5 to 20 pm. Viscosity: T (43-1) flow threshold in Pa . s- 18 Analytical assay at TO 98.7 5 The physical and chemical stabilities of this composition were measured. The results are given below: TI month T2 months Viscosity: T NR NR (4s-1) in Pa.s 1 Macroscopic Compliance Compliance appearance RT pH Microscopic Compliance Compliance appearance Analytical 98.5% 98.6 assay Macroscopic Compliance Compliance appearance 4 0 C Microscopic Compliance Compliance I appearance WO 2007/031883 PCT/IB2006/003852 - 42 Macroscopic Compliance Compliance appearance 40 0 C Microscopic Compliance Compliance appearance Analytical 98.8% 101.7% assay The composition is thus physically and chemically stable. 5 Example 27: Formulation of the type lotion containing 0.3% adapalene and 3% PP-2 The formula is prepared according to the procedure described in Example 7. 10 Composition Content (% m/m) Titriplex 1II 0.1 Pemulen TR1 NF 0.3 Glycerol 5.0 Carbopol 981 NF 0.2 Nipasol M 0.2 Nipabutyl 0.2 Miglyol 812 N 7.0 Benzyl alcohol 1 Polyolprepolymer-2 3.0 Synperonic PE/L44 0.2 Tween 80 V Pharma 1.0 Propylene glycol USP/EP 7.0 Adapalene 0.3 10 m/m% sodium hydroxide qs pH 5,5±0.5 Purified water qs 100 Specifications at time zero: Macroscopic appearance Gelled glossy white milk pH at T=24 hours 5.6 Globules 2.5 ptm to 7.5 pm.

WO 2007/031883 PCT/IB2006/003852 - 43 Microscopic appearance Adapalene in globules of 2.5 to 12.5 pm. Viscosity: t (4s-1) in Pa.s- 34 Analytical assay at TO 99.4 The physical and chemical stabilities of this composition were measured. The results are given below: TI month T2 months T3 months Viscosity: T 38 35 36 (4s-1) in Pa. s~ 1 Macroscopic Compliance Compliance Compliance appearance RT pH 5.7 5.6 5.6 Microscopic Compliance Compliance Compliance appearance Analytical 99.7 99.2 100.2 assay Macroscopic Compliance Compliance Compliance appearance 4 0 C Microscopic Compliance Compliance Compliance appearance Macroscopic Compliance Compliance Compliance appearance 40 0 C Microscopic Compliance Compliance Compliance appearance Analytical 99.5 106.2 100.3 assay 5 The composition is thus physically and chemically stable. Example 28: Study of in vitro release-penetration 10 The present study is aimed at comparing in vitro the WO 2007/031883 PCT/IB2006/003852 - 44 release-penetration into human skin without occlusion of adapalene formulated at 0.1% (m/m) in a gel containing 1% PP-2 (formulation according to Example 2), formulated at 0.1% (m/m) in a gel containing 3% 5 PP-2 (formulation according to Example 3) and in a reference gel containing 0.1% adapalene. The absorption studies were performed using excized human skin mounted under static conditions for a period 10 of 16 hours. Three samples of skin obtained from women (68 years old) were used. An amount of 10 mg of each formula (10 tg of adapalene) was applied to a 1 cm 2 area of skin. The adapalene concentrations in the fluid fractions collected over time and remaining in the skin 15 at the end of the study were evaluated by the HPLC method with fluorescence detection (based on a validated method. Quantification limit: 1 ng.mL'). The experimental results are collated in the table 20 below: Reference gel Formulation Formulation containing 0.1% according to according to adapalene Example 2 Example 3 Dose absorbed in epidermis + 0.11 Rg 0.10 pig 0.21 Rg stratum corneum Dose absorbed in 0.013 pg 0.003 pg 0.009 pg dermis Epidermis/dermis 9 33 23 ratio These results show that, irrespective of the formula tested, the adapalene is mainly distributed in the 25 epidermis (stratum corneum included) and to a lesser extent in the dermis. The epidermis/dermis ratios for the formulations according to Examples 2 and 3 are markedly higher than the epidermis/dermis ratio for the reference gel containing 0.1% adapalene. These results WO 2007/031883 PCT/IB2006/003852 - 45 suggest that the presence of PP-2 in the formulations according to the invention considerably modifies the distribution of adapalene in the skin by retaining the adapalene mainly in the stratum corneum and epidermis 5 upper layers. This example thus demonstrates the "reservoir effect" of the formulations according to the invention. Example 29: Tolerance study in BALB/c mice 10 The present study is aimed at comparing the irritant power of a reference gel containing 0.1% adapalene with that of three 0.1% adapalene formulations in gel form containing a polyurethane polymer at various 15 concentrations, and also placebos thereof, on the skin of the ear of the BALB/c mouse after repeated topical applications for 6 days. The daily topical application (20 pl) of the test 20 products is performed on the inner face of the ear of BALB/c mice divided into ten groups (female mice about 8 weeks old) at a rate of one application per day for 6 days. The test products are: Group 1: acetone (control vehicle) 25 Group 2: placebo reference gel (control vehicle) Group 3: placebo formulation (without 0.1% adapalene) of Example 2 (1% PP-2) (control vehicle) Group 4: placebo formulation (without 0.1% adapalene) of Example 3 (3% PP-2) (control vehicle) 30 Group 5: placebo formulation (without 0.1% adapalene) of Example 4 (10% PP-2) (control vehicle) Group 6: reference gel containing 0.1% adapalene Group 7: formulation of Example 2 (1% PP-2) Group 8: formulation of Example 3 (3% PP-2) 35 Group 9: placebo formulation of Example 4 (10% PP-2) Group 10: acetone + 0.1% (m/m) adapalene The evaluation is performed by measuring the thickness of the ear by means of the Oditest and by clinical WO 2007/031883 PCT/IB2006/003852 - 46 observation of the animals from the 2 nd to the 19th day. The results are given in the table below and in Figures 1 to 4, in which: 5 - Figure 1 shows the kinetics of the mean thickness of the mouse ears between the 2"n and 1 9 th days for the various test products with: 10 e acetone (curve (lA)) " placebo reference gel (curve (1B)) * placebo Ex. 2 (1% PP-2) (curve (1C)) * placebo Ex. 3 (3% PP-2) (curve (1D)) " placebo Ex. 4 (10% PP-2) (curve (1E)) 15 These placebo kinetics show that the various placebo formulations used are not irritant and behave like acetone. 20 - Figure 2 shows the kinetics of the mean thickness of the mouse ears between the 2 nd and 1 9 th days for the various test products with: 0 acetone (curve (2A)) 25 * acetone + 0.1% adapalene (curve (2B)) * placebo reference gel (curve (2C)) * reference gel containing 0.1% adapalene (curve (2D)) e placebo Example 2 (1% PP-2) (curve (2E)) 30 e Example 2 (1% PP-2) (curve (2F)) These kinetics show that the reference gel containing 0.1% adapalene is irritant from the sixth day with a 31% increase in the area under the curve relative to 35 its placebo (placebo reference gel) . Similarly, the product acetone + 0.1% adapalene is also irritant and shows a 30% increase in the area under the curve relative to its placebo (acetone). Surprisingly, the formulation according to Example 2 (1% PP-2) is only WO 2007/031883 PCT/IB2006/003852 - 47 half as irritant as the reference gel containing 0.1% adapalene and shows an increase in the area under the curve of only 15% relative to its placebo (placebo Example 2 (1% PP-2)). 5 - Figure 3 shows the kinetics of the mean thickness of the mouse ears between the 2 nd and 1 9 th days for the various test products with: 10 e acetone (curve (3A)) e acetone + 0.1% adapalene (curve (3B)) * placebo reference gel (curve (3C)) e reference gel containing 0.1% adapalene (curve (3D)) 15 e placebo Example 3 (3% PP-2) (curve (3E)) 0 Example 3 (3% PP-2) (curve (3F)) These kinetics also show, surprisingly, that the formulation according to Example 3 is less irritant 20 than the reference gel containing 0.1% adapalene. This formulation according to Example 3 (3% PP-2) also shows an increase in the area under the curve of only 19% relative to its placebo (placebo Example 3 (3% PP-2)). 25 - Figure 4 shows the kinetics of the mean thickness of the mouse ears between the 2 "d and 1 9 th days for the various test products with: * acetone (curve (4A)) 30 e acetone + 0.1% adapalene (curve (4B)) * placebo reference gel (curve (4C)) e reference gel containing 0.1% adapalene (curve (4D)) e placebo Example 4 (10% PP-2) (curve (4E)) 35 * Example 4 (10% PP-2) (curve (4F)) These kinetics show that the formulation according to Example 4 is less irritant than the reference gel containing 0.1% adapalene. This formulation according WO 2007/031883 PCT/IB2006/003852 - 48 to Example 3 (3% PP-2) similarly shows an increase in the area under the curve of 22% relative to its placebo (placebo Example 4 (3% PP-2)). 5 When a comparison is made of the kinetics of the various formulations described, respectively, in Examples 2 to 4, it is seen that these three formulations have very similar kinetics. It is impossible to differentiate them. Surprisingly, these 10 three formulations are all less irritant than the reference gel containing 0.1% adapalene and than 0.1% (m/m) adapalene in acetone. Summary table of the results of the areas under the 15 curve (AUC) for the ear thickness kinetics AUC 02-D19 Standard Increase in Mean error of AUC versus mean (SEM) placebo (%) Group 2 (placebo reference gel) 383.3 2.1 Group 3 (placebo Example 2) 385.8 3.1 Group 4 (placebo Example 3) 380.7 2.2 Group 5 (placebo Example 4) 379.5 2.6 Group 6 (reference gel containing 502.0 30.2 31.0 0.1% adapalene) Group 7 (Example 2) 445.4 15.0 15.4 Group 8 (Example 3) 453.6 11.7 19.2 Group 9 (Example 4) 461.8 17.1 21.7 WO 2007/031883 PCT/IB2006/003852 - 49 The results of the study show that, after repeated topical applications of 20 pl of test product from Dl to D6 to the BALB/c mouse ear: 5 - the test placebos (respectively, "placebo reference gel", "placebo Example 2", "placebo Example 3" and "placebo Example 4") are not irritant and show fully superposable kinetics; 10 - the test formulations described in Examples 2, 3 and 4 increase the thickness of the ear by 15%, 19% and 22%, respectively, relative to their placebos. They are all less irritant than the "reference gel containing 0.1% adapalene" and difficult to 15- differentiate from each other. This example demonstrates that the formulae according to the invention show better in vivo tolerance than the "reference gel containing 0.1% adapalene". 20 The table below compares the various formulations containing 0.1% adapalene with the untreated placebo so as to demonstrate the effect of the polyurethane polymer on the tolerance. 25 AUC D2-D19 Comparison Standard Increase reference gel error of in AUS containing Mean mean versus 0.1% (SEM) untreated adapalene/ (%) test formula Group 2 (placebo 383.3 2.1 reference gel) Group 3 (placebo 385.8 3.1 - Example 2) Group 4 (placebo 380.7 2.2 WO 2007/031883 PCT/IB2006/003852 - 50 Example 3) Group 5 (placebo 379.5 2.6 Example 4) Group 6 (reference gel containing 0.1% 502.0 30.2 31.2 1.0 adapalene) Group 7 445.4 15.0 16.4 1.9 (Example 2) Group 8 453.6 11.7 18.6 1.7 (Example 3) Group 9 461.8 17.1 17.2 1.8 (Example 4) Thus, irrespective of the content of polyurethane polymer 1: 3% or 10%, the formulations are tolerated 2 times better than in the absence of polyurethane 5 polymers. Example 30: Study of the comedolytic activity on Rhino mice 10 The present study is aimed at evaluating the comedolytic activity of the reference gel containing 0.1% adapalene and of two 0.1% adapalene formulations in gel form with a polyurethane polymer at different concentrations, and also their placebos, on the skin of 15 the back of RHINO FVB/N RJ-hrrh mice (Rhino) after repeated topical applications for 18 days. The daily topical application (50 pl) of the test products is performed on the skin of the back of Rhino 20 mice divided into seven groups (approximately 7-week old mice) at a rate of one application per day for 18 days. The test products are: Group 1: acetone (control vehicle) Group 2: placebo formulation (without 0.1% adapalene) 25 of Example 3 (3% PP-2) (control vehicle) WO 2007/031883 PCT/IB2006/003852 - 51 Group 3: acetone + 0.01% (m/m) 2 -(5,5,8,8-tetramethyl 5, 6, 7, 8-tetrahydronaphthalen-2-yl) benzo [b] thiophene-6 carboxylic acid (positive control) Group 4: acetone + 0.1% (m/m) adapalene 5 Group 5: reference gel containing 0.1% adapalene Group 6: formulation of Example 2 (1% PP-2) Group 7: formulation of Example 3 (3% PP-2) The tolerance evaluation is made by clinical 10 observation of the dorsal epidermis with the following observation parameters: oedema, erythema and squamae 3 times a week for 19 days. The comedolytic activity is evaluated by measuring the 15 transepidermal water loss (TWL) on days D4, D11 and D19, by measuring the thickness of the epidermis, by counting the number of comedones/cm and by weighing the animals on days D1, D4, D11 and D19. 20 Figure 5 shows the results of the areas under the curve for the tolerance evaluation between the 1 't and 1 9 th day for the various test products with: * acetone (control vehicle) (curve (5A)) 25 e formulation of Example 3 (3% PP-2) without 0.1% adapalene (control vehicle) (curve (5B)) e acetone + 0.01% (m/m) 2 -(5,5,8,8-tetramethyl 5,6,7,8-tetrahydronaphthalen-2-yl)benzo[b]thio phene-6-carboxylic acid (positive control) (curve 30 (5C)) e acetone + 0.1% (m/m) adapalene (curve 5D)) e reference gel containing 0.1% adapalene (curve (5E)) a formulation of Example 2 (1% PP-2) (curve (5F)) 35 e formulation of Example 3 (3% PP-2) (curve (5G)) The results of this study show that the formulations according to Examples 2 and 3 are less irritant than the reference gel containing 0.1% adapalene. These WO 2007/031883 PCT/IB2006/003852 - 52 formulations according to Examples 2 (1% PP-2) and 3 (3% PP-2) effectively show a reduction in the area under the curve of 45% and 22%, respectively, relative to the reference gel containing 0.1% adapalene. 5 Figure 6 shows the results of the areas under the curve (AUC) for the transepidermal water loss (TWL) after 18 days of topical treatment for the various test products with: 10 e acetone (control vehicle) (curve (6A)) * formulation of Example 3 (3% PP-2) without 0.1% adapalene (control vehicle) (curve (6B)) " acetone + 0.01% (m/m) 2 -(5, 5,8,8-tetramethyl 15 5,6,7,8-tetrahydronaphthalen-2-yl)benzo[b]thio phene-6-carboxylic acid (positive control) (curve (6C)) e acetone + 0.1% (m/m) adapalene (curve 6D)) " reference gel containing 0.1% adapalene (curve 20 (6E)) e formulation of Example 2 (1% PP-2) (curve (6F)) " formulation of Example 3 (3% PP-2) (curve (6G)) The TWL quantifies the impairment in the skin barrier 25 by measuring the gradient of water vapour that is established in a layer 10 mm thick above the surface of the skin. The results of this study show that the formulations of 30 Examples 2 and 3 according to the invention increase the TWL by 129% and 118%, respectively. These values are markedly lower than the TWL increases observed for the acetone + 0.01% (m/m) 2 -(5,5,8,8-tetramethyl 5,6,7, 8-tetrahydronaphthalen-2-yl)benzo [b] thiophene-6 35 carboxylic acid (332%) and acetone + 0.1% (m/m) adapalene (299%) formulations and less than the TWL increase observed for the reference gel formulation containing 0.1% adapalene (152%). Figure 6 thus shows that the formulations according to the invention afford WO 2007/031883 PCT/IB2006/003852 - 53 better protection of the skin barrier than the reference gel containing 0.1% adapalene. Figure 7 shows the results of the measurement of the 5 thickness of the epidermis after 18 days of topical treatment for the various test products with: e acetone (control vehicle) (curve (7A)) * formulation of Example 3 (3% PP-2) without 0.1% 10 adapalene (control vehicle) (curve (7B)) " acetone + 0.01% (m/m) 2 -(5,5,8,8-tetramethyl 5,6,7,8-tetrahydronaphthalen-2-yl)benzo[b]thio phene-6-carboxylic acid (positive control) (curve (7C)) 15 e acetone + 0.1% (m/m) adapalene (curve 7D)) e reference gel containing 0.1% adapalene (curve (7E)) e formulation of Example 2 (1% PP-2) (curve (7F)) * formulation of Example 3 (3% PP-2) (curve (7G)) 20 The results of this study show that an equivalent increase in the thickness of the epidermis is observed for all the formulations containing adapalene. 25 Figure 8 shows the results of the counting of the number of comedones per centimetre (cm) on the back of Rhino mice after 18 days of topical treatment for the various test products with: 30 e acetone (control vehicle) (curve (8A)) * formulation of Example 3 (3% PP-2) without 0.1% adapalene (control vehicle) (curve (8B)) e acetone + 0.01% (m/m) 2 -(5,5,8,8-tetramethyl 5,6,7, 8 -tetrahydronaphthalen-2-yl)benzo [b] thio 35 phene-6-carboxylic acid (positive control) (curve (8C)) " acetone + 0.1% (m/m) adapalene (curve 8D)) e reference gel containing 0.1% adapalene (curve (8E)) WO 2007/031883 PCT/IB2006/003852 - 54 " formulation of Example 2 (1% PP-2) (curve (8F)) " formulation of Example 3 (3% PP-2) (curve (8G)) The results of this study show that the skins treated 5 with the placebos (acetone or formulation of Example 3 (3% PP-2) without 0.1% adapalene) show a similar and high number of comedones per centimetre, of between 58 and 60. On the other hand, the skins treated with formulations containing the active principle adapalene 10 (acetone + 0.1% (m/m) adapalene, reference gel containing 0.1% adapalene, formulations of Examples 2 and 3) show a comparable and low number of comedones per centimetre, of between 25 and 27. It appears, with regard to Figure 8, that the formulations according to 15 the invention have comedolytic activity comparable to the reference gel containing 0.1% adapalene. The table below shows the changes in the weight of the mice of the 7 groups of the study, between the 1 9 th day 20 and the 1 't day: change in weight of the Rhino mice (%) D19-D1 Mean Standard error of mean (SEM) Group 1: acetone (control 13.2 1.41 vehicle) Group 2: Example 3 without 0.1% 11.0 2.42 adapalene (control vehicle) Group 3: acetone + 0.01% (m/m) 2-(5,5,8,8-tetramethyl-5,6,7,8 tetrahydronaphthalen-2 yl)benzo[b]thiophene-6- 10.4 5.97 carboxylic acid (positive control) Group 4: acetone + 0.1% (m/m) 9.2 1.54 adapalene Group 5: reference gel 11.0 2.20 containing 0.1% adapalene WO 2007/031883 PCT/IB2006/003852 - 55 Group 6: formulation of 8.1 1.70 Example 2 (1% PP-2) Group 7: formulation of 8.6 2.18 Example 3 (3% PP-2) The results of this study show that after 18 days of topical treatment, the animals do not show any weight loss. Furthermore, the above table shows that there is 5 no significant difference between the animals treated with the controls and the animals treated with the various adapalene formulations. This example, and the studies that follow therefrom, 10 demonstrates that the formulae according to the invention show better in vivo tolerance than the reference gel containing 0.1% adapalene, while having comedolytic activity equivalent to that of the reference gel containing 0.1% adapalene. 15 Example 31: Study of in vitro release-penetration The present study is aimed at comparing in vitro the 20 release-penetration into human skin without occlusion of adapalene formulated at 0.3% (m/m) in a lotion containing 3% PP-2 (formulation according to Example 23), formulated at 0.3% (m/m) in a lotion containing 3% PP-2 (formulation according to Example 25) and in a 25 reference gel containing 0.1% adapalene. The absorption studies were performed using excized human skin mounted under static conditions for a period of 16 hours. Three samples of skin obtained from women 30 (68 years old) were used. An amount of 30 mg of each formula (30 pig of adapalene) was applied to a 1 cm 2 area of skin. The adapalene concentrations in the fluid fractions collected over time and remaining in the skin at the end of the study were evaluated by the HPLC 35 method with fluorescence detection (based on a - 56 validated method. Quantification limit: 1 ng.mL'1). The experimental results are collated in the table below: 5 Reference 0,1% Formulation Formulation adapalene gel example 23 example 25 Dose absorbed in 0,14pg 0,39pg 0,41 pg Stratum corneum Dose absorbed in Epidcrmc 0,05 pg 0,08 pg 0,10 pg Dose absorbed in 0,004 pg 0,005 pg 0,01 pg derme Dose absorbed in Epiderme + 0,194pg 0,47pg 0,52pg Stratum corneum+ Derme These results show that in invention formula tested, the adapalene is mainly distributed in the stratum corneum. These results suggest that the presence of PP 10 2 in the formulations according to the invention does not interfere with the active principal penetration. In the claims which follow and in the preceding description of the invention, except where the context 15 requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition 20 of further features in various embodiments of the invention. 33388411 (GHMatters) P78970.AU - 57 It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in 5 Australia or any other country. 3338841_1 (GHMatters) P76970.AU

Claims

1. Composition comprising, in a physiologically acceptable medium, at least one naphthoic acid 5 derivative and at least one compound of polyurethane polymer type or derivatives thereof, the said naphthoic acid derivative being in dispersed form in the said composition, the said composition not comprising any extract of saw 10 palmetto berries.

2. Composition according to Claim 1, wherein the naphthoic acid derivative is a compound of formula (I): O OH R (I) 15 in which R represents a hydrogen atom, a hydroxyl radical, a branched or unbranched alkyl radical containing from 1 to 4 carbon atoms, an alkoxy radical containing from 1 to 10 carbon atoms or a cycloaliphatic radical. 20

3. Composition according to Claim 1 or 2, wherein the concentration of the naphthoic acid derivative is between 0.001% and 10% by weight relative to the total weight of the composition. 333841_1 (GHMatters) P76970.AU - 59

4. Composition according to any one of the preceding claims, wherein the concentration of the naphthoic acid derivative is between 0.01% and 5% by weight relative to the total weight of the composition. 5

5. Composition according to any one of the preceding claims, wherein the concentration of the naphthoic acid derivative is between 0.05% and 2% by weight relative to the total weight of the composition. 10

6. Composition according to any one of the preceding claims, wherein the naphthoic acid derivative is chosen from 6-[3-(1-adamantyl)-4-methoxyphenyll-2-naphthoic acid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic 15 acid, 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid and 6-[3-(l-adamantyl)-4-hexyloxyphenyl)-2 naphthoic acid.

7. Composition according to any one of the preceding 20 claims, wherein the naphthoic acid derivative is 6-[3 (1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid.

8. Composition according to Claim 7, wherein the concentration of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2 25 naphthoic acid is about 0.1% by weight relative to the total weight of the composition.

9. Composition according to Claim 7, wherein the concentration of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2 30 naphthoic acid is about 0.3% by weight relative to the total weight of the composition.

10. Composition according to any one of the preceding claims, wherein the naphthoic acid derivative is the 35 only active principle present. 333841_1 (GHMatters) P76970 AU - 60

11. Composition according to any one of the preceding claims, wherein the compound of polyurethane polymer type is chosen from the polyolprepolymer of type 2, the polyolprepolymer of type 14 and the polyolprepolymer of 5 type 15, taken alone or as a mixture.

12. Composition according to claim 11, wherein the compound of polyurethane polymer type is the polyolprepolymer of type 2. 10

13. Composition according to any one of the preceding claims, wherein the concentration of the compound of polyurethane polymer type is between 0.5% and 20% by weight relative to the total weight of the composition. 15

14. Composition according to any one of the preceding claims, wherein the concentration of the compound of polyurethane polymer type is between 1% and 10% by weight relative to the total weight of the composition. 20

15. Composition according to Claim 13 or 14, wherein the concentration of the compound of polyurethane polymer type is 1%, 3%, 7% or 10% by weight relative to the total weight of the composition. 25

16. Composition according to any one of Claims 13, 14 or 15, wherein the concentration of the compound of polyurethane polymer type is lower than or equal to 7%. 30

17. Composition according to any one of the preceding claims, wherein the composition is in the form of an aqueous, aqueous-alcoholic or oily dispersion, a dispersion of the lotion type, an aqueous, anhydrous or lipophilic gel, an emulsion of liquid or semi-liquid 35 consistency of the milk type, obtained by dispersing a fatty phase in an aqueous phase or vice versa, or a 3338841_1 (GHMatters) P76970.AU - 61 suspension or emulsion of soft, semi-liquid or solid consistency of the cream, gel, cream-gel or pomade type, or alternatively a microemulsion, microcapsules, microparticles or vesicular dispersions of ionic and/or 5 nonionic type.

18. Composition according to Claim 17, wherein the composition is in the form of a gel. 10

19. Composition according to Claim 17, wherein the composition is in the form of a cream.

20. Composition according to Claim 17, wherein the composition is in the form of a lotion. 15

21. Composition according to Claim 17, wherein the composition is in the form of a cream-gel.

22. Composition according to Claim 18, wherein the 20 composition comprises in water: - from 0.1% to 0.3% of a naphthoic acid derivative; - from 1% to 10% of one or more polyurethane polymers or derivatives; - from 0.1% to 3% of gelling agents; 25 - from 0.01% to 1.5% of chelating agents; - from 1% to 10% of a wetting agent; and - from 0.01% to 3% of preserving agents.

23. Composition according to any one of Claims 19 to 30 21, wherein the composition comprises in water: - from 0.1% to 0.3% of a naphthoic acid derivative; - from 1% to 10% of one or more polyurethane polymers or derivatives; - from 0.1% to 3% of gelling agents or suspending 35 agents; - from 0.01% to 1.5% of chelating agents; 33388411 (GHMatters) P76970.AU - 62 - from 0.1% to 10% of a wetting agent; - from 0.1% to 20% of an emollient; - from 0.1% to 30W of fatty phase; - from 0.01% to 3% of preserving agents; 5 - from 0 to 10% of emulsifiers.

24. Composition according to Claim 23, wherein it comprises in water: - 0,1% of a naphtoic acid derivative 10 - 3% of one or more polyurethane polymers or derivatives; - 0,2% of gelling agents or suspending agents - 0,1% of chelating agents ; - from 2% to 6% of a wetting agent; 15 - from 0,1% to 20% of an emollient - 7% of fatty phase ; - from 1% to 1,5% of preserving agents - from 4% to 6% of emulsifiers. 20

25. Composition according to Claim 24, wherein the one or more polyurethane polymers or derivatives is a polyolprepolymer of type 2.

26. Composition according to Claim 24 or Claim 25, 25 wherein the wetting agent is at 4%.

27. Composition according to any one of the preceding claims, as a medicament. 30

28. Process for preparing a composition according to any one of Claims 1 to 26, wherein the composition comprises the step of mixing a physiologically acceptable vehicle comprising at least one naphthoic acid derivative with at least one compound of 35 polyurethane polymer type or derivatives thereof, the 3369072_1 (GHMatters) P76970.AU - 63 said naphthoic acid derivative being in a form dispersed in the said composition.

29. Preparation process according to Claim 28, wherein 5 the process comprises the following steps: a) the naphthoic acid derivative is mixed with at least one wetting agent, at least one chelating agent, at least one gelling agent, optionally hydrophilic emulsifiers and emollients, in water, until the said 10 naphthoic acid derivative is fully dispersed, in order to obtain the aqueous active phase; b) optionally, to produce an emulsion, at least lipophilic emulsifiers, oils and/or solid fatty 15 substances are mixed with preserving agents, in order to obtain the fatty phase; c) optionally, the said fatty phase obtained in b) is introduced into the aqueous active phase obtained 20 in a) in order to obtain an emulsion; d) if necessary, a gelling-agent neutralizer is introduced into the emulsion obtained in c) or into the aqueous phase obtained in a) in order to 25 obtain the desired pH, and the remaining amount of water is added; the compound of polyurethane polymer type or derivatives thereof being introduced into the aqueous active phase obtained in a) or into the 30 fatty phase obtained in step b) or during step d) as a function of its lipophilic or hydrophilic nature.

30. Process for preparing the composition according to 35 Claim 28 or 29, wherein the process comprises the following steps: 333841_1 (GHMatters) P78970 AU - 64 step a): preparation of the aqueous active phase: the purified water, the naphthoic acid derivative, optionally the hydrophilic emulsifiers in the case of preparing an oil-in-water emulsion, the emollients, the 5 wetting agents, the chelating agent and the gelling agent(s) are introduced into a beaker with stirring using a deflocculator; the mixture is stirred without heating until fully dispersed; 10 when the mixture is homogeneous, the aqueous phase is brought to 60 0 C on a water bath and the preserving agent methyl paraben is introduced; optional step b): preparation of the fatty phase: 15 the lipophilic emulsifiers, the oily compounds and the preserving agents are introduced into an additional beaker with stirring using a deflocculator; the mixture is brought to 60 0 C on a water bath and the volatile silicone is introduced, if necessary, after 20 homogenization; optional step c): emulsification: the fatty phase is introduced gently into the aqueous phase at a temperature of 60 0 C and with stirring using 25 a deflocculator, in order to perform the emulsification; heating is continued for 5 minutes, and the product is then allowed to cool; the stirring is regulated as a function of the 30 viscosity; step d): neutralization: the gelling-agent neutralizer is introduced, if necessary, at 40 0 C, up to a pH of 5.5 ± 0.5; 35 the pH is again checked and the volume is made up with water; 3338841_1 (GHMatters) P78970 AU - 65 the product is homogenized and is then packaged; the compound of polyurethane polymer type or derivatives thereof being introduced during step a) or during step b) or during step d) as a function of its 5 lipophilic or hydrophilic nature.

31. Use of a composition according to any one of Claims 1 to 26 for the preparation of a pharmaceutical composition for treating and/or preventing 10 dermatological complaints associated with a keratinization disorder that has a bearing on cell differentiation and proliferation.

32. Use of a composition according to any one of 15 Claims 1 to 26 for the preparation of a pharmaceutical composition for preventing or treating simple acne.

33. Use of a composition according to any one of Claims 1 to 26 for treating and/or preventing 20 dermatological complaints associated with a keratinization disorder that has a bearing on cell differentiation and proliferation.

34. Use of a composition according to any one of 25 Claims 1 to 26 for preventing or treating simple acne.

35. Cosmetic use of a composition according to any one of Claims 1 to 26 for the treatment of acne-prone skin, for combating the greasy appearance of the skin or the 30 hair, in the protection against the harmful aspects of sunlight or in the treatment of physiologically greasy skin, or for preventing and/or combating light-induced or chronological ageing. 35

36. A method of treating and/or preventing dermatological complaints associated with a 3338841_1 (GHMatters) P76970.AU - 66 keratinization disorder that has a bearing on cell differentiation and proliferation; which comprises administering a therapeutically effective amount of the composition according to one of Claims 1 to 26, to a 5 subject in need thereof.

37. Use according to any one of Claims 31 to 35, or the method according to Claim 36, for treating simple acne, comedonic acne, papulopustular acne, 10 papulocomedonic 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 medication-related acne. 15

38. Composition according to Claim 1, processes for preparing the composition, uses of the composition and methods of treatment involving the composition, substantially as herein described with reference to the 20 accompanying drawings or examples. 3338841_1 (GHMaters) P70970.AU