AU2013269583A1 - Oil/water-emulsion-type topical compositions containing a retinoid - Google Patents

Abstract

The invention relates to a composition in the form of an oil-in-water emulsion, preferably free of emulsifying agents, comprising, in a physiologically acceptable medium, at least one particular retinoid. The invention also relates to the method for preparing such a composition and to the cosmetic and dermatological use thereof.

Description

WO 2013/178760 PCT/EP2013/061201 1 Oil/water-emulsion-type topical compositions containing a retinoid The invention relates to a composition in the form of emulsion comprising, in a physiologically acceptable environment, at least one new retinoid with the general formula (1) R 4 Y R 2 N O R R R Ar O 3 x where: - R 1 is a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a -CF 3 radical; - R 2 is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms or a chlorine atom; - R 3 is a hydrogen atom, or a linear or branched alkyl or alkoxy radical of 1 to 10 carbon atoms possibly substituted by a methoxy group; - R 4 is a hydrogen atom or an alkyl radical of I to 3 carbon atoms; - R 5 is a hydrogen atom or an alkyl radical of I to 3 carbon atoms; - or R 4 and R 5 together form, with the -N-C(=Y)- bond, a ring of the pyrrolidine, pyrrolidinone, piperidine or piperidinone type; - Y denotes two hydrogen atoms or a heteroatom such as oxygen or sulfur; - Ar denotes a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; - X denotes an oxygen atom, possibly substituted by an alkyl or alkylamine chain or a single C C bond; - A denotes a hydrogen atom or the following formula: R ''1 Q R ' 6 R 7 7 where o Q is an oxygen atom or the bond -NH-; o R6 denotes a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(O)CH 2 or -C(O)CH 2

CH

3 radical; 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 2 PCT/EP2013/061201 o R 7 and R 7 ' denote, independently of each other, a hydrogen atom or a hydroxyl group, on condition that R 7 and R 7 ' are not simultaneously a hydroxyl group; n is equal to 0, 1, 2, 3, 4 or 5. These compounds, described in patent EP1831149, are potent retinoids modulating the nuclear receptor of retinoic acid (RAR), more specifically of the gamma subtype of this receptor (RARy). The receptors RARs activate the transcription by binding with elements of DNA sequences, called the RAR Element (RARE) response elements, in the form of a heterodimer with the X receptors of the retinoids (called RXRs). Three subtypes of human RARs have been identified and described: RARa, RAR3 and RARy. Since the gamma RAR receptors are located in the epidermis it is important for the compounds described in the general formula (1) to be released in this part of the skin to provide clinical efficacy. The topical application of retinoids may result in irritation of the skin, dryness and erythema. Numerous articles describe this irritating effect, such as the articles by StOcker & al. Skin Res Technol. 2002 May;8(2):133-40 or by Thielitz & al. Am J Clin Dermatol. 2008;9(6):369-81. To obtain topical preparations for pharmaceutical use containing retinoids, numerous techniques are used, in particular emulsions such as those referred to in the patent EP-826366, which describes emulsions which may contain retinoids, or even patent EP-989846, which describes emulsions containing retinoids and at least one emulsifier. Emulsifiers are molecules that belong to the chemical family of amphiphilic molecules, which are often irritating. Compositions without emulsifiers are in fact less irritating that those containing them. The fact that emulsifiers are not used in the compositions containing retinoids would therefore enable cutaneous irritation due to the presence of this class of molecule to be limited. The prior art describes O/W emulsions with or without emulsifier. We may cite, in particular, patent US 5,851,538, which describes formulations with or without emulsifier with porous microspheres containing a practically continuous network of pores open to the outside and comprising retinoids. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 3 PCT/EP2013/061201 Nevertheless, although the compounds described by the general formula (1) exhibit interesting chemical and physical stability properties for preparations for pharmaceutical uses, they degrade chemically in many of their solvents. There is therefore a need for stable, well tolerated pharmaceutical compositions containing compounds described by general formula (1). 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 4 PCT/EP2013/061201 A first subject according to the invention relates to an oil-in-water emulsion-type composition comprising - a fatty phase comprising: a compound with general formula (1) R 4 Y R 2 N O R R R Ar O 3 x A where: - R 1 is a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a -CF 3 radical; - R 2 is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms or a chlorine atom; - R 3 is a hydrogen atom, or a linear or branched alkyl or alkoxy radical of 1 to 10 carbon atoms possibly substituted by a methoxy group; - R 4 is a hydrogen atom or an alkyl radical of I to 3 carbon atoms; - R 5 is a hydrogen atom or an alkyl radical of I to 3 carbon atoms; - or R 4 and R 5 together form, with the -N-C(=Y)- bond, a ring of the pyrrolidine, pyrrolidinone, piperidine or piperidinone type; - Y denotes two hydrogen atoms or a heteroatom such as oxygen or sulfur; - Ar denotes a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; - X denotes an oxygen atom, possibly substituted by an alkyl or alkyamine chain or a single C-C bond; - A denotes a hydrogen atom or the following formula: R -Q 6 R R7 where: o Q is an oxygen atom or the bond -NH-; o R6 denotes a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(O)CH 2 or -C(O)CH 2

CH

3 radical; 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 5 PCT/EP2013/061201 o R 7 and R 7 ' denote, independently of each other, a hydrogen atom or a hydroxyl group, on condition that R 7 and R 7 ' are not simultaneously a hydroxyl group; n is equal to 0, 1, 2, 3, 4 or 5; at least one principal solvent of the compound (1) and at least one co-solvent oil of the compound (1), and - an aqueous phase comprising at least one gelifying agent. A second subject according to the invention relates to a composition such as described above for its use as a medicinal product. A third subject according to the invention relates to a composition as described above for its use in the treatment of pathologies such as: 1) dermatological complaints associated with a keratinisation disorder relating to cellular differentiation and proliferation, particularly for treating common acnes, comedonic acnes, polymorphic acnes, rosacea acnes, nodulocystic acnes, conglobata acne, senile acnes and secondary acnes such as solar, medicamentous or professional acne; 2) keratinisation disorders, in particular ichtyoses, ichtyosiform conditions, lamellar ichtyosis, Darrier's disease, palmoplantar keratodermias, leukoplasias, pityriasis rubra pilaris and leukoplasiform conditions, cutaneous or mucous (oral) lichen; 3) dermatological disorders with an inflammatory immune-allergic component, with or without cellular proliferation disorder, and in particular all forms of psoriasis, whether cutaneous, mucous or ungueal, and even psoriasic rheumatism, or atopical dermatitis and the different forms of eczema; 4) cutaneous disorders due to exposure to UV radiation, as well as to repair or control ageing of the skin, whether photo-induced or chronological, or to reduce pigmentations and actinic keratoses, or all pathologies associated with chronological or actinic ageing, such as xerosis, pigmentations and wrinkles; 5) Any condition associated with benign dermal or epidermal proliferations, whether or not of viral origin, such as common warts, flat warts, molluscum contagiosum and verruciform epidermodysplasia, oral or florid papillomatoses; 6) dermatological complaints such as immune dermatoses such as erythematous lupus, bullous immune diseases and collagenic diseases such as sclerodermia; 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 6 PCT/EP2013/061201 7) stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy; 8) healing complaints, or to prevent or repair stretch marks, or else to promote healing; 9) any disorder of fungal origin in the cutaneous region, such as tinea pedis and tinea versicolor; 10) pigmentation disorders such as hyperpigmentation, melasma, hypopigmentation or vitiligo ; 11) cancerous or pre-cancerous, cutaneous or mucous conditions such as actinic keratoses, Bowen's disease, carcinomas in-situ, keratoacanthoma and skin cancers such as basocellular carcinoma (BCC), spinocellular carcinoma (SCC) and cutaneous lymphomas such as T lymphoma. A fourth subject according to the invention relates to a method for preparing an oil-in-water emulsion-type composition as described above and comprising the following stages: a) solubilisation of the hydrophilic excipients under agitation b) solubilisation under agitation of the retinoid in the principal solvent c) addition of the lipophilic excipients d) gelification of the aqueous phase by adding the gelifier e) addition of the oily phase, then the silicone oil. A fifth object according to the invention relates to the compositions comprising a compound with general formula (I) R4 Y R2 N 0 RIR Ar O 3 x A And at least one polyacrylamide gelifier, characterised in that the maximum quantity of active ingredient absorbed in the epidermis 16 hours after application is between 6 ng/cm 2 and 19 ng/cm 2 . A sixth object according to the invention relates to the oil-in-water emulsion-type compositions comprising a compound with general formula (1) 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 7 PCT/EP2013/061201 R 4 Y R 2 N O R , Ar O 3 X And at least one polyacrylamide gelifier, characterised in that the maximum quantity of active ingredient absorbed in the epidermis is obtained between 3 and 10 hours after application and preferably between 5 and 7 hours after application. The invention will be described in greater detail in the description and the examples which follow, and also in the appended figures in which: Figure 1 presents the distribution profile in the various compartments of the skin of a composition according to the invention. Figure 2 presents the kinetics of penetration into the epidermis of a composition according to the invention. Figure 3 presents the results of a study of tolerance of a composition according to the invention, compared with a reference gel. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 8 PCT/EP2013/061201 Detailed description of the invention To facilitate the reading of this description reference will be made to general formula (1) and compound A in the remaining text, as being described thus: General formula (1) R 4 Y R 2 N O R R R Ar O 3 x A where: - R 1 is a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a -CF 3 radical; - R 2 is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms or a chlorine atom; - R 3 is a hydrogen atom, or a linear or branched alkyl or alkoxy radical of 1 to 10 carbon atoms optionally substituted by a methoxy group; - R 4 is a hydrogen atom or an alkyl radical of I to 3 carbon atoms; - R 5 is a hydrogen atom or an alkyl radical of I to 3 carbon atoms; - or R 4 and R 5 together form, with the -N-C(=Y)- bond, a ring of the pyrrolidine, pyrrolidinone, piperidine or piperidinone type; - Y denotes two hydrogen atoms or a heteroatom such as oxygen or sulfur; - Ar denotes a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; - X denotes an oxygen atom, possibly substituted by an alkyl or alkyamine chain or a single C-C bond; - A denotes a hydrogen atom or the following formula: Q R - R '1 6 7 where o Q is an oxygen atom or the bond -NH-; o R6 denotes a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(O)CH 2 or -C(O)CH 2

CH

3 radical; 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 9 PCT/EP2013/061201 o R 7 and R 7 ' denote, independently of each other, a hydrogen atom or a hydroxyl group, on condition that R 7 and R 7 ' are not simultaneously a hydroxyl group; n is equal to 0, 1, 2, 3, 4 or 5. Compound A: as being 3"-tert-butyl-4'-(2-hydroxy-ethoxy)-4"-pyrrolidin-1-yl-[1,1';3',1I"]-terphenyl-4 carboxylic acid. Due to the physico-chemical characteristics of the active ingredient, the Applicant has had to face a certain number of constraints in the use of the compounds described by general formula (1). These compounds: -are soluble in few solvents normally used in the fatty phases of the topical emulsions - degrade chemically in many of their solvents - degrade chemically in the presence of numerous emulsifiers. A first subject according to this invention describes compositions containing at least one compound with general formula (1) in the form of emulsions of the type O/W (Oil in Water) and in which the active ingredient is solubilised in the fatty phase. According to a particularly preferred embodiment, the composition according to the invention does not contain any emulsifier. These emulsions exhibit good physical and chemical stability, a rapid rate of penetration and a high level of penetration in the epidermis and/or the dermis. Emulsion is understood to mean a macroscopically homogeneous but microscopically heterogeneous mixture of two immiscible liquid substances that we shall call phases. An O/W (oil in water) emulsion consists of a fatty (or oily) phase dispersed in an aqueous phase. In the invention the compositions contain the active ingredient described by general formula (1) at concentrations ranging from 0.00001% to 1% by weight, preferably from 0.0001 to 0.1 % by weight, and more preferably from 0.001 to 0.1 % by weight, relative to the total weight of the composition. Preferably the active ingredient described by general formula (1) is compound A. In the invention the compositions contain at least one gelifying agent. The term "gelifying agent" is intended to mean a polymer compound capable of conferring on the composition the texture of a gel. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 10 PCT/EP2013/061201 The gelifying agent (s) may in particular be selected from polymers of plant origin, gums, pectins, cellulose and its derivatives, polymers of microbiological origin, such as xanthan gum, and gelifying polymers of synthetic origin. By way of non-exhaustive example of gelifiers that may enter into the compositions, mention may be made of Acrylates/C10-30 Alkyl Acrylate Crosspolymer, sold under the name of Pemulen TR-1 or Pemulen TR-2 by the company Lubrizol, gelifiers in the polyacrylamide family, such as the mixture of Sodium acrylamide/acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80, sold under the name of Simulgel 600PHA by the company SEPPIC, and the mixture of polyacrylamide/isoparaffin C13-14/laureth-7 sold under the name of Sepigel 305 by the company SEPPIC, the carbomers sold under the name of Ultrez 20@, Ultrez 10@, Carbopol 1382@ or Carbopol ETD2020NF@, Carbopol 981 or even Carbopol 980 by the company Lubrizol, the polysaccharides with, by way of non-exhaustive examples, xanthan gum, such as Xantural180@ sold by the company Kelco, gellan gum sold under the name of Kelcogel by the company Kelco, guar gum, cellulose and its derivatives, such as microcrystalline cellulose and carboxymethyl cellulose of sodium sold under the name of Avicel CL-611 by the company FMC Biopolymer, hydroxypropylmethylcellulose, in particular the product sold under the name of Methocel E4M premium by the company Dow Chemical, or hydroxyethylcellulose, in particular the product sold under the name of Natrosol HHX 250@ by the company Ashland, sodium carboxymethylcellulose, in particular Blanose cellulose gum 7F sold by the company Ashland, the family of aluminium magnesium silicates, such as Veegum K sold by the company Vanderbilt, the family of acrylic polymers coupled to hydrophobic chains such as PEG 150/decyl/SMDI copolymer sold under the name of Aculyn 44 (polycondensate, comprising, at least as elements, a polyethylene glycol with 150 or 180 mols of ethylene oxide, decyclic alcohol and methylene bis(4-cyclohexylisocyanate) (SMDI), at 35% by weight in a mixture of propylene glycol (39%) and water (26%)), the family of modified starches such as modified potato starch sold under the name of Structure Solanacee or their mixtures, the family of the carrageenans, particularly those distributed among four major families: K, X, P, w, such as Viscarin* and the Gelcarin* marketed by the company IMCD. Preferably a gelifying agent of the polyacrylamide type, such as Simulgel 600 PHA@, which has thickening and stabilising properties, is used in concentrations ranging from 0.005 to 5 % by weight, and preferably ranging from 1% to 4% by weight. The person skilled in the art knows that for an emulsifier system the proportion of emulsifier required to emulsify a fatty phase in an oil in water emulsion is normally of the order of 1/5 of the % of the fatty phase. By way of non-exhaustive example a fatty phase representing at least 11% of the ingredients of the formulas would require a minimum of 2.2% of emulsifiers. According to a preferred embodiment of the invention, no emulsifier is used. However, it is possible in spite of this that certain ingredients contain low percentages of emulsifier in their own composition. Because of the low percentage that may result from this in the composition according 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 11 PCT/EP2013/061201 to the invention, they cannot have the function of an emulsifier in the composition (content preferably lower than 0.6% by weight, relative to the total weight of the composition). In the invention the compositions contain a fatty phase that may consist of: - a principal solvent of an active ingredient described by general formula (1), which may be in particular benzyl alcohol, laureth-4, phenoxyethanol, propylene glycol monocaprylate, pentylene glycol or dimethyl isosorbide, and preferably phenoxyethanol sold, for example, under the name phenoxetol by Clariant. When the principal solvent is phenoxyethanol, the amount of phenoxyethanol ranges from 0.2 to 5% by weight and preferably from 0.5 to 2% by weight relative to the total weight of the composition. The term "principal solvent" is intended to mean a liquid which has the property of dissolving, diluting or extracting other substances without causing any chemical modification of these substances and without itself being modified. According to the invention, a principal solvent is such a liquid, in which the compounds with the general formula (1) (and more preferably the compound A) have a solubility, at ambient temperature and atmospheric pressure, greater than or equal to 0.1% by weight. - one or more co-solvent oils of an active ingredient described by general formula (1), which may be, in preference, chosen from the following co-solvent oils: Caprylic/ capric triglycerides (Miglyol 812N) supplied by IMCD, Prunus Amygdalus Dulcis (Sweet Almond) oil supplied by SICTIA, Propylene glycol monocaprylate (Capryol 90) supplied by GATTEFOSSE, Propylene glycol laurate (Lauroglycol FCC) supplied by GATTEFOSSE, Sorbitan Sesquioleate (Arlacel 83VPharma) supplied by CRODA, Diisopropyl Adipate (Crodamol DA) supplied by CRODA, PPG 15 stearyl ether (Arlamol PS15E-LQ) supplied by CRODA, Apricot Kernel Oil PEG-6 Ester (Labrafil M1944CS) supplied by GATTEFOSSE in proportions which can range from 0.5 to 50% by weight and preferably from 4 to 30% by weight. The term "co-solvent" is intended to mean a substance having the role of solvent in combination with another substance. In the invention the compositions described above may also contain additives (among which mention may be made of the following categories, used alone or in combination): - One or more silicone oils that improve the properties of the formula on application, such as Cyclomethicone (St-Cyclomethicone 5NF) or Dimethicone (Q7 9120 silicon fluid, with a viscosity of 20 cst to 12500 cst from Dow Corning) between 0 and 10%, and preferably between 0 and 4%. - One or more preservatives such as methyl parabene, propyl parabene, benzalconium chloride, phenoxyethanol sold under the name of phenoxetol by Clariant, benzyl alcohol sold 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 12 PCT/EP2013/061201 under the name benzyl alcohol by Merck, potassium sorbate sold under the name of potassium Sorbate by VWR, benzoic acid sold under the name Benzoic Acid by VWR, 2-Bromo 2-Nitropropane-1,3-Diol sold under the name of Bronopol by Jan Dekker International, Chlorohexidine sold under the name of Chlorohexidine digluconate 20% solution by Arnaud Pharmacie, chlorocresol and its derivatives, sodium benzoate sold under the name of Probenz SP by the company Unipex, ethyl alcohol and diazolidinyl urea. These preservatives may be used alone or in combination for effective protection of formulas against all bacterial contamination in contents ranging from 0% to 5% by weight, and preferably from 0.01 to 2% by weight. The term "preservative" denotes any substance capable of opposing the modifications of chemical or microbiological origin of a product. - Ethanol, the quantity of which may be between 0 and 30% by weight and preferably between 0 and 10% by weight. - Moistening agents, preferably polyols and preferably selected from among propylene glycol, glycerine, diglycerine or sorbitol (Neosorb supplied by ROQUETTE, Parteck SI supplied by Merck, but also Sorbitol USP Powder supplied by LIPO CHEMICALS), whose quantity ranges from 0 to 40% by weight relative to the total weight of the composition, and preferably from 5 to 35%. -Chelating agents such as EDTA (ethylene diamine tetraacetic acid) and its derivatives or salts, dihydroglycerine, citric and tartaric acids, gluconolactone sold under the name glucono delta-lactone SG by Jungbunzlauer or mixtures thereof. -Antioxidants such as vitamin E and its derivatives, such as DL alpha tocopherol or tocopherol acetate from Roche; vitamin C and its derivatives, such as Ascorbyl Palmitate from Roche, Butylhydroxy toluene sold under the name of Nipanox BHT by Clariant. -Palliatives and/or anti-irritants such as PPG-12/SMDI copolymer sold by Bertek Pharmaceuticals under the commercial name of Polyolprepolymer-2, glycyrrhetinic acid or its derivatives, for example Enoxolone sold by the company BASF, hyaluronic acid as such or in its form of sodium hyaluronate sold under the commercial name of HYAL. NA PWD PH 15 51-45 by the company Contipro, allantoin sold under the name of RONACARE ALLANTOINE by MERCK. - Any other additive normally used in the pharmaceutical and cosmetic fields enabling specific properties to be assigned to the said preparation. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 13 PCT/EP2013/061201 GENERAL COMPOSITION FOR ACNE: When it is intended for the treatment of acne, the composition according to the invention advantageously contains the following ingredients, the percentages being expressed by weight in relation to the total weight of the composition of the oil in water emulsion type. - from 0.00001% to 1% and preferably from 0.0001 to 0.1 % of compound with the general formula (I) - from 0.005 to 10 % and preferably from 1 to 5% of gelifier - from 0.2 to 5% and preferably from 0.5 to 2% of principal solvent of the compound with the general formula (I) - from 0.5 to 50% and preferably from 4 to 15% of co-solvent oils of the compound with the general formula (I) - from 0 to 20% and preferably from 0 to 5% of mineral oils - from 0 to 50% and preferably from 5 to 35% of polyol - from 0 to 10% and preferably from 0 to 4% of silicone oil - from 0 to 5% and preferably from 0.01 to 2% of preservative system - from 0 to 30% and preferably from 0 to 10% of ethanol - from 0 to 15% and preferably from 0.1 to 10% of additives COMPOSITIONS SUITABLE FOR ICHTYOSIS, PALMOPLANTAR HYPERKERATOSIS OR PSORIASIS: In this case, the composition according to the invention advantageously contains the following ingredients, the percentages being expressed by weight in relation to the total weight of the composition of the oil-in-water emulsion type. - from 0.00001% to 1% and preferably from 0.0001 to 0.1% of compound with the general formula (I) - from 0.005 to 10 % and preferably from 1 to 5% of gelifier - from 0.2 to 5% and preferably from 0.5 to 2% of principal solvent of the compound with the general formula (I) - from 0.5 to 50% and preferably from 10 to 30% of co-solvent oils of the compound with the general formula (I) - from 1 to 50% and preferably from 10 to 30% of polyol - from 0 to 10% and preferably from 0 to 4% of silicone oil - from 0 to 5% and preferably from 0.01 to 2% of preservative system - from 0 to 15% and preferably from 0.1 to 10% of additives Another object according to the invention relates to a method of preparing a composition described as above and comprising the following stages: 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 14 PCT/EP2013/061201 A) Preparation of the aqueous phase Solubilisation of the hydrophilic excipients under agitation, if necessary under heat B) Preparation of the oily phase In a suitable receptacle, solubilisation under agitation, of compound A in Phenoxyethanol, under heat if necessary. Allow to return to ambient temperature and add the lipophilic excipients except the silicone oil (for example ST-cyclomethicone 5) when this is present. C) Mixing of the two phases. At ambient temperature gelify the aqueous phase by adding the gelifier (for example Simulgel 600PHA), then add the oily phase then the silicone oil when this is present. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 15 PCT/EP2013/061201 Examples Example 1 - Pre-formulation In order to obtain an oil in water emulsion containing a compound with the general formula (1) in the fat phase, pre-formulation studies have been conducted to identify the excipients allowing good solubilisation as well as good stability of the active ingredient. (1) List of fat phase excipients in which the maximum solubility has been determined by HPLC: Excipients Maximum solubility Commercial name INCI name % Benzyl alcohol Benzyl Alcohol 2.388 Brij 30 Laureth-4 2.03 Phenoxetol Phenoxyethanol 1.957 Capryol 90 Propylene glycol monocaprylate 0.802 Hydrolite 5P Pentylene glycol 0.482 Arlasolve DMI Dimethyl Isosorbide 0.400 Crodamol IPM Isopropyl myristate < 0.1 The limit below which the compounds with the general formula (1) are considered as being not solubilised is 0.1% by weight. - (2) Stability of compound A in its principal solvents: These stability studies of compound A in its principal solvents show that compound A degrades chemically in a number of its solvents. These results have enabled us to select our principal solvent (phenoxyethanol) and our co-solvent oils from among the solvent oils which exhibit good stability results, with the aim of developing O/W emulsions in which compound A is solubilised in the oily phase. Excipients COMPOUND A Stability results Commercial name INCI name % Miglyol 812N Caprylic/ capric triglycerides 0.005% Stable/ Ok 6Months 40"C Sweet almond oil Prunus Amygdalus Dulcis (Sweet Almond) 0.005% Stable/ Ok 6Months 40"C Oil Capryol 90 Propylene glycol monocaprylate 0.05% Stable/ Ok 6Months 40"C 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 16 PCT/EP2013/061201 Arlacel 83V Pharma Sorbitan Sesquioleate 0.05% Stable/ Ok 6Months 40"C Crodamol DA Diisopropyl Adipate 0.05% Stable/ Ok 6Months 40"C Lauroglycol FCC Propylene glycol laurate 0.05% Stable/ Ok 6Months 40"C Arlamol PS15E-LQ PPG-15 stearyl ether 0.05% Stable/ Ok 6Months 40"C Phenoxetol Phenoxyethanol 0.05% Stable/ Ok 6Months 40"C Labrafil M1944CS Apricot Kernel Oil PEG-6 Ester 0.05% Stable/ Ok 6Months 40"C Dipropylene Glycol Dipropylene glycol 0.05% Unstable Care Brij 30 Laureth-4 0.05% Unstable Benzyl Alcohol Benzyl Alcohol 0.05% Unstable Eutanol G Octyldodecanol 0.05% Unstable Myritol PC Propylene glycol dicaprylate/ dicaprate 0.05% Unstable Arlasolve DMI Dimethyl Isosorbide 0.05% Unstable Marcol 152 Paraffinum Liquidum 0.05% N/A (3) Stability of compound A in mixtures of excipients (solvent/surfactants) determined by HPLC: Studies of stability of compound A solubilised in oils (in which it is stable) in the presence of surfactants have been conducted: Mixture of excipients COMPOUND A Stability results Commercial name INCI name % Simulsol M45/ PEG-8 Stearate/ Diisopropyl Adipate 0,05% Unstable Crodamol DA Cremophor EL/ PEG-35 Castor Oil/ Apricot Kernel Oil PEG-6 0,05% Unstable Labrafil M1944CS Ester Tween 80/ Arlamol Polysorbate-80/ PPG-15 stearyl ether 0,05% Unstable PS15E-LQ Cremophor EL/ PEG-35 Castor Oil/ Propylene glycol laurate 0,05% Unstable Lauroglycol FCC Tween 80/ Hexylene Polysorbate-80/ Hexylene glycol 0,2% Unstable glycol Cremophor EL/ PEG-35 Castor Oil/ Apricot Kernel Oil PEG-6 0,2% Unstable Labrafil M1944CS Ester Cremophor RH40/ PEG-40 Hydrogenated Castor Oil/ 0,2% Unstable Crodamol DA Diisopropyl Adipate Tween 80/ Polysorbate-80/ Propylene glycol laurate 0,2% Unstable Lauroglycol FCC Simulsol M45/ PEG-8 Stearate/ Diisopropyl Adipate 0,2% Unstable Crodamol DA Arlacel 165/ Glyceryl Stearate 0,05% Unstable Lauroglycol FCC PEG-100 Stearate/ Propylene glycol laurate GlucateSS-Glucamate Methyl Glucose Sesquistearate- PEG-20 0,05% Unstable SSE-20/ Methyl Glucose Sesquistearate/ PPG-15 Arlamol PS15E-LQ stearyl ether Brij 721/ Arlamol Steareth-21/ PPG-15 stearyl ether 0,05% Stable/ Ok 3Months 40"C PS15E-LQ Brij 721/ Lauroglycol Steareth-21/ Propylene glycol laurate 0,05% Stable/ Ok 3Months 40"C FCC Eumulgin B2/ Arlamol Ceteareth-20/ PPG-15 stearyl ether 0,05% Stable/ Ok 3Months 40"C E Arlacel 165/ Arlamol Glyceryl Stearate 0,05% Stable/ Ok 3Months 40"C E PEG-100 Stearate/ PPG-15 stearyl ether 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 17 PCT/EP2013/061201 The limits fixed for high stability are 95%-105% as a percentage relative to TO. These studies showed that compound A degrades chemically in the presence of numerous surfactants. Following these results we therefore decided to develop an O/W emulsion without emulsifier. EXAMPLE 2: Formulations In the following examples the formulae are characterised at TO. The physical and chemical stability of the formulations is achieved after storage at ambient temperature (TA) and at +4 0 'C after T+lMonth and/or T+2Months or T+3Months or T+6Months. The equipment and methods used for these characteristics are described below. Compound A is defined as 3"-tert-butyl-4'-(2-hydroxy-ethoxy)-4"-pyrrolidin-1-yl-[1,1';3',1"] terphenyl-4-carboxylic acid. -Chemical assaying of compound A: -Equipment: HPLC -Expression of the results: the titre of the active ingredient is expressed as a % related to the initial % achieved at TO. The limits fixed for high stability are 95%-105%. -Macroscopic observation: - Macroscopic observation enables the physical integrity of the products at TO and after stability to be guaranteed. -Microscopic observation: - Microscopic observation enables good solubilisation of compound A from TO, non recrystallisation in the course of time, as well as the size of the globules in the oily phase to be evaluated. -Equipment: AXIO ZEISS Microscope -pHl: -Equipment: METTLER TOLEDO Seven Multi pH meter -Method : Measurements carried out at ambient temperature after 24h stabilisation in an enclosure at 25*C of all the samples. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 18 PCT/EP2013/061201 -Viscosity: -The measurement of the viscosity enables the consistency of the formulas produced to be evaluated. -Equipment: Brookfield RV DVII + Pro -Method: Measurements carried out at ambient temperature after 24h stabilisation in an enclosure at 25*C of all the samples. The value is read after 1 minute. The choice of spindle and speed will be described in each composition example. The values obtained are expressed in centipoises (Cps). -Centrifuging: -The centrifuging enables the resistance of the formulas to a mechanical stress to be evaluated. -Equipment: Galaxy 14D VWR -Method: 30 minutes at 5000 rpm -A conforming result means that there is neither separation of phases nor exudate. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 19 PCT/EP2013/061201 Formula 1 COMMERCIAL NAME INCI NAME % COMPOUND A COMPOUND A 0.010 PROPYLENE GLYCOL Propylene Glycol 30.000 ETHANOL 95-96% Ethanol 5.000 RONACARE ALLANTOIN Allantoln 0,200 Acrylamide, AMPS Copolymer 3.000 SIMULGEL 600 PHA Dispersion 40%/ Isohexadecane/ polysorbate 80 MIGLYOL 812 N Medium-Chain Triglycerides 8.000 ST-CYCLOMETHICONE 5-NF Cyclopentasiloxane 2.000 PHENOXETOL Phenoxyethanol 1.000 PURIFIED WATER Purified water QS 100.000 MACROSCOPIC APPEARANCE White, smooth, brilliant cream MICROSCOPIC Absence of crystals. Very fine, homogeneous CHARACTERISATION APPEARANCE emulsion. 0 < 5 pm: 90% ATTO pH 5 VISCOSITY Needle 6, Rate 5. 176 000cp CENTRIFUGING Conforming STABILITY MONITORING 1 Month 2 Months 3 Months 6 Months pH TA/ 40*C 5.28/5.31 5.45/5.81 5.30/5.67 5.23/5.75 - AT 169 OOOcP 166 OOOcP 175 OOOcP 172 OOOcP 0u U 5 40*C 174 OOOcP 173 OOOcP 165 OOOcP 159 OOOcP AT 98.70 100.40 100.30 103.10 a 0 0_ _ _ S2 40*C 99.40 101.30 98.80 104.90 U These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 20 PCT/EP2013/061201 Formula 2 COMMERCIAL NAME INCI NAME % COMPOUND A COMPOUND A 0.005 PROPYLENE GLYCOL Propylene Glycol 30.000 ETHANOL 95-96% Ethanol 5.000 RONACARE ALLANTOIN Allantoin 0. 200 Acrylamide, AMPS Copolymer 3.000 SIMULGEL 600 PHA Dispersion 40%/ Isohexadecane/ polysorbate 80 MIGLYOL 812 N Medium-Chain Triglycerides 8.000 ST-CYCLOMETHICONE 5 Cyclopentasiloxane 2.000 PHENOXETOL Phenoxyethanol 1.000 PURIFIED WATER Purified water QS 100.000 MACROSCOPIC White, smooth, brilliant cream APPEARANCE MICROSCOPIC Absence of crystals. Very fine, CHARACTERISATION APPEARANCE homogeneous emulsion. 0 < 5 pm: 90% ATTO pH 5 VISCOSITY 176 OOOcP CENTRIFUGING Conforming AT 100.60 100.20 98.00 100.50 6 - 40*C 99.40 100.40 96.80 96.60 C U These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 21 PCT/EP2013/061201 Formula 3 COMMERCIAL NAME INCI NAME COMPOUNDA COMPOUNDA 0.010 PROPYLENE GLYCOL Propylene Glycol 30.000 BLANOSE CELLULOSE GUM 7H4F Cellulose Gum 0.800 ETHANOL 95-96% Ethanol 5.000 RONACARE ALLANTOIN Allantoin 0. 200 Acrylamide, AMPS Copolymer 2.000 SIMULGEL 600 PHA Dispersion 40%/ Isohexadecane/ polysorbate 80 MIGLYOL 812 N Triglycerides Medium-Chain 8.000 ST-CYCLOMETHICONE 5 Cyclopentasiloxane 2.000 PHENOXETOL Phenoxyethanol 1.000 PURIFIED WATER Purified water QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE MICROSCOPIC Absence of crystals. Very fine, homogeneous CHARACTERISATION APPEARANCE emulsion. 0 < 5 pm: 90% ATTO pH 6,36 VISCOSITY Needle 6, Rate 10. 57 500cP CENTRIFUGING NR STABILITY MONITORING 1 Month 2 Months 3 Months 6 Months pH AT/ 40*C 6.61 / 6.31 6,37 / 6.21 6.48 /,6.18 6.40 / 6.08 - AT 64 500cP 59 800cP 67 000cP 64 600cP 0 0u, U V1 5 40*C 59 000cP 59 000cP 55 100cP 57 300cP AT 104.00 100.5 100.00 95.00 6 40*C 104.8 100.00 99.60 94.70 C U These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 22 PCT/EP2013/061201 Formula 4 COMMERCIAL NAME INCI NAME % COMPOUNDA COMPOUNDA 0.010 PROPANEDIOL-1,2 Propylene Glycol 30.000 ETHANOL 95-96% Ethanol 5.000 RONACARE ALLANTOIN Allantoin 0, 200 SIMULGEL 600 PHA Acrylamide, AMPS Copolymer 3.000 Dispersion 40%/ Isohexadecane/ polysorbate 80 MIGLYOL 812 N Caprylic/Capric Triglyceride 8.000 LABRAFIL M1944CS Apricot Kernel Oil PEG-6 Ester 2.000 ST-CYCLOMETHICONE 5 Cyclopentasiloxane 2.000 PHENOXETOL Phenoxyethanol 1.000 PURIFIED WATER Purified water QS 100.000 MACROSCOPIC White, smooth, brilliant cream APPEARANCE MICROSCOPIC Absence of crystals. Very fine, homogeneous CHARACTERISATION APPEARANCE emulsion. 0 < 5 pm: 90% AT TO pH 4,72 VISCOSITY Needle 6, Rate 2.5. 215 000 cP CENTRIFUGING NR STABILITY MONITORING 1 Month 2 Months 3 Months 6 Months pH AT/ 40'C NR / 5.58 NR / 5.47 NR / 5.53 NR/NR U A NR NR NR NR u~3 AT 0 Vu U tn 5 40*C 183 OOOcP 168 OOOcP 158 OOOcP NR AT 1.5 Months: 99.90 99.90 NR 6 40*C 1.5 Months: 99.00 99.40 NR C U These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 23 PCT/EP2013/061201 Formula 5 COMMERCIAL NAME INCI NAME % COMPOUND A COMPOUNDA 0.010 PROPANEDIOL-1,2 Propylene Glycol 30.000 ETHANOL 95-96% Ethanol 5.000 RONACARE ALLANTOIN Allantoin 0. 200 SIMULGEL 600 PHA Acrylamide, AMPS Copolymer 3.000 Dispersion 40%/ Isohexadecane/ polysorbate 80 MIGLYOL 812 N Caprylic/Capric Triglyceride 8.000 ARLAMOL PS15E-LQ (WL) PPG-15 stearyl ether 2.000 ST-CYCLOMETHICONE 5-NF Cyclopentasiloxane 2.000 PHENOXETOL Phenoxyethanol 1.000 PURIFIED WATER Purified water QS 100.000 MACROSCOPIC White, smooth, brilliant cream APPEARANCE MICROSCOPIC Absence of crystals. Fine, homogeneous CHARACTERISATION APPEARANCE emulsion. 0 < 10 pm: 90% AT TO pH 4,64 VISCOSITY Needle 6, Rate 2,5. 314 000 cP CENTRIFUGING NR STABILITY MONITORING 1 Month 2 Months 3 Months 6 Months pH AT/ 40*C NR / 5.62 NR / 5.68 NR / 5.65 NR / 5.81 AT NR NR NR NR 0 5 40*C 267 OOOcP 268 OOOcP 262 OOOcP 246 OOOcP _ AT 1.5 Months: 98.80 100.70 107.00 6 40*C 1.5 Months: 106.00 100.70 107.70 C U These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 24 PCT/EP2013/061201 Formula 6 COMMERCIAL NAME INCI NAME % COMPOUND A COMPOUNDA 0.030 PROPANEDIOL-1,2 Propylene Glycol 30.000 ETHANOL 95-96% Ethanol 5.000 RONACARE ALLANTOIN Allantoin 0. 200 SIMULGEL 600 PHA Acrylamide, AMPS Copolymer 3.000 Dispersion 40%/ Isohexadecane/ polysorbate 80 ST-CYCLOMETHICONE 5NF Cyclopentasiloxane 2.000 CASTOR OIL PH Ricinus Communis (Castor) Seed Oil 8.000 PHENOXETOL Phenoxyethanol 1.000 PURIFIED WATER Purified water QS 100.000 MACROSCOPIC APPEARANCE White, smooth, brilliant cream MICROSCOPIC Absence of crystals. Fine, homogeneous CHARACTERISATION APPEARANCE emulsion. 0 < 5 pm: 90% ATTO pH 5,67 VISCOSITY Needle 29, Rate 0.5. 1180 000 cP CENTRIFUGING Conforming STABILITY MONITORING 1 Month 2 Months 3 Months 6 Months pH AT/ 40*C 5.66 /5.55 5.73 /5.82 5.44 /5.84 5.44 /5.84 AT 1160 000cP 1080000 1080 000 cP 1080 000cP 5 40*C 1 130 OOOcP 1030 000 1090 000 cP 1030 OOOcP AT 99.8 100.0 100.4 100.0 6 40*C 99.6 99.5 99.2 99.5 C U These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 25 PCT/EP2013/061201 Formula 7 COMMERCIAL NAME INCI NAME % COMPOUND A COMPOUNDA 0.030 PROPANEDIOL-1,2 Propylene Glycol 30.000 ETHANOL 95-96% Ethanol 5.000 RONACARE ALLANTOIN Allantoin 0. 200 SIMULGEL 600 PHA Acrylamide, AMPS Copolymer 3.000 Dispersion 40%/ Isohexadecane/ polysorbate 80 MIGLYOL 812 N Caprylic/Capric Triglyceride 4.000 ARLAMOL PS15E-LQ (WL) PPG-15 stearyl ether 4.000 ST-CYCLOMETHICONE 5-NF Cyclopentasiloxane 2.000 PHENOXETOL Phenoxyethanol 1.000 PURIFIED WATER Purified water QS 100.000 MACROSCOPIC White, smooth, brilliant cream APPEARANCE MICROSCOPIC Absence of crystals. Fine homogeneous CHARACTERISATION APPEARANCE emulsion. 0 < 5 pm: 90% ATTO pH 5,87 VISCOSITY Needle 29, Rate 5. 139 000 cP CENTRIFUGING Conforming STABILITY MONITORING 1 Month 2 Months 3 Months 6 Months pH AT/ 40*C 5.90/ 5.50 5.71 / 5.71 5.66/5.90 5.66/5.90 U& AT 148 000 cP 132000cP 134 000 cP 132000cP 0 0u, U V1 5 40*C 142 000cP 130000cP 137 000 cP 130000cP _ AT 97.8 109.6 100.7 100.7 6 40*C 100.0 110.2 100.6 100.2 C U These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 26 PCT/EP2013/061201 Formula 8 COMPOSITIONS Commercial Name INCI name % COMPOUNDA COMPOUNDA 0.010 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 15.00 CASTOR OIL PH RICINUS COMMUNIS (CASTOR) SEED OIL 8.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2.00 Q7-9120 SILICON FLUID 350 cst DIMETHICONE 5.00 RONACARE ALLANTOIN ALLANTOIN 0.200 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDE, AMPS COPOLYMER DISPERSION 40%/ 3.00 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC CHARACTERISATION emulsion. APPEARANCE AT TO 0 6 pm pH 4.92 VISCOSITY Needle 6, Rate 0,5 NR CENTRIFUGING Conforming Stability monitoring 1 MONTH 2 MONTHS 3 MONTHS 6 MONTHS pH AT/ 40*C 4.92/4.88 NR 4.93/5.22 / 4AT 192.0 4 cp NR 182. 10 4 cp / 0 4 40*C 187.10 4 cp NR 167.10cp / These results demonstrate a good physical stability of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 27 PCT/EP2013/061201 Formula 9 COMPOSITIONS Commercial Name INCI name % COMPOUNDA COMPOUNDA 0.010 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 8.00 ARLAMOL PS15E-LQ PPG-15 STEARYL ETHER 15.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2.00 RONACARE ALLANTOIN ALLANTOIN 0.200 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDE, AMPS COPOLYMER DISPERSION 40%/ 2.5 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC CHARACTERISATION APPEARANCE emulsion. AT TO 0 < 7 pm pH 4.79 VISCOSITY Needle 6, Rate 5 187000cp CENTRIFUGING RAS Stability monitoring 1 MONTH 2 MONTHS 3 MONTHS 6 MONTHS pH AT/ 40*C 4.76/4.87 4.92/4.99 4.83/5.08 4.59/5.13 AT 160000cp 175000cp 186000cp 132000cP 00 40*C 154000cp 146000cp 146000cp 137000cP These results demonstrate a good physical stability of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 28 PCT/EP2013/061201 Formula 10 COMPOSITIONS Commercial Name INCI name % COMPOUND A COMPOUND A 0.030 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 8.00 ARLAMOL PS15E-LQ PPG-15 STEARYL ETHER 15.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2.00 RONACARE ALLANTOIN ALLANTOIN 0.200 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDE, AMPS COPOLYMER DISPERSION 40%/ 2.5 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC CHARACTERISATION emulsion. APPEARANCE AT TO 0 < 7 pm pH 4.76 VISCOSITY Needle 6, Rate 2.5 381000cp CENTRIFUGING RAS 6 Stability monitoring 1 MONTH 2 MONTHS 3 MONTHS MONTHS pH AT/ 40*C 4.74/4.97 4.88/5.00 4.85/5.16 4.96/5.12 UAT 374000cp 364000cp 334000cp 298000cP 00 40*C 288000cp 266000cp 269000cp 260000cP These results demonstrate a good physical stability of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 29 PCT/EP2013/061201 Formula 11 COMPOSITIONS Commercial Name INCI name % COMPOUND A COMPOUND A 0.04 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 8.00 ARLAMOL PS15E-LQ PPG-15 STEARYL ETHER 15.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2.00 RONACARE ALLANTOIN ALLANTOIN 0.200 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDE, AMPS COPOLYMER DISPERSION 40%/ 2.5 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC CHARACTERISATION emulsion. APPEARANCE AT TO 0 < 5 pm pH 4.76 VISCOSITY Needle 6, Rate 2,5 340000cp CENTRIFUGING RAS Stability monitoring 1 MONTH 2 MONTHS 3 MONTHS 6 MONTHS pH AT/ 40*C 4.77/4.90 4.92/5.02 5.20/5.15 / AT 343000cp 330000cp 325000cp / 00 40*C 292000cp 263000cp 271000cp / These results demonstrate a good physical stability of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 30 PCT/EP2013/061201 Formula 12 COMPOSITIONS Commercial Name INCI name % COMPOUND A COMPOUND A 0.05 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 8.00 ARLAMOL PS15E-LQ PPG-15 STEARYL ETHER 15.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2.00 RONACARE ALLANTOIN ALLANTOIN 0.200 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDE, AMPS COPOLYMER DISPERSION 40%/ 2.50 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC CHARACTERISATION emulsion. APPEARANCE TO TO 0<6 pm pH 4.92 VISCOSITY Needle 6, Rate 2,5 363000cp CENTRIFUGING RAS Stability monitoring 1 MONTH 2 MONTHS 3 MONTHS 6 MONTHS pH AT/ 40*C 4.93/4.88 4.79/4.93 4.87/5.12 / AT 334000cp 356000cp 346000cp / 00 40*C 298000cp 282000cp 275000cp / These results demonstrate a good physical stability of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 31 PCT/EP2013/061201 Formula 13 COMPOSITIONS Commercial Name INCI name % COMPOUND A COMPOUND A 0.01 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 8.00 ARLAMOL PS15E-LQ PPG-15 STEARYL ETHER 15.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2.00 RONACARE ALLANTOIN ALLANTOIN 0.200 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDE, AMPS COPOLYMER DISPERSION 40%/ 3.00 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 BENZYL ALCOHOL BENZYL ALCOHOL 0.40 POTASSIUM SORBATE POTASSIUM SORBATE 0.10 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC CHARACTERISATION emulsion. APPEARANCE AT TO 0 < 5 pm pH 6.64 VISCOSITY Needle 6, Rate 5 147000cp CENTRIFUGING RAS Stability monitoring 1 MONTH 2 MONTHS 3 MONTHS 6 MONTHS pH AT/ 40*C 6.37/6.36 6.60/6.22 6.40/6.13 AT 160000cp 157000cp 121000cp These results demonstrate a good physical stability of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 32 PCT/EP2013/061201 Formula 14 COMPOSITIONS Commercial Name INCI name % COMPOUND A COMPOUND A 0.01 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 8.00 ARLAMOL PS15E-LQ PPG-15 STEARYL ETHER 15.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2.00 RONACARE ALLANTOIN ALLANTOIN 0.200 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDE,AMPS COPOLYMER DISPERSION 40%/ 3.00 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 SODIUM BENZOATE SODIUM BENZOATE 0.20 GLUCONO-DELTA-LACTONE SG GLUCONOLACTONE 0.25 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC CHARACTERISATION emulsion. APPEARANCE AT TO 0 < 8 pm pH 5.44 VISCOSITY Needle 6, Rate 20 36450cp CENTRIFUGING RAS Stability monitoring 1 MONTH 2 MONTHS 3 MONTHS 6 MONTHS Physical pH AT/ 40*C 4.59/4.58 4.70/4.78 NR NR stability These results demonstrate a good physical stability of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 33 PCT/EP2013/061201 Formula 15 COMPOSITIONS Commercial Name INCI name % COMPOUND A COMPOUND A 0.01 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 8.00 ARLAMOL PS15E-LQ PPG-15 STEARYL ETHER 15.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2.00 RONACARE ALLANTOIN ALLANTOIN 0.200 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDE,AMPS COPOLYMER DISPERSION 40%/ 3.00 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 BENZYL ALCOHOL BENZYL ALCOHOL 0.80 POTASSIUM SORBATE POTASSIUM SORBATE 0.20 TITRIPLEX III DISODIUM EDTA 0.10 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC CHARACTERISATION emulsion. APPEARANCE AT TO 0 < 6 pm pH 6.34 VISCOSITY Needle 5, Rate 5 67920cp CENTRIFUGING RAS 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 34 PCT/EP2013/061201 Formula 16 COMPOSITIONS Commercial Name INCI name % COMPOUNDA COMPOUNDA 0.01 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 8.00 ARLAMOL PS15E-LQ PPG-15 STEARYL ETHER 15.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2.00 RONACARE ALLANTOIN ALLANTOIN 0.200 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDE,AMPS COPOLYMER DISPERSION 40%/ 3.00 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 BENZOIC ACID BENZOIC ACID 0.20 POTASSIUM SORBATE POTASSIUM SORBATE 0.20 TITRIPLEX III DISODIUM EDTA 0.10 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC CHARACTERISATION emulsion. APPEARANCE AT TO 0 < 10pm pH 5.43 VISCOSITY Needle 5, Rate 5 59520cp CENTRIFUGING RAS 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 35 PCT/EP2013/061201 Formula 17 COMPOSITIONS Commercial Name INCI name % COMPOUNDA COMPOUNDA 0.01 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 8.00 ARLAMOL PS15E-LQ PPG-15 STEARYL ETHER 15.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2.00 RONACARE ALLANTOIN ALLANTOIN 0.200 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDE,AMPS COPOLYMER DISPERSION 40%/ 2.5 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 BENZALKONIUM CHLORIDE BENZALKONIUM CHLORIDE 0.05 PURIFIED WATER PURIFIED WATER 5.00 POTASSIUM SORBATE POTASSIUM SORBATE 0.20 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC CHARACTERISATION emulsion. APPEARANCE AT TO 0< 7pm pH 6.82 VISCOSITY Needle 6, Rate 50 11520cp CENTRIFUGING RAS Stability monitoring 1 month 2 months 3 months 6 months pH AT/40*C 6.60/6.43 6.80/6.34 6.61/6.24 6.54/6.23 AT 11080cp 10200cp 11200cp 9680cp Ln 40*C 11760cp 11400cp 10720cp 9520cp 0 U 6015213_1 (GHMattors) P98740.AU BELAG WO 2013/178760 36 PCT/EP2013/061201 AT 98.6 100.3 99.7 99.2 C U a) t 40*C 97 98.1 97.4 95.4 U 0 These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 37 PCT/EP2013/061201 Formula 18 (0298.0113) COMPOSITIONS Commercial Name INCI name % COMPOUNDA COMPOUNDA 0.04 PHENOXETOL PHENOXYETHANOL 1.00 MIGLYOL 812N CAPRYLIC/CAPRIC TRIGLYCERIDES 8.00 ARLAMOL PS15E-LQ PPG-15 STEARYL ETHER 15.00 ST-CYCLOMETHICONE 5NF CYCLOPENTASILOXANE 2,00 RONACARE ALLANTOIN ALLANTOIN 0.20 GLYCERINE 4810 VEGETABLE GLYCERIN 20.00 ACRYLAMIDEAMPS COPOLYMER DISPERSION 40%/ 2.5 SIMULGEL 600 PHA ISOHEXADECANE/ POLYSORBATE 80 BENZALKONIUM CHLORIDE BENZALKONIUM CHLORIDE 0.05 PURIFIED WATER PURIFIED WATER 5.00 PURIFIED WATER PURIFIED WATER QS 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE Absence of crystals. Fine, homogeneous MICROSCOPIC emulsion. APPEARANCE CHARACTERISATION 0 < 7pm ATTO pH 6.80 VISCOSITY Needle 6, Rate 50 10920cp CENTRIFUGING RAS 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 38 PCT/EP2013/061201 Stability monitoring 1 month 2 months 3 months 6 months pH AT/40*C 6.63/6.37 6.67/6.22 6.62/6.25 6.61/6.28 AT 13340cp 10450cp 10540cp 10840cp - a n 40*C 11040cp NR 10400cp 9240cp U a) a) V~* > z AT 100.2 98.3 99.8 99.4 - C .U0 E a -L 40*C 99.9 97.5 99.0 96.8 These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 39 PCT/EP2013/061201 Formula 19' Commerce Name MWCI Name 5 COMPOUND A COMPOUND A 0,01 PNNQXEUO PHENOXYEFTNANOL LOG M$GL'812W CAPRYUC CAPPXCTRIGISCENiO!S S ArtAklst$3.I ~ PP-15SXTEAPft £tE$S.O ST*-c'taOMRtNCOfNE 5WF (CCWPfNTASL(OXAN £ 2.01 f0QNA(AR AULANR)IN ALUANTO1N 0.20 G 1.VCff 1 NE 4, 10 VIQtTA9LGLYCEIN 00 AC RYLA M iDE CAWS CO POti YM ER Q S PER ION 40%/f3.1 SiMULGEt 600 P14A fSOHERAtWCAN -,-. POLYSORSiATf So PRO&NZQ SP SODIUM BENZOATE 2 PROPYLENE GLYCOt P19opyLt"KrCLYCOt vk P~l~l~) ATAPUiWUEiWATER 12 000X) MACROSCOPICwhtmotuiincem APPEARANCE Wie moh rlin ra CHARACTERISATION MICROSCOPIC Absence of crystals. Fine, APPEARANCE homogeneous emulsion. AT TO eH - VISCOSITY Needle 6, Rate 10 592O0cp CENTRIFUGING A 6015213_1 (GHMattors) P98740.AU BELAG WO 2013/178760 40 PCT/EP2013/061201 Formula 20: CDOMPOSII IONS commecial Name INS Name % COMPOUND A COMPOUND A P1ENOX0,L PHUNOXYVHANOL 15) M6GLY0L SI2N CAPRYUC/CAPIC (hGYCERYOES SA00 A RIAMOI PS15 E;.Q PPGW, STEARY PTHEf 15.0O ST-CYCLOMETHICONE SNF YC0PNRTASiH.0XAN 2.00 RONACAM AWAMTOiN ALLANTO'N 020 GYERINE 4810 VEGETASL GLYCERN 13.00 ACRYAMIDE,AMPS COPOLYMER DtSPERS ON 40%j 3.00 00EXADECANE/ POLYSORSATE80 GLO(ON,0*t 3A4ACTONU SGo G LCONOLAC3ON E 0325 06NNYLA600$10I. 8ENtYL ALC0H01 s.0 PROENZSP> SOiUM BENZOATE 0.20 PROPYIENE GLYOL PROPYLENEGLYCOL 7.00 PUNWDE WATEW PURifiGO WATER 05 100,00 MACROSCOPIC white, smooth, brilliant cream APPEARANCE CHARACTERISATION MICROSCOPIC Absence of crystals. Fine, APPEARANCE homogeneous emulsion, AT TO pH 4.89 VISCOSITY Needle 29, Rate 20 29650c o CENTRIFUGING RAS 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 41 PCT/EP2013/061201 Formula 21 : COMPOSE TONS Cnmerde Name INCI Name COMPOUND A COMPOUND A PIILNOXE'IGL PIENOXVETHANOL 400 MiGLYOL IM2N CAPRYLIC/CAPRiCTR GLYCERiD S V,00 ARLAMOL PSISEAQ PPG-S5TEARYt ETHER 15,00 ST CYCLOMETHICONE SNF CYCOPENTASILOXANE 2.00 RONACARE ALANTO ALLANTOW 0.20 GLYCERINE. 410 VEGETABLE GLYCERIN 15.00 ACRYLAMiD' AMPS COPOLYMER ISPERS ON 40% .00 SM~UIQLG 300SOHEXAcOCANE/ POtYSORAT E SW GLUC.ONOSELTA4ACTONE $G GWCONCLACIONE 02S BENZY. ALCO*41 SENTYL ALCOHOL 1.00 PROUIE SP SODIUM DWNZOAW 0.20 PROPYLENE GLYCOL PROPYLENE GLYCOL 5.00 PUREED WATER PURWIED WATER QSP 100.00 MACROSCOPIC White, smooth, brilliant cream APPEARANCE MICROSCOPIC Absence of crystals. Fine, CHARACTE RISATION APPEARANCE homogeneous emulsion, AT TO pH 4,82 VISCOSITY Needle 29, Rate 12 4S83cp CENTRIFUGING RAS 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 42 PCT/EP2013/061201 Formula 22 : COMPO$irONS Commarde Name INC Name % COMPOUND A COMPOUND A .,.. PHENOXETC'L PHENOXYCWANCJL 1.00 MiG.Y0L 812N CAPRYtK;/CAPRPC TRIGLYCERIOS S.0 ANAMRA PSiSE-*t PP9-5 STEARYL CTHER S5<0 ST-CYCLOMETHICONE NF CYCLOPENTASILOKANE -- 00 RONACARE ALLANTOIN ALLANTOiN 0.20 TITRSPLEX hI EDTA 0.20 G;XCERINE A610 VUGETAUL GLYCERUN 20.0 ACRVYAMIW( AMPs COPOLYMER DISPCRS00N 40% 20 SIMULGEL 600PHA SOEXAQECANE/ POLYSORBATE 80 GWCONQ-DETA-ACTONE SG GIC0NOLACTONaE SEN2YL ALCOHOL PEN2YL ALCOHOL 1,00 PROBENZ SP SCDiUM ENAh 0. PUIfED WATER PURRED WATER OSP 100.00 MACROSCOPIC APPEARANCE White, smooth, brilliant cream CHARACTERSATION MICROSCOPIC Absence of crystals. Fine, APPEARANCE homogeneous emulsion. AT TO pH 4,97 VISCOSITY Needle 29, Rate 20 29500cp CENTRIFUGING RAS 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 43 PCT/EP2013/061201 Formuda 23. COMPOSITIONS commercial Name Wt Name COMPOUND A COMPOUND A PHENOXETOL PHENOXYETHANOL MIGLYOL 812N CAPRYU1C/CANPRC TRiGLYCERIDES ARLAMOL PSISEIQ PPG-5 STEARYL ETHER STCYCLOMETHICONE SNF CYCLOPENrASIOXANF 2,00 RONACARE AL.ANTOIN ALLANTOIN 0.20 GLYCERIE. 4810 VEGETABLE GLYCEIN 20.00 ACRYLAMILDh AMPS COPOLYMER SIMULGEL 600 PHA DISPERSION 40%! SOt-IEXADECANE/ POLYSORBATE 80 BENZALKONIU1M CHLORIDE BENZALKONIONI CHLORIDE V.05, POTASNUM SOR BATE POTASSIUM SORBATE 20 PURIFIED WATER PURIFIED WATER Qsp icom MACROSCOPIC White, smooth, brilliant cream APPEARANCE MICROSCOPIC Absence of crystals. Fine, CHARACTERISATION APPEARANCE homogeneous emulsion. AT TO pH 6,64 VISCOSITY Needle 5, Rate 10 32 32Ocp CENTRIFUGING RAS Stability monitoring MONTH MONTHS MONTHS MONTHS 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 44 PCT/EP2013/061201 H TA/4C 658/641 644/6,23 NR 6A8/6-17 Lscosity AT pH3 AT/40C 3090cp 2510Ocp 287000cp 300000cp Rate 1 Phyiscal stability Vscosity 40C Physical stability 32000cp 374000cp 324000cp 317000cp Needle 5 1 Rate 1 These results demonstrate a good physical stability of the composition as a whole over time. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 45 PCT/EP2013/061201 Example 3: Characterisation of the formulations by cutaneous penetration studies on human skin: The cutaneous penetration studies enable the formulations to be characterised and the parameters peculiar to each of the formulations to be demonstrated. Two types of cutaneous penetration studies were carried out ex vivo on human skin. In these studies compound A corresponds to 3"-tert-butyl-4'-(2-hydroxy-ethoxy)-4"-pyrrolidin-1-yl-[1,1';3',1I"] terphenyl-4-carboxylic acid. The reference gel is described as follows: Constituents % by weight COMPOUND A 0.01 Propylene Glycol 30.00 Ethanol 95-96% 67.99 Klucel HF Pharma 2.00 1- "Single time" cutaneous penetration study: In this study the formula is applied for 16 hours to the surface of the skin. After the application, compound A (COMPOUND A) is quantified in the different compartments of the skin: stratum corneum, epidermis, dermis and receiving liquid according to a validated bioanalysis method. The details of the cutaneous application are given in the table below. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 46 PCT/EP2013/061201 Skin: 3 donors, 2 samples per donor Source Entire abdominal human skin Thickness 0.79-1.22mm Age 39-64 years. Franz cells 2 cm 2 Volume of receiving liquid 3mL Barrier function Evaluated by determination of the Insensitive Loss in Water, acceptable except where contraindicated Formulations A: Reference gel containing 100ig/g of B: Oil in water emulsion without COMPOUND A emulsifier, containing 100pag/g of COMPOUND A (Formula 3) Application Application ~2mg/cm 2 Quantity of active ingredient applied 142~241ng/cm 2 Exposure time 16h Samples taken Donor compartment lavage Kleenex (enabling the surplus product to be removed) "Excess" / Unabsorbed dose 1 st strip ___ strip M a ba la nce Stratum corneum (2-15 strips max) Epidermis Total skin Total Denetration Dermis Receiving Liquid Absorbed dose 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 47 PCT/EP2013/061201 The bioanalysis was conducted by mass spectrometry in tandem by positive electrospray ionisation using a Xevo device (Waters). The limit of quantification for compound A is 1 ng/mL. The conditions of LC/MS/MS developed enabled up to 0.1% of the dose applied in each of the compartments to be detected (unabsorbed dose, stratum, epidermis, dermis and receiving liquid). The technical conditions are given in the table below. LC column Hypersil gold 50*2.1mm (UPLC) Mobile phase Phase A: ACN + 0.1% Formic Acid Phase B : H 2 0 + 0.1% Formic acid Lavage of CAN Needle Lavage of ACN/H 2 0 50:50 septum Gradient Time (min) flow rate %A %B Curve 1. Initial 0.700 15.0 85.0 0 2. 2.5 0.700 90.0 10.0 6 3. 3.20 0.700 90.0 10.0 6 4. 3.25 0.700 15.0 85.0 6 Temperature of columns MSMS ESI+ MRM (Positive electrospray) detection Canal Reaction Dwell (secs) Voltage (cone) Col. Energy Tr (min) Compound 1: 460.26 > 318.20 0.100 50.0 40.0 1.58 Compound A Deuterated internal 1: 464.06 > 372.10 0.100 55.0 40.0 1.58 standard 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 48 PCT/EP2013/061201 Volume 5ptL Injection Run time 4 minutes In this type of "single point" study the parameters considered are: a. The distribution profile in the different compartments (qualitative data) b. The penetration in the epidermis + dermis compartment (numerical data) a-Distribution profile in the different compartments: This profile is shown in Figure 1. The distribution profile between the different compartments is of the same time for the 2 formulae evaluated: accumulation in the stratum corneum, lower rate of penetration in the epidermis, and very low penetration in the dermis. Compound A is not detected in the receiving liquid. b-Penetration values in the epidermis + dermis compartment: The penetration values for the oil in water type emulsion without emulsifier, containing 100.ig/g (0.01%) of compound A are between 6.8ng/cm 2 and 10.6ng/cm 2 . The levels of penetration of compound A after application of the oil in water type emulsion without emulsifier tend to be higher than those obtained after application of the reference gel. 2- Penetration kinetics study: In this type of study the penetration of the active ingredient is quantified in each compartment of the skin after 0.5 h, 1 h, 3 h, 6 h and 24 h of application. The penetration kinetics in each compartment are then determined and characterised. The details of the cutaneous application are given in the table below: 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 49 PCT/EP2013/061201 Skin 3 donors, 2 samples per donor per time, n=6 Source Abdominal human skin dermatomed from corpse Thickness 500Ipm Age Not Indicated Franz cells 1-2cm 2 Volume of Receiving Liquid Not Indicated Barrier Function Evaluated by tritiated water Products Reference gel 100pag/g Oil in water type emulsion without emulsifier 100pag/g (Formula 1) Formula Application ~2mg/cm 2 Quantity of active ingredient applied Between 100-200ng/cm 2 Exposure time Up to 24h Samples taken Exposure time 0.5, 1, 3, 6, 24h Lavage of donor compartment Kleenex (enabling the surplus product to be removed) "Excess" / Unabsorbed dose 1 st strip Mass balance Stratum corneum (2-15 strips max) Epidermis Total Skin Dermis Analyses LC/UV and LC/MS Limit of quantification ing/ml 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 50 PCT/EP2013/061201 The quantity of active ingredient in each compartment at each time was determined by LC/UV or by LC/MS. The bioanalysis method was validated so that at least 0.1% of the dose applied in each compartment could be detected. In this type of study the parameters considered are: a. The penetration kinetics profile in the epidermis (qualitative data) b. The initial rate of penetration in the epidermis c. The maximum quantity that has penetrated the epidermis a. Penetration kinetics profile in the epidermis: This is shown in Figure 2. The release kinetics of compound A obtained for the oil in water type emulsion without emulsifier exhibit a high initial gradient followed by a ceiling during which the penetration of compound A no longer increases in the course of time. The reference formula (gel) shows the same kinetics with rapid release for the first few hours, after which a plateau is reached. As seen in Section 1 ("Single time" cutaneous penetration study), these two formulae have different penetration levels at 16h, and the penetration of compound A in the epidermis after application of the oil in water emulsion without emulsifier tends to be higher than that obtained after application of the reference gel. b. Initial rate of the kinetics: The initial value of the rate of the kinetics or gradient in the first 3 hours is 4.2ng/cm 2 /h. c. Maximum quantity in the epidermis: The maximum quantity in the epidermis is 18.7ng/cm 2 . 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 51 PCT/EP2013/061201 Example 4 Tolerance study In this study: - 10 subjects received 2 grams of gel (reference gel) applied to 1000 cm 2 for 4 weeks. A reference gel is understood to mean a gel described as follows: Constituents % Compound A 0.01 Propylene Glycol 30.00 Ethanol 95-96% 67.99 Klucel HF Pharma 2.00 - 10 subjects received 2 grams of Cream B (oil in water emulsion without emulsifier-Formula 1) applied to 1000 cm 2 for 4 weeks. During the study the investigators had the opportunity of changing the area of application where irritation was excessive. The results of the study are presented in the table below: The numerical values are the number of patients for whom a change of area was made (value N in the table), and the value in brackets is the percentage corresponding to N. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 52 PCT/EP2013/061201 Development of the percentage of subjects for whom there is no change of area of application Gel 50pg/g Cream B Gel 50pg/g Gel Gel 1000 cm 2 50pg/g 2000 cm 2 100g/g 1000 cm 2 25pg/g 1000 cm 2 1000 cm 2 Day 2 N(%) - - - - Day 4 N(%) 1(10) - - - Day 5 N(%) - 1(10) 2(20) 1(10) Day 6 N(%) 1(10) - - 1(10) Day 7 N(%) - - 2(20) 1(10) 1(10) Day 8 N(%) 1(10) 1(10) - 2(20) 1(10) Day 9 N(%) 3(30) 1(10) 2(20) 1(10) Day 10 N(%) - - 1(10) 1(10) 1(10) Day 11 N(%) 2(20) 1(10) - 1(10) 1(10) Day 12 N(%) - 1(10) 1(10) - 1(10) Day 13 N(%) - 1(10) - - Day 14 N(%) 1(10) 1(10) 2(20) 1(10) 2(20) Day 16 N(%) 1(10) 1(10) - 1(10) Day 18 N(%) - - - - 1(10) Day 19 N(%) - - - - Day 24 N(%) - 1(10) - - 1(10) No change in the course of the study N(%) - 1 ( 10) - - 1 ( 10) Figure 3 shows the percentage of subjects for whom there was no change in the area of application as a function of the day of application. For example, on day 5, for 90% of the subjects receiving Cream B, there was no need to change the area of application. In other words, 10% of the subjects who received Cream B suffered from an irritation requiring a change of area of application. 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 53 PCT/EP2013/061201 It is therefore established that the irritation occurs more quickly in the subjects who received the gel than in the subjects who received Cream B. A marked difference is observed from day 9 onwards. 6015213_1 (GHMatters) P98740.AU BELAG

Claims (19)

1. An oil-in-water emulsion-type composition comprising - a fatty phase comprising: a compound with general formula (1) R 4 Y R 2 N O R R R Ar O 3 X where: - R 1 is a hydrogen atom, an alkyl radical of 1 to 4 carbons or a -CF 3 radical; - R 2 is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms or a chlorine atom; - R 3 is a hydrogen atom, or a linear or branched alkyl or alkoxy radical of 1 to 10 carbon atoms possibly substituted by a methoxy group; - R 4 is a hydrogen atom or an alkyl radical of I to 3 carbon atoms; - R 5 is a hydrogen atom or an alkyl radical of I to 3 carbon atoms; - or R 4 and R 5 together form, with the -N-C(=Y)- bond, a ring of the pyrrolidine, pyrrolidinone, piperidine or piperidinone type; - Y denotes two hydrogen atoms or a heteroatom such as oxygen or sulfur; - Ar denotes a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; - X denotes an oxygen atom, possibly substituted by an alkyl or alkylamine chain or a single C-C bond; - A denotes a hydrogen atom or the following formula: RQ 4Z0 6 R 7 7 where o Q is an oxygen atom or the bond -NH-; 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 55 PCT/EP2013/061201 o R6 denotes a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(O)CH 2 or -C(O)CH 2 CH 3 radical; o R 7 and R 7 ' denote, independently of each other, a hydrogen atom or a hydroxyl group, on condition that R 7 and R 7 ' are not simultaneously a hydroxyl group; n is equal to 0, 1, 2 , 3, 4 or 5 ; at least one principal solvent of compound (1) and at least one co-solvent oil of compound (1), and - an aqueous phase comprising at least one gelifying agent.

2. The composition according to Claim 1, characterised in that the compound with general formula (1) is defined so that: RI is a hydrogen atom, the t-butyl or i-propyl radical; R2 is a hydrogen atom, the t-butyl or i-propyl radical; R3 is a hydrogen atom or the ethyl radical; R4, R5 are independently from each other the methyl or ethyl radical or together form a pyrrolidine ring; A is as previously defined, where R6 denotes a hydrogen atom, the i-propyl or t-butyl radical, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(O)CH 2 or -C(O)CH 2 CH 3 radical.

3. The composition according to Claim 1, characterised in that the compound is 3"-tert-butyl-4'-(2 hydroxy-ethoxy)-4"-pyrrolidin-1-yl-[1,1';3',1"]-terphenyl-4-carboxylic acid.

4. The composition according to any one of the preceding claims, characterised in that it is deprived of an emulsifying agent.

5. The composition according to any one of the preceding claims, characterised in that the gelifying agent is selected from polymers of plant origin, gums, pectins, cellulose and its derivatives, polymers of microbiological origin, such as xanthan gum, and gelifying polymers of synthetic origin, and preferably from: - the Acrylates/C1O-30 Alkyl Acrylate Crosspolymer sold under the name of Pemulen TR-1 or Pemulen TR-2 - the gelifiers in the family of polyacrylamides, such as the mixture Sodium acrylamide/acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 sold under the name of Simulgel 600PHA - the mixture polyacrylamide/isoparaffin C13-14/laureth-7 sold under the name of Sepigel 305, 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 56 PCT/EP2013/061201 - the carbomers sold under the name of Ultrez 20@, Ultrez 10@, Carbopol 1382@ or Carbopol ETD202ONF@, Carbopol 981 or even Carbopol 980, - the polysaccharides with, by way of non-exhaustive example, xanthan gum such as Xantural180@, gellan gum sold under the name of Kelcogel, guar gum, cellulose and its derivatives, such as microcrystalline cellulose and carboxymethyl cellulose of sodium sold under the name of Avicel CL 611, hydroxypropylmethylcellulose, in particular the product sold under the name of Methocel E4M premium or hydroxyethylcellulose , in particular the product sold under the name of Natrosol HHX 250@, sodium carboxymethylcellulose, in particular Blanose cellulose gum 7F, - the family of aluminium magnesium silicates, such as Veegum K, - the family of acrylic polymers linked to hydrophobic chains such as PEG-150/decyl/SMDI copolymer sold under the name of Aculyn 44, - the family of modified starches such as modified potato starch, sold under the name of Structure Solanace or their mixtures, - the family of carrageenans, in particular those distributed among four major families : K, X, P, W such as the Viscarins* and Gelcarins*.

6. The composition according to any one of the preceding claims, characterised in that the principal solvent is selected from among benzyl alcohol, laureth-4, phenoxyethanol, propylene glycol monocaprylate, pentylene glycol, dimethyl isosorbide and mixtures thereof.

7. The composition according to Claim 6, characterised in that the principal solvent is phenoxyethanol.

8. The composition according to any one of the preceding claims, characterised in that the co-solvent oil is selected from among the caprylic/ capric triglycerides, sweet almond oil, propylene glycol monocaprylate, propylene glycol laurate, sorbitan sesquioleate, diisopropyl adipate, PPG-15 stearyl ester, apricot kernel oil, PEG-6 ester, and mixtures thereof.

9. The composition according to any one of the preceding claims, characterised in that it also contains one or more additives selected from among: -One or more preserving agents selected from among methyl parabene, propyl parabene, benzalconium chloride, phenoxyethanol sold under the name of phenoxetol, benzyl alcohol sold under the name of benzyl alcohol, Potassium sorbate sold under the name of potassium sorbate, benzoic acid, 2-bromo-2-nitropropane-1,3-diol sold under the name of Bronopol, Chlorohexidine, Chlorohexidine digluconate, chlorocresole and its derivatives, ethyl alcohol and diazolidinyl urea, 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 57 PCT/EP2013/061201 -One or more chelating agents such as EDTA (ethylene diamine tetraacetic acid) and its derivatives or salts, dihydroglycerine, citric and tartaric acids, gluconolactone sold under the name of glucono delta-lactone SG or mixtures thereof, - One or more antioxidants such as vitamin E and its derivatives, such as DL alpha tocopherol or tocopherol acetate; vitamin C and its derivatives, such as Ascorbyl Palmitate, Butylhydroxy toluene sold under the name of Nipanox BHT, - One or more palliatives and/or anti-irritants such as PPG-12/SMDI copolymer under the commercial name of Polyolprepolymer-2, glycyrrhetinic acid or its derivatives, for example Enoxolone, hyaluronic acid as such or in its form of sodium hyaluronate sold under the commercial name of HYAL. NA PWD PH 15-51-45, allantoin sold under the name of RONACARE ALLANTOINE.

10. The composition according to any one of the preceding claims, characterised in that it also contains a mineral oil.

11. The composition according to any one of the preceding claims, characterised in that it also contains a moistening agent.

12. The composition according to any one of the preceding claims, characterised in that it also contains a silicone oil.

13. The composition according to any one of the preceding claims, characterised in that it also contains ethanol.

14. The composition according to any one of Claims 1 to 13, characterised in that it comprises the following ingredients: from 0.00001% to 1% by weight and preferably from 0.0001 to 0.1 % by weight and more preferably from 0.001 by weight to 0.1% of compound of formula (1) from 0.005 to 10 % by weight and preferably from 1 to 5% by weight of gelifying agent from 0.2 to 5% by weight and preferably from 0.5 to 2% by weight of principal solvent from 0.5 to 50% by weight and preferably from 4 to 30% by weight of co-solvent oil(s), and optionally: from 0 to 20% by weight and preferably from 0 to 5% by weight of mineral oil(s) from 0 to 50% by weight and preferably from 5 to 35% by weight of polyol(s) from 0 to 10% by weight and preferably 0 to 4% by weight of silicone oil(s) 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 58 PCT/EP2013/061201 from 0 to 5% by weight and preferably from 0.01 to 2% by weight of preservative agent(s) from 0 to 30% by weight and preferably from 0 to 10% by weight of ethanol from 0 to 15% by weight and preferably from 0.1 to 10% by weight of additive(s).

15. The composition according to any one of the preceding claims, characterised in that the maximum quantity of active ingredient absorbed in the dermis and epidermis 16 hours after application is between 6 ng/cm 2 and 19 ng/cm 2 .

16. The composition according to Claim 15, characterised in that the maximum quantity of active ingredient absorbed in the dermis and epidermis 16 hours after application is between 6.8 ng/cm 2 and 10.6 ng/cm 2 .

17. The composition according to any one of the preceding claims, characterised in that the maximum quantity of active ingredient absorbed in the epidermis is obtained between 3 and 10 hours after application.

18. The composition according to any one of Claims 1 to 17 for use as a medicinal product.

19. The composition according to any one of Claims 1 to 18 for use for the treatment of one or more of the following pathologies: -Dermatological complaints associated with a keratinisation disorder relating to cellular differentiation and proliferation, particularly for treating common acne, comedonic acne, polymorphic acne, rosacea acne, nodulocystic acne, conglobata acne, senile acne and secondary acnes such as solar, medicamentous or professional acne; -Keratinisation disorders, in particular ichtyoses, ichtyosiform conditions, lamellar ichtyosis, Darrier's disease, palmoplantar keratodermias, leukoplasias, pityriasis rubra pilaris and leukoplasiform conditions, cutaneous or mucous (oral) lichen; -Dermatological disorders with an inflammatory immune-allergic component, with or without cellular proliferation disorder, and in particular all forms of psoriasis, whether cutaneous, mucous or ungueal, and even psoriasic rheumatism, or atopical dermatitis and the different forms of eczema; -Cutaneous disorders due to exposure to UV radiation, as well as to repair or control ageing of the skin, whether photo-induced or chronological, or to reduce pigmentations and actinic keratoses, or all pathologies associated with chronological or actinic ageing, such as xerosis, pigmentations and wrinkles; 6015213_1 (GHMatters) P98740.AU BELAG WO 2013/178760 59 PCT/EP2013/061201 -Any condition associated with benign dermal or epidermal proliferations, whether or not of viral origin, such as common warts, flat warts, molluscum contagiosum and verruciform epidermodysplasia, oral or florid papillomatoses; -Dermatological complaints such as immune dermatoses such as erythematous lupus, bullous immune diseases and collagenic diseases such as sclerodermia; -Stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy; -Healing complaints, or to prevent or repair stretch marks, or even to promote healing; -Any disorder of fungal origin in the cutaneous region, such as tinea pedis and tinea versicolor; -Pigmentation disorders such as hyperpigmentation, melasma, hypopigmentation or vitiligo; -Cancerous or pre-cancerous, cutaneous or mucous conditions such as actinic keratoses, Bowen's disease, carcinomas in-situ, keratoacanthoma and skin cancers such as basocellular carcinoma (BCC), spinocellular carcinoma (SCC) and cutaneous lymphomas such as T lymphoma. 6015213_1 (GHMatters) P98740.AU BELAG