Abstract:
A composition in the form of an oil in water emulsion, preferably without emulsifier, is described. The composition can include, in a physiologically acceptable environment, at least one new retinoid. Also described, is the method of preparing the composition and its use in cosmetics and dermatology.

Description:
CROSS-REFERENCE TO EARLIER APPLICATION 
       [0001]    This application is a non provisional of U.S. Application No. 61/654,729, filed Jun. 1, 2012, which is hereby expressly incorporated by reference in its entirety. 
     
    
       [0002]    The invention relates to a composition in the form of emulsion comprising, in a physiologically environment, at least one new retinoid with the general formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    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, an alkyl or alkoxy radical of 1 to 10 linear or branched carbon atoms, possibly substituted by a methoxy group;   R 4  is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms;   R 5  is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms;   or R 4  and R 5  together form, with the bond —N—C(═Y)—, a ring of the type pyrrolidine, pyrrolidinone, piperidine or piperidinone;   Y denotes two hydrogen atoms or one heteroatom such as oxygen or sulphur;   Ar denotes a cyclo 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl;   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:       
 
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             where
           Q is an oxygen atom or the bond —NH—;   R 6  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;   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;   
         
           
         
       
     
         [0018]    These compounds, described in patent EP1831149, are potent retinoids modulating the nuclear receptor/receptors of retinoic acid (RAR), more specifically of the gamma subtype of this receptor (RARγ). 
         [0019]    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). 
         [0020]    Three subtypes of human RARs have been identified and described: RARα, RARβ and RARγ. 
         [0021]    Since the gamma RAR receptors are located in the epidermis it is important for the compounds described in the general formula (I) to be released in this part of the skin to provide clinical efficacy. 
         [0022]    The topical application of retinoids may result in irrigation of the skin, dryness and erythema. Numerous articles describe this irritating effect, such as the articles by Stucker &amp; al. Skin Res Technol. 2002 May; 8(2):133-40 or by Thielitz &amp; al. Am J Clin Dermatol. 2008; 9(6):369-81. 
         [0023]    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. 
         [0024]    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. 
         [0025]    The fact that emulsifiers are not used in the compositions containing retinoids would therefore enable eliminating cutaneous irritation due to the presence of this class of molecule. 
         [0026]    The prior art describes H/E emulsions with or without emulsifier. We may cite, in particular, U.S. Pat. No. 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. 
         [0027]    Nevertheless, although the compounds described by the general formula (I) exhibit interesting chemical and physical stability properties for preparations for pharmaceutical uses, they degrade chemically in a number of their solvents. 
         [0028]    There is therefore a need for stable, well tolerated pharmaceutical compositions containing compounds described by general formula (I). 
         [0029]    A first object according to the invention relates to a pharmaceutical composition comprising a compound with the general formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    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, an alkyl or alkoxy radical of 1 to 10 linear or branched carbon atoms, possibly substituted by a methoxy group;   R 4  is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms;   R 5  is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms;   or R 4  and R 5  together form, with the bond —N—C(═Y)—, a ring of the type pyrrolidine, pyrrolidinone, piperidine or piperidinone;   Y denotes two hydrogen atoms or one heteroatom such as oxygen or sulphur;   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:       
 
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             where:
           Q is an oxygen atom or the bond —NH—;   R 6  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;   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 gelling agent of the aqueous phase, at least one principal solvent of the compound (I) and at least one co-solvent oil of the compound (I).
   
         
           
         
       
     
         [0045]    A second object according to the invention relates to a pharmaceutical composition such as described above for its use as a medicinal product. 
         [0046]    A third object according to the invention relates to a pharmaceutical composition as described above for its use in the treatment of pathologies such as: 
         [0000]    1) dermatological complaints associated with a keratinisation disorder relating to cellular differentiation and proliferation, particularly for treating common, comedonic, polymorphic acnes, rosaceas, nodulocystic acnes, conglobata, senile acnes and secondary acnes such as solar, medicamentous or professional acne;
 
2) keratinisation disorders, in particular ichtyoses, ichtyosiform conditions, lamellar ichtyosis, Darrier&#39;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 rheumatic, 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;
 
7) stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy;
 
8) scarring complaints, or to prevent or repair stretch marks, or even to promote scarring;
 
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&#39;s disease, carcinomas in-situ, keratocanthoma and skin cancers such as basocellular carcinoma (BCC), spinocellular carcinoma (SCC)(and cutaneous lymphomas such as T lymphoma.
 
         [0047]    A fourth object according to the invention relates to a method for preparing a pharmaceutical 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 phenoxyethanol   c) addition of the lipophilic excipients   d) gelification of the aqueous phase by adding the polyacryl amide polymer   e) addition of the oily phase then the silicone oil       
 
         [0053]    A fifth object according to the invention relates to the compositions comprising a compound with general formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0054]    And at least one polyacryl amide gelifier, characterised in that the maximum quantity of active ingredient absorbed in the epidermis 16 hours after application, i.e. between 6 ng/cm 2  and 19 ng/cm 2 . 
         [0055]    A sixth object according to the invention relates to the compositions comprising a compound with general formula (I) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0056]    And at least polyacryl amide gelifier, characterised in that the maximum quantity of active ingredient absorbed in the epidermis is obtained between 3 and 10 hours after application. 
         [0057]    Preferably between 5 and 7 hours after application. 
         [0058]    A more detailed description of the invention is detailed hereafter, in the examples and in the figures 
     
    
     DESCRIPTION OF THE INVENTION 
       [0059]    To facilitate a reading of this description reference will be made to general formula (1) and compound A in the remaining text, as described thus: 
         [0060]    General formula (I): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    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, an alkyl or alkoxy radical of 1 to 10 linear or branched carbon atoms, possibly substituted by a methoxy group;   R 4  is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms;   R 5  is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms;   or R 4  and R 5  together form, with the bond —N—C(═Y)—, a ring of the type pyrrolidine, pyrrolidinone, piperidine or piperidinone;   Y denotes two hydrogen atoms or one heteroatom such as oxygen or sulphur;   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:       
 
         [0000]    
       
                 
         
             
             
         
       
       
         
           
             where
           Q is an oxygen atom or the bond —NH—;   R 6  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;   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;   
         
           
         
       
     
         [0076]    Compound A: as being 3″-tert-butyl-4′-(2-hydroxy-ethoxy)-4″-pyrrolidin-1-yl-[1,1′;3′,1″]-terphenyl-4-carboxylic acid. 
         [0077]    Due to the physico-chemical characteristics of the active ingredient, we have had to face a certain number of constraints in the use of the compounds described by general formula (I). These compounds:
       are soluble in few solvents normally used in the fat phases of the topical emulsions   are chemically degraded in a number of their solvents   degrade chemically in the presence of numerous emulsifiers.       
 
         [0081]    A first object according to this invention describes compositions containing at least one compound with general formula (I) in the form of emulsions of the type O/W (Oil in Water) and in which the active ingredient is solubilised in the fat phase. 
         [0082]    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. 
         [0083]    In a preferred mode, the composition according to the invention is without emulsifier. 
         [0084]    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 fat (or oily) phase dispersed in an aqueous phase. 
         [0085]    In the invention the compositions contain a quantity of active ingredient described by general formula (I) at concentrations ranging from 0.00001% to 1% w/w, preferably from 0.0001 to 0.1% w/w, and more preferably from 0.001 to 0.1% w/w. 
         [0086]    Preferably the active ingredient described by general formula (I) is compound A.
       In the invention the compositions contain at least one aqueous phase gelifier used alone or in combination:   Gelling agent means agent capable of giving a composition the texture of a polymeric gel compound.   Gelling agents may be chosen from the plant polymers, gums, pectins, cellulose and its derivatives, microbiological origin polymers such as xanthan gum, gelling and synthetic polymers.   By way of non-exhaustive example of gelifiers that may enter into the compositions, mention may be made of Acrylates/C10-30 Alkyl Acrylate Cross polymer, sold under the name of Pemulen TR-1 or Pemulen TR-2 by the company Noveon, gelifiers in the polyacryl amide 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/isoparaffine 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 Noveon, the polysaccharides with, by way of non-exhaustive examples, xanthan gum, such as Xantura1180® sold by the company Kelco, gellan gum, solder 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 Aqualon, sodium carboxymethylcellulose, in particular Blanose cellulose gum 7F sold by the company Aqualon, 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 Solanaceae or their mixtures, the family of the carrageenans, particularly those distributed among four manor families: κ, λ, β, ω, such as Viscarin® and the Gelcarin® marketed by the company IMCD.       
 
         [0092]    In preference a gelifier of the polyacrylamide type, such as Simulgel 600 PHA®, which has thickening and stabilising properties, will be used in concentrations ranging from 0.005 to 5% w/w, and preferably ranging from 1% to 4% w/w, alone or associated with at least one of the above-mentioned gelifiers. 
         [0093]    The person skilled in the art knows that for an emulsifier system the proportion of emulsifier required to emulsify a fat phase in an oil in water emulsion is normally of the order of ⅕ of a % of the fat phase. By way of non-exhaustive example a fat phase representing at least 11% of the ingredients of the formulae would require a minimum of 2.5% of emulsifiers. 
         [0094]    In the invention, no emulsifier is used as an ingredient in our compositions. However, it is possible that certain ingredients contain low percentages of emulsifier in their own composition. Because of the low percentage that may result from this in our compositions they cannot be used as an emulsifier (lower than 0.6%).
       In the invention the compositions contain a fat phase that may consist of:
           a solvent of an active ingredient described by general formula (I), which may be benzyl alcohol, laureth-4, phenoxyethanol, propylene glycol monocaprylate, pentylene glycol or dimethyl isosorbide, and preferably phenoxyethanol sold under the name phenoxetol by Clariant, the quantity of phenoxyethanol being 0.2 to 5%, and preferably 0.5 to 2%.   one or more co-solvent oils which may be, in preference, 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 E) supplied by CRODA, Apricot Kernel Oil PEG-6 Ester (Labrafil M1944CS) supplied by GATTEFOSSE in proportions ranging from 0.5 to 50% and preferably from 4 to 30%.   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):   Silicon oils that improve the properties of the formula for the formulation, 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%.   Preservatives such as methyl parabene, propyl parabene, benzalconium chloride, phenoxyethanol sold under the name of phenoxetol by Clariant, benzyl alcohol sold 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, ethyl alcohol and diazolidinyl urea. These preservatives may be used alone or in combination for effective protection of formulae against all bacterial contamination from 0% to 5%, and preferably from 0.01 to 2%.   Ethanol, the quantity of which is between 0 and 30%, preferably between 0 and 10%.   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 D-(+)-glucono-delta-lactone by MERCK 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 Cognis, 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 Laserson, 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.   
               
 
       General Composition for Acne: 
       [0107]    The percentages are 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 0.001 to 0.1% of compound with the general formula (I)   from 0.005 to 10% and preferably from 1 to 5% of gelling agent   from 0.2 to 5% and preferably from 0.5 to 2% of solvent of compound with the general formula (I)   from 0.5 to 50% and preferably from 4 to 15% of co-solvent oils of 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: 
       [0118]    The percentages are expressed by weight in relation to the total weigh of the composition of the oil in water type.
       From 0.00001% to 1% and preferably from 0.001 to 0.12% of compound with the general formula (I)   from 0.005 to 10% and preferably from 1 to 5% of gelling agent   from 0.2 to 5% and preferably from 0.5 to 2% of solvent of compound with the general formula (I)   from 0.5 to 50% and preferably from 10 to 30% of co-solvent oils of 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       
 
         [0127]    Another object according to the invention relates to a method of preparing a composition described as above and comprising the following stages: 
         [0000]    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 (ST-cyclomethicone 5 as an example) when this oil is present in the formula to be achieved.
 
C) Mixing of the two phases.
 
At ambient temperature gelify the aqueous phase by adding Simulgel 600PHA, then add the oily phase then the ST-cyclomethicone 5.
 
       EXAMPLES 
     Example 
     Pre-Formulation 
       [0128]    In order to obtain an oil in water emulsion containing a compound with the general formula (I) in the fat phase, pre-formulation studies have been conducted to provide evidence of the excipients allowing good solubilisation as well as good stability of the active ingredient. 
         [0000]    (1) List of fat phase excipients in which the maximum solubility has been determined by HPLC: 
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 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 
                 &lt;0.1 
               
               
                   
               
             
          
         
       
     
         [0129]    The limit, below which the compounds of general formula (1) are considered non-solubilized, is 0.1% by weight. 
         [0000]    (2) Stability of compound A in its principal solvents: 
         [0130]    These stability studies of compound A in its principal solvents show that compound A degrades chemically in a number of its solvents. 
         [0131]    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 W/O emulsions in which compound A is solubilised in the oily phase. 
         [0000]                                                  Excipients                Commercial       COMPOUND A           name   INCI name   %   Stability results               Miglyol 812N   Caprylic/capric triglycerides   0.005%    Stable/Ok 6 Months                   40° C.       Sweet almond oil     Prunus Amygdalus Dulcis  (Sweet   0.005%    Stable/Ok 6 Months           Almond) Oil       40° C.       Capryol 90   Propylene glycol monocaprylate   0.05%   Stable/Ok 6 Months                   40° C.       Arlacel 83V   Sorbitan Sesquioleate   0.05%   Stable/Ok 6 Months       Pharma           40° C.       Crodamol DA   Diisopropyl Adipate   0.05%   Stable/Ok 6 Months                   40° C.       Lauroglycol FCC   Propylene glycol laurate   0.05%   Stable/Ok 6 Months                   40° C.       Arlamol E   PPG-15 stearyl ether   0.05%   Stable/Ok 6 Months                   40° C.       Phenoxetol   Phenoxyethanol   0.05%   Stable/Ok 6 Months                   40° C.       Labrafil   Apricot Kernel Oil PEG-6 Ester   0.05%   Stable/Ok 6 Months       M1944CS           40° C.       Dipropylene   Dipropylene glycol   0.05%   Unstable       Glycol 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/   0.05%   Unstable           dicaprate       Arlasolve DMI   Dimethyl Isosorbide   0.05%   Unstable       Marcol 152   Parrafinum liquidum   0.05%   Unstable                    
(3) Stability of compound A in mixtures of excipients (solvent/surfactants) determined by HPLC:
 
         [0132]    Studies of stability of compound A solubilised in oils (in which it is stable) in the presence of surfactants have been conducted: 
         [0000]    
       
         
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 Mixture of excipients 
                   
               
             
          
           
               
                 Commercial 
                   
                 COMPOUND A 
                   
               
               
                 name 
                 INCI name 
                 % 
                 Stability results 
               
               
                   
               
               
                 Simulsol M45/ 
                 PEG-8 Stearate/Diisopropyl 
                 0.05% 
                 Unstable 
               
               
                 Crodamol DA 
                 Adipate 
               
               
                 Cremophor EL/ 
                 PEG-35 Castor Oil/Apricot 
                 0.05% 
                 Unstable 
               
               
                 Labrafil 
                 Kernel Oil PEG-6 Ester 
               
               
                 M1944CS 
               
               
                 Tween 80/ 
                 Polysorbate-80/PPG-15 stearyl 
                 0.05% 
                 Unstable 
               
               
                 Arlamol E 
                 ether 
               
               
                 Cremophor EL/ 
                 PEG-35 Castor Oil/Propylene 
                 0.05% 
                 Unstable 
               
               
                 Lauroglycol 
                 glycol laurate 
               
               
                 FCC 
               
               
                 Tween 80/ 
                 Polysorbate-80/Hexylene 
                  0.2% 
                 Unstable 
               
               
                 Hexylene glycol 
                 glycol 
               
               
                 Cremophor EL/ 
                 PEG-35 Castor Oil/Apricot 
                  0.2% 
                 Unstable 
               
               
                 Labrafil 
                 Kernel Oil PEG-6 Ester 
               
               
                 M1944CS 
               
               
                 Cremophor 
                 PEG-40 Hydrogenated Castor 
                  0.2% 
                 Unstable 
               
               
                 RH40/ 
                 Oil/Diisopropyl Adipate 
               
               
                 Crodamol DA 
               
               
                 Tween 80/ 
                 Polysorbate-80/Propylene 
                  0.2% 
                 Unstable 
               
               
                 Lauroglycol 
                 glycol laurate 
               
               
                 FCC 
               
               
                 Simulsol M45/ 
                 PEG-8 Stearate/Diisopropyl 
                  0.2% 
                 Unstable 
               
               
                 Crodamol DA 
                 Adipate 
               
               
                 Arlacel 165/ 
                 Glyceryl Stearate 
                 0.05% 
                 Unstable 
               
               
                 Lauroglycol 
                 PEG-100 Stearate/Propylene 
               
               
                 FCC 
                 glycol laurate 
               
               
                 GlucateSS- 
                 Methyl Glucose Sesquistearate- 
                 0.05% 
                 Unstable 
               
               
                 Glucamate 
                 PEG-20 Methyl Glucose 
               
               
                 SSE-20/ 
                 Sesquistearate/PPG-15 stearyl 
               
               
                 Arlamol E 
                 ether 
               
               
                 Brij 721/ 
                 Steareth-21/PPG-15 stearyl 
                 0.05% 
                 Stable/Ok 3 Months 
               
               
                 Arlamol E 
                 ether 
                   
                 40° C. 
               
               
                 Brij 721/ 
                 Steareth-21/Propylene glycol 
                 0.05% 
                 Stable/Ok 3 Months 
               
               
                 Lauroglycol 
                 laurate 
                   
                 40° C. 
               
               
                 FCC 
               
               
                 Eumulgin B2/ 
                 Ceteareth-20/PPG-15 stearyl 
                 0.05% 
                 Stable/Ok 3 Months 
               
               
                 Arlamol E 
                 ether 
                   
                 40° C. 
               
               
                 Arlacel 165/ 
                 Glyceryl Stearate 
                 0.05% 
                 Stable/Ok 3 Months 
               
               
                 Arlamol E 
                 PEG-100 Stearate/PPG-15 
                   
                 40° C. 
               
               
                   
                 stearyl ether 
               
               
                 GlucateSS- 
                 Methyl Glucose Sesquistearate- 
                 0.05% 
                 Stable/Ok 3 Months 
               
               
                 Glucamate 
                 PEG-20 Methyl Glucose 
                   
                 40° C. 
               
               
                 SSE-20/ 
                 Sesquistearate/Propylene 
               
               
                 Lauroglycol 
                 glycol laurate 
               
               
                 FCC 
               
               
                   
               
             
          
         
       
     
         [0133]    The limits fixed for high stability are 95%-105% as a percentage relative to TO. 
         [0134]    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 without emulsifier. 
       Example 2 
     Formulations 
       [0135]    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 40° C. after T+1 Month and/or T+2 Months or T+3 Months or T+6 Months. The equipment and methods used for these characteristics are described below. 
         [0136]    Since 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 Dose of Compound A: 
       [0000]    
       
         
           
             Equipment: HPLC 
             Expression of the results: the titre of the active ingredient is expressed as a % related to the initial % achieved at T0. The limits fixed for high stability are 95%-105%. 
           
         
       
     
       Macroscopic Observation: 
       [0000]    
       
         
           
             Macroscopic observation enables the physical integrity of the products at T0 and after stability to be guaranteed. 
           
         
       
     
       Microscopic Observation: 
       [0000]    
       
         
           
             Microscopic observation enables good solubilisation of compound A from T0, 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
 
pH:
 
             Equipment: METTLER TOLEDO Seven Multi pH meter 
             Method: Measurements carried out at ambient temperature after 24 h stabilisation in an enclosure at 25° C. of all the samples. 
           
         
       
     
       Viscosity 
       [0000]    
       
         
           
             The measurement of the viscosity enables the consistency of the formulae produced to be evaluated. 
             Equipment: Brookfield RV DVII+Pro 
             Method: Measurements carried out at ambient temperature after 24 h stabilisation in an enclosure at 25° C. of all the samples. The value is read after 1 minute. The choice of mobile phase and speed will be described in each composition example. The values obtained are expressed in centipoises (Cps). 
           
         
       
     
       Centrifuging: 
       [0000]    
       
         
           
             The centrifuging enables the resistance of the formulae 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. 
           
         
       
     
       Formula 1 
       [0151]      
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 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 
               
               
                   
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS Copolymer 
                 3.000 
               
               
                   
                   
                 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 
                 QSP 100.000 
               
               
                   
                   
               
             
          
           
               
                   
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 AT T0 
                 APPEARANCE 
               
               
                   
                   
                 MICROSCOPIC 
                 Absence of crystals. Very fine, 
               
               
                   
                   
                 APPEARANCE 
                 homogeneous crystal. Ø &lt; 5 μm: 
               
               
                   
                   
                   
                 90% 
               
               
                   
                   
                 pH 
                 5 
               
               
                   
                   
                 VISCOSITY 
                 Needle 6, Rate 5. 176 000 cp 
               
               
                   
                   
                 CENTRIFUGING 
                 Conforming 
               
               
                   
                   
               
             
          
           
               
                 STABILITY 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                 MONITORING 
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 5.28/5.31 
                 5.45/5.81 
                 5.30/5.67 
                 5.23/5.75 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 169 000 cP 
                 166 000 cP 
                 175 000 cP 
                 172 000 cP 
               
               
                   
                   
                 40° C. 
                 174 000 cP 
                 173 000 cP 
                 165 000 cP 
                 159 000 cP 
               
               
                 Chemical 
                 Dose 
                 TA 
                 98.70 
                 100.40 
                 100.30 
                 103.10 
               
               
                 stability 
                 COMPOUND A 
                 40° C. 
                 99.40 
                 101.30 
                  98.80 
                 104.90 
               
               
                   
                 Initial % 
               
               
                   
               
             
          
         
       
     
       Formula 2 
       [0152]      
         [0000]    
       
         
               
               
               
             
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 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 
               
               
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS 
                 3.000 
               
               
                   
                 Copolymer Dispersion 
               
               
                   
                 40%/Isohexadecane/ 
               
               
                   
                 polysorbate 80 
               
               
                 MIGLYOL 812 N 
                 Medium-Chain 
                 8.000 
               
               
                   
                 Triglycerides 
               
               
                 ST-CYCLOMETHICONE 5 
                 Cyclopentasiloxane 
                 2.000 
               
               
                 PHENOXETOL 
                 Phenoxyethanol 
                 1.000 
               
               
                 PURIFIED WATER 
                 Purified water 
                 QSP 100.000 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, 
               
               
                 AT T0 
                 APPEARANCE 
                 brilliant cream 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Very 
               
               
                   
                 APPEARANCE 
                 fine, homogeneous 
               
               
                   
                   
                 emulsion. Ø &lt; 5 μm: 90% 
               
               
                   
                 pH 
                 5 
               
               
                   
                 VISCOSITY 
                 176 000 cP 
               
               
                   
                 CENTRIFUGING 
                 Conforming 
               
               
                   
               
             
          
           
               
                 Chemical 
                 Dose 
                 TA 
                 100.60 
                 100.20 
                 98.00 
                 100.50 
               
               
                 stability 
                 COMPOUND 
                 40° C. 
                 99.40 
                 100.40 
                 96.80 
                 96.60 
               
               
                   
                 A Initial % 
               
               
                   
               
             
          
         
       
     
       Formula 3 
       [0153]      
         [0000]    
       
         
               
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMMERCIAL NAME 
                 INCI NAME 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 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 
               
               
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS Copolymer 
                 2.000 
               
               
                   
                 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 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                 AT T0 
                 APPEARANCE 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Very fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion. Ø &lt; 5 μm: 
               
               
                   
                   
                 90% 
               
               
                   
                 pH 
                 6.36 
               
               
                   
                 VISCOSITY 
                 Needle 6, Rate 10. 57 500 cP 
               
               
                   
                 CENTRIFUGING 
                 NR 
               
               
                   
               
             
          
           
               
                 STABILITY 
                   
                   
                   
                   
               
               
                 MONITORING 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 6.61/6.31 
                 6.7/6.21 
                 6.48/6.18 
                 6.40/6.08 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 64 500 cP 
                 59 800 cP 
                 67 000 cP 
                 64 600 cP 
               
               
                   
                   
                 40° C. 
                 59 000 cP 
                 59 000 cP 
                 55 100 cP 
                 57 300 cP 
               
               
                 Chemical 
                 Dose 
                 TA 
                 104.00 
                 100.5 
                 100.00 
                 95.00 
               
               
                 stability 
                 COMPOUND 
                 40° C. 
                 104.8 
                 100.00 
                 99.60 
                 94.70 
               
               
                   
                 A Initial % 
               
               
                   
               
             
          
         
       
     
       Formula 4 
       [0154]      
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 COMMERCIAL NAME 
                 INCI NAME 
                 % 
               
               
                   
                   
               
               
                   
                 COMPOUND A 
                 COMPOUND A 
                 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 
                 QSP 100.000 
               
               
                   
                   
               
             
          
           
               
                   
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 AT T0 
                 APPEARANCE 
               
               
                   
                   
                 MICROSCOPIC 
                 Absence of crystals. Very fine, 
               
               
                   
                   
                 APPEARANCE 
                 homogeneous emulsion. Ø &lt; 5 μm: 
               
               
                   
                   
                   
                 90% 
               
               
                   
                   
                 pH 
                 4.72 
               
               
                   
                   
                 VISCOSITY 
                 Needle 6, Rate 2.5. 215 000 cP 
               
               
                   
                   
                 CENTRIFUGING 
                 NR 
               
               
                   
                   
               
             
          
           
               
                 STABILITY 
                   
                   
                   
                   
               
               
                 MONITORING 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 NR/5.58 
                 NR/5.47 
                 NR/5.53 
                 NR/NR 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 NR 
                 NR 
                 NR 
                 NR 
               
               
                   
                   
                 40° C. 
                 183 000 cP 
                 168 000 cP 
                 158 000 cP 
                 NR 
               
             
          
           
               
                 Chemical 
                 Dose 
                 TA 
                 1.5 Months: 99.90 
                 99.90 
                 NR 
               
               
                 stability 
                 COMPOUND 
                 40° C. 
                 1.5 Months: 99.00 
                 99.40 
                 NR 
               
               
                   
                 A Initial % 
               
               
                   
               
             
          
         
       
     
       Formula 5 
       [0155]      
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 COMMERCIAL NAME 
                 INCI NAME 
                 % 
               
               
                   
                   
               
               
                   
                 COMPOUND A 
                 COMPOUND A 
                 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 
                 QSP 100.000 
               
               
                   
                   
               
             
          
           
               
                   
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 AT T0 
                 APPEARANCE 
               
               
                   
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                   
                 APPEARANCE 
                 homogeneous emulsion. Ø &lt; 10 μm: 
               
               
                   
                   
                   
                 90% 
               
               
                   
                   
                 pH 
                 4.64 
               
               
                   
                   
                 VISCOSITY 
                 Needle 6, Rate 2.5. 314 000 cP 
               
               
                   
                   
                 CENTRIFUGING 
                 NR 
               
               
                   
                   
               
             
          
           
               
                 STABILITY 
                   
                   
                   
                   
               
               
                 MONITORING 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 NR/5.62 
                 NR/5.68 
                 NR/5.65 
                 NR/5.81 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 NR 
                 NR 
                 NR 
                 NR 
               
               
                   
                   
                 40° C. 
                 267 000 cP 
                 268 000 cP 
                 262 000 cP 
                 246 000 cP 
               
             
          
           
               
                 Chemical 
                 Dose 
                 TA 
                 1.5 Months: 98.80 
                 100.70 
                 107.00 
               
               
                 stability 
                 COMPOUND A 
                 40° C. 
                 1.5 Months: 106.00 
                 100.70 
                 107.70 
               
               
                   
                 Initial % 
               
               
                   
               
             
          
         
       
     
       Formula 6 
       [0156]      
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 COMMERCIAL NAME 
                 INCI NAME 
                 % 
               
               
                   
                   
               
               
                   
                 COMPOUND A 
                 COMPOUND A 
                 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 SEED PH 
                   Ricinus Communis  (Castor) 
                 8.000 
               
               
                   
                   
                 Seed Oil 
               
               
                   
                 PHENOXETOL 
                 Phenoxyethanol 
                 1.000 
               
               
                   
                 PURIFIED WATER 
                 Purified water 
                 QSP 100.000 
               
               
                   
                   
               
             
          
           
               
                   
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 AT T0 
                 APPEARANCE 
               
               
                   
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                   
                 APPEARANCE 
                 homogeneous emulsion. Ø &lt; 5 μm: 
               
               
                   
                   
                   
                 90% 
               
               
                   
                   
                 pH 
                 5.67 
               
               
                   
                   
                 VISCOSITY 
                 Needle 29, Rate 0.5. 1 180 000 cP 
               
               
                   
                   
                 CENTRIFUGING 
                 Conforming 
               
               
                   
                   
               
             
          
           
               
                 STABILITY 
                   
                   
                   
                   
               
               
                 MONITORING 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 5.66/5.55 
                 5.73/5.82 
                 5.44/5.84 
                 5.44/5.84 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 1 160 000 cP 
                 1 080 000 
                 1 080 000 cP 
                 1 080 000 cP 
               
               
                   
                   
                 40° C. 
                 1 130 000 cP 
                 1 030 000 
                 1 090 000 cP 
                 1 030 000 cP 
               
               
                 Chemical 
                 Dose 
                 TA 
                 99.8 
                 100.0 
                 100.4 
                 100.0 
               
               
                 stability 
                 COMPOUND A 
                 40° C. 
                 99.6 
                  99.5 
                  99.2 
                  99.5 
               
               
                   
                 Initial % 
               
               
                   
               
             
          
         
       
     
       Formula 7 
       [0157]      
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 COMMERCIAL NAME 
                 INCI NAME 
                 % 
               
               
                   
                   
               
               
                   
                 COMPOUND A 
                 COMPOUND A 
                 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 
                 QSP 100.000 
               
               
                   
                   
               
             
          
           
               
                   
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 AT T0 
                 APPEARANCE 
               
               
                   
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine 
               
               
                   
                   
                 APPEARANCE 
                 homogeneous emulsion. Ø &lt; 5 μm: 
               
               
                   
                   
                   
                 90% 
               
               
                   
                   
                 pH 
                 5.87 
               
               
                   
                   
                 VISCOSITY 
                 Needle 29, Rate 5. 139 000 cP 
               
               
                   
                   
                 CENTRIFUGING 
                 Conforming 
               
               
                   
                   
               
             
          
           
               
                 STABILITY 
                   
                   
                   
                   
               
               
                 MONITORING 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 5.90/5.50 
                 5.71/5.71 
                 5.66/5.90 
                 5.66/5.90 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 148 000 cP 
                 132000 cP 
                 134 000 cP 
                 132000 cP 
               
               
                   
                   
                 40° C. 
                 142 000 cP 
                 130000 cP 
                 137 000 cP 
                 130000 cP 
               
               
                 Chemical 
                 Dose 
                 TA 
                  97.8 
                 109.6 
                 100.7 
                 100.7 
               
               
                 stability 
                 COMPOUND 
                 40° C. 
                 100.0 
                 110.2 
                 100.6 
                 100.2 
               
               
                   
                 A Initial % 
               
               
                   
               
             
          
         
       
     
       Formula 8 
       [0158]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.010 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC/CAPRIC 
                 15.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 CASTOR OIL PH 
                 RICINUS COMMUNIS (CASTOR) 
                 8.00 
               
               
                   
                 SEED OIL 
               
               
                 ST-CYCLOMETHICONE 5NF 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 Q7-9120 SILICON FLUID 
                 DIMETHICONE 
                 5.00 
               
               
                 350 cst 
               
               
                 RONACARE ALLANTOIN 
                 ALLANTOIN 
                 0.200 
               
               
                 GLYCERINE 4810 
                 GLYCERINE 
                 20.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, AMPS COPOLYMER 
                 3.00 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/polysorbate 80 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                 AT T0 
                 APPEARANCE 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                 Ø 6 μm 
               
               
                   
                 pH 
                 4.92 
               
               
                   
                 VISCOSITY 
                 Needle 6, Rate 0.5 NR 
               
               
                   
                 CENTRIFUGING 
                 Conforming 
               
               
                   
               
             
          
           
               
                 Stability monitoring 
                 1 MONTH 
                 2 MONTHS 
                 3 MONTHS 
                 6 MONTHS 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 4.92/4.88 
                 NR 
                 4.93/5.22 
                 / 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 192 · 10 4  cp 
                 NR 
                 182 · 10 4  cp 
                 / 
               
               
                   
                   
                 40° C. 
                 187 · 10 4  cp 
                 NR 
                 167 · 10 4  cp 
                 / 
               
               
                   
               
             
          
         
       
     
       Formula 9 
       [0159]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.010 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC//CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 5NF 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 RONACARE ALLANTOIN 
                 ALLANTOIN 
                 0.200 
               
               
                 GLYCERINE 4810 VEGETABLE 
                 Glycerine 
                 20.00 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, AMPS 
                 2.5 
               
               
                   
                 COPOLYMER DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/polysorbate 80 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                 AT T0 
                 APPEARANCE 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                 Ø &lt; 7 μm 
               
               
                   
                 pH 
                 4.79 
               
               
                   
                 VISCOSITY 
                 Needle 6, Rate 5 187000 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
           
               
                 Stability monitoring 
                 1 MONTH 
                 2 MONTHS 
                 3 MONTHS 
                 6 MONTHS 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 4.76/4.87 
                 4.92/4.99 
                 4.83/5.08 
                 4.59/5.13 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 160000 cp 
                 175000 cp 
                 186000 cp 
                 132000 cP 
               
               
                   
                   
                 40° C. 
                 154000 cp 
                 146000 cp 
                 146000 cp 
                 137000 cP 
               
               
                   
               
             
          
         
       
     
       Formula 10 
       [0160]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.030 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC//CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 5NF 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 RONACARE 
                 ALLANTOIN 
                 0.200 
               
               
                 ALLANTOIN 
               
               
                 GLYCERINE 4810 VEGETABLE 
                 Glycerine 
                 20.00 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, AMPS 
                 2.5 
               
               
                   
                 COPOLYMER DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/polysorbate 80 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                 AT T0 
                 APPEARANCE 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                 Ø &lt; 7 μm 
               
               
                   
                 pH 
                 4.76 
               
               
                   
                 VISCOSITY 
                 Needle 6, Rate 2.5 381000 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
           
               
                 Stability monitoring 
                 1 MONTH 
                 2 MONTHS 
                 3 MONTHS 
                 6 MONTHS 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 4.74/4.97 
                 4.88/5.00 
                 4.85/5.16 
                 4.96/5.12 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 374000 cp 
                 364000 cp 
                 334000 cp 
                 298000 cP 
               
               
                   
                   
                 40° C. 
                 288000 cp 
                 266000 cp 
                 269000 cp 
                 260000 cP 
               
               
                   
               
             
          
         
       
     
       Formula 11 
       [0161]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.04 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC//CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE ALLANTOIN 
                 ALLANTOIN 
                 0.200 
               
               
                 GLYCERINE 4810 
                 Glycerine 
                 20.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, AMPS COPOLYMER 
                 2.5 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/polysorbate 80 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                   
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 AT T0 
                 APPEARANCE 
               
               
                   
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                   
                 Ø &lt; 5 μm 
               
               
                   
                   
                 pH 
                 4.76 
               
               
                   
                   
                 VISCOSITY 
                 Needle 6, Rate 2.5 340000 cp 
               
               
                   
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
                   
               
             
          
           
               
                 Stability monitoring 
                 1 MONTH 
                 2 MONTHS 
                 3 MONTHS 
                 6 MONTHS 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 4.77/4.90 
                 4.92/5.02 
                 5.20/5.15 
                 / 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 343000 cp 
                 330000 cp 
                 325000 cp 
                 / 
               
               
                   
                   
                 40° C. 
                 292000 cp 
                 263000 cp 
                 271000 cp 
                 / 
               
               
                   
               
             
          
         
       
     
       Formula 12 
       [0162]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.05 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC//CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE 
                 ALLANTOIN 
                 0.200 
               
               
                 ALLANTOIN 
               
               
                 GLYCERINE 4810 
                 Glycerine 
                 20.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, AMPS 
                 2.50 
               
               
                   
                 COPOLYMER DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/polysorbate 80 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                   
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 TO T0 
                 APPEARANCE 
               
               
                   
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                   
                 Ø &lt; 6 μm 
               
               
                   
                   
                 pH 
                 4.92 
               
               
                   
                   
                 VISCOSITY 
                 Needle 6, Rate 2.5 363000 cp 
               
               
                   
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
                   
               
             
          
           
               
                 Stability monitoring 
                 1 MONTH 
                 2 MONTHS 
                 3 MONTHS 
                 6 MONTHS 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 4.93/4.88 
                 4.79/4.93 
                 4.87/5.12 
                 / 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 334000 cp 
                 356000 cp 
                 346000 cp 
                 / 
               
               
                   
                   
                 40° C. 
                 298000 cp 
                 282000 cp 
                 275000 cp 
                 / 
               
               
                   
               
             
          
         
       
     
       Formula 13 
       [0163]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.01 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC//CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE ALLANTOIN 
                 ALLANTOIN 
                 0.200 
               
               
                 GLYCERINE 4810 
                 Glycerine 
                 20.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, AMPS COPOLYMER 
                 3.00 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/polysorbate 80 
               
               
                 BENZYL ALCOHOL 
                 BENZYL ALCOHOL 
                 0.40 
               
               
                 SORBATE DE 
                 POTASSIUM SORBATE 
                 0.10 
               
               
                 POTASSIUM 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                   
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 AT T0 
                 APPEARANCE 
               
               
                   
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                   
                 Ø &lt; 5 μm 
               
               
                   
                   
                 pH 
                 6.64 
               
               
                   
                   
                 VISCOSITY 
                 Needle 6, Rate 5 147000 cp 
               
               
                   
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
                   
               
             
          
           
               
                 Stability monitoring 
                 1 MONTH 
                 2 MONTHS 
                 3 MONTHS 
                 6 MONTHS 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 6.37/6.36 
                 6.60/6.22 
                 6.40/6.13 
                 / 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 160000 cp 
                 157000 cp 
                 121000 cp 
                 / 
               
               
                   
               
             
          
         
       
     
       Formula 14 
       [0164]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.01 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC//CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE ALLANTOIN 
                 ALLANTOIN 
                 0.200 
               
               
                 GLYCERINE 4810 
                 Glycerine 
                 20.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, AMPS COPOLYMER 
                 3.00 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/polysorbate 80 
               
               
                 SODIUM BENZOATE 
                 SODIUM BENZOATE 
                 0.20 
               
               
                 D-(+)-GLUCONO-DELTA- 
                 GLUCONOLACTONE 
                 0.25 
               
               
                 LACTONE 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION AT T0 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 APPEARANCE 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                 Ø &lt; 8 μm 
               
               
                   
                 pH 
                 5.44 
               
               
                   
                 VISCOSITY 
                 Needle 6, Rate 20 36450 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
           
               
                 Stability monitoring 
                 1 MONTH 
                 2 MONTHS 
                 3 MONTHS 
                 6 MONTHS 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/ 
                 4.59/4.58 
                 4.70/4.78 
                 NR 
                 NR 
               
               
                 stability 
                 40° C. 
               
               
                   
               
             
          
         
       
     
       Formula 15 
       [0165]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.01 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC//CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE 
                 ALLANTOIN 
                 0.200 
               
               
                 ALLANTOIN 
               
               
                 GLYCERINE 4810 
                 Glycerine 
                 20.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, 
                 3.00 
               
               
                   
                 AMPS COPOLYMER 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 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 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant 
               
               
                 AT T0 
                 APPEARANCE 
                 cream 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                 Ø &lt; 6 μm 
               
               
                   
                 pH 
                 6.34 
               
               
                   
                 VISCOSITY 
                 Needle 5, Rate 5 67920 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
         
       
     
       Formula 16 
       [0166]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.01 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC//CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE 
                 ALLANTOIN 
                 0.200 
               
               
                 ALLANTOIN 
               
               
                 GLYCERINE 4810 
                 Glycerine 
                 20.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, 
                 3.00 
               
               
                   
                 AMPS COPOLYMER 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 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 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant 
               
               
                 AT T0 
                 APPEARANCE 
                 cream 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                 Ø &lt; 10 μm 
               
               
                   
                 pH 
                 5.43 
               
               
                   
                 VISCOSITY 
                 Needle 5, Rate 5 59520 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
         
       
     
       Formula 17 
       [0167]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.01 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC//CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE ALLANTOIN 
                 ALLANTOIN 
                 0.200 
               
               
                 GLYCERINE 4810 
                 Glycerine 
                 20.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE,AMPS COPOLYMER 
                 2.5 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/polysorbate 80 
               
               
                 BENZALCONUM 
                 BENZALKONIUM CHLORIDE 
                 0.05 
               
               
                 CHLORIDE 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 5.00 
               
               
                 POTASSIUM SORBATE 
                 POTASSIUM SORBATE 
                 0.20 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION AT T0 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 APPEARANCE 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                 Ø &lt; 7 μm 
               
               
                   
                 pH 
                 6.82 
               
               
                   
                 VISCOSITY 
                 Needle 6, Rate 50 11520 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
           
               
                 STABILITY 
                   
                   
                   
                   
               
               
                 MONITORING 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 6.60/6.43 
                 6.80/6.34 
                 6.61/6.24 
                 6.54/6.23 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 11080 cp 
                 10200 cp 
                 11200 cp 
                 9680 cp 
               
               
                   
                   
                 40° C. 
                 11760 cp 
                 11400 cp 
                 10720 cp 
                 9520 cp 
               
               
                 Chemical 
                 Dose 
                 TA 
                 98.6 
                 100.3 
                 99.7 
                 99.2 
               
               
                 stability 
                 COMPOUND A 
                 40° C. 
                 97 
                 98.1 
                 97.4 
                 95.4 
               
               
                   
                 initial % 
               
               
                   
               
             
          
         
       
     
       Formula 18 
       [0168]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.04 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC//CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 Cyclopentasiloxane 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE ALLANTOIN 
                 ALLANTOIN 
                 0.20 
               
               
                 GLYCERINE 4810 
                 Glycerine 
                 20.00 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, AMPS COPOLYMER 
                 2.5 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/polysorbate 80 
               
               
                 BENZALCONIUM 
                 BENZALKONIUM CHLORIDE 
                 0.05 
               
               
                 CHLORIDE 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 5.00 
               
               
                 SORBATE 
                 POTASSIUM SORBATE 
                 0.20 
               
               
                 DE POTASSIUM 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION AT T0 
                 MACROSCOPIC 
                 White, smooth, brilliant cream 
               
               
                   
                 APPEARANCE 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                   
                 Ø &lt; 7 μm 
               
               
                   
                 pH 
                 6.80 
               
               
                   
                 VISCOSITY 
                 Needle 6, Rate 50 10920 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
           
               
                 STABILITY 
                   
                   
                   
                   
               
               
                 MONITORING 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH TA/40° C. 
                 6.63/6.37 
                 6.67/6.22 
                 6.62/6.25 
                 6.61/6.28 
               
             
          
           
               
                 stability 
                 Viscosity 
                 TA 
                 13340 cp 
                 10450 cp 
                 10540 cp 
                 10840 cp 
               
               
                   
                   
                 40° C. 
                 11040 cp 
                 NR 
                 10400 cp 
                  9240 cp 
               
               
                 Chemical 
                 Dose 
                 TA 
                 100.2 
                 98.3 
                 99.8 
                 99.4 
               
               
                 stability 
                 COMPOUND 
                 40° C. 
                 99.9 
                 97.5 
                 99.0 
                 96.8 
               
               
                   
                 A initial % 
               
               
                   
               
             
          
         
       
     
       Formula 19 
       [0169]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.01 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC/CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 CYCLOPENTASILOXANE 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE 
                 ALLANTOIN 
                 0.20 
               
               
                 ALLANTOIN 
               
               
                 GLYCERINE 4810 
                 GLYCERIN 
                 10.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, 
                 3.00 
               
               
                   
                 AMPS COPOLYMER 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/ 
               
               
                   
                 POLYSORBATE 80 
               
               
                 GLUCONO-DELTA- 
                 GLUCONOLACTONE 
                 0.25 
               
               
                 LACTONE SG 
               
               
                 PROBENZ SP 
                 SODIUM BENZOATE 
                 0.20 
               
               
                 PROPYLENE GLYCOL 
                 PROPYLENE GLYCOL 
                 10.00 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant 
               
               
                 AT T0 
                 APPEARANCE 
                 cream 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion. 
               
               
                   
                 pH 
                 6.80 
               
               
                   
                 VISCOSITY 
                 Needle 6, Rate 10 59200 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
         
       
     
       Formula 20 
       [0170]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.01 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC/CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 CYCLOPENTASILOXANE 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE 
                 ALLANTOIN 
                 0.20 
               
               
                 ALLANTOIN 
               
               
                 GLYCERINE 4810 
                 GLYCERIN 
                 13.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, 
                 3.00 
               
               
                   
                 AMPS COPOLYMER 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/ 
               
               
                   
                 POLYSORBATE 80 
               
               
                 GLUCONO-DELTA- 
                 GLUCONOLACTONE 
                 0.25 
               
               
                 LACTONE SG 
               
               
                 BENZYL ALCOHOL 
                 BENZYL ALCOHOL 
                 1.00 
               
               
                 PROBENZ SP 
                 SODIUM BENZOATE 
                 0.20 
               
               
                 PROPYLENE GLYCOL 
                 PROPYLENE GLYCOL 
                 7.00 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant 
               
               
                 AT T0 
                 APPEARANCE 
                 cream 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion 
               
               
                   
                 pH 
                 4.89 
               
               
                   
                 VISCOSITY 
                 Needle 29, Rate 20 
               
               
                   
                   
                 29650 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
         
       
     
       Formula 21 
       [0171]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.01 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC/CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 CYCLOPENTASILOXANE 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE 
                 ALLANTOIN 
                 0.20 
               
               
                 ALLANTOIN 
               
               
                 GLYCERINE 4810 
                 GLYCERIN 
                 15.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, 
                 3.00 
               
               
                   
                 AMPS COPOLYMER 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/ 
               
               
                   
                 POLYSORBATE 80 
               
               
                 GLUCONO-DELTA- 
                 GLUCONOLACTONE 
                 0.25 
               
               
                 LACTONE SG 
               
               
                 ALCOOL BENZYLIQUE 
                 BENZYL ALCOHOL 
                 1.00 
               
               
                 PROBENZ SP 
                 SODIUM BENZOATE 
                 0.20 
               
               
                 PROPYLENE GLYCOL 
                 PROPYLENE GLYCOL 
                 5.00 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant 
               
               
                 AT T0 
                 APPEARANCE 
                 cream 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion 
               
               
                   
                 pH 
                 4.82 
               
               
                   
                 VISCOSITY 
                 Needle 29, Rate 12 
               
               
                   
                   
                 48583 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
         
       
     
       Formula 22 
       [0172]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.01 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC/CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 CYCLOPENTASILOXANE 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE 
                 ALLANTOIN 
                 0.20 
               
               
                 ALLANTOIN 
               
               
                 TITRIPLEX III 
                 EDTA 
                 0.20 
               
               
                 GLYCERINE 4810 
                 GLYCERIN 
                 20.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, 
                 2.50 
               
               
                   
                 AMPS COPOLYMER 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/ 
               
               
                   
                 POLYSORBATE 80 
               
               
                 GLUCONO-DELTA- 
                 GLUCONOLACTONE 
                 0.25 
               
               
                 LACTONE SG 
               
               
                 ALCOOL BENZYLIQUE 
                 BENZYL ALCOHOL 
                 1.00 
               
               
                 PROBENZ SP 
                 SODIUM BENZOATE 
                 0.20 
               
               
                 PURIFIED WATER 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant 
               
               
                 AT T0 
                 APPEARANCE 
                 cream 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion 
               
               
                   
                 pH 
                 4.97 
               
               
                   
                 VISCOSITY 
                 Needle 29, Rate 20 
               
               
                   
                   
                 29500 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
         
       
     
       Formula 23 
       [0173]      
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 COMPOSITIONS 
                   
               
             
          
           
               
                 Commercial Name 
                 INCI name 
                 % 
               
               
                   
               
               
                 COMPOUND A 
                 COMPOUND A 
                 0.06 
               
               
                 PHENOXETOL 
                 PHENOXYETHANOL 
                 1.00 
               
               
                 MIGLYOL 812N 
                 CAPRYLIC/CAPRIC 
                 8.00 
               
               
                   
                 TRIGLYCERIDES 
               
               
                 ARLAMOL PS15E-LQ 
                 PPG-15 STEARYL ETHER 
                 15.00 
               
               
                 ST-CYCLOMETHICONE 
                 CYCLOPENTASILOXANE 
                 2.00 
               
               
                 5NF 
               
               
                 RONACARE 
                 ALLANTOIN 
                 0.20 
               
               
                   
                 ALLANTOIN 
               
               
                 GLYCERINE 4810 
                 GLYCERIN 
                 20.00 
               
               
                 VEGETABLE 
               
               
                 SIMULGEL 600 PHA 
                 ACRYLAMIDE, 
                 2.50 
               
               
                   
                 AMPS COPOLYMER 
               
               
                   
                 DISPERSION 40%/ 
               
               
                   
                 ISOHEXADECANE/ 
               
               
                   
                 POLYSORBATE 80 
               
               
                 CHLORURE DE 
                 BENZALKONIUM 
                 0.05 
               
               
                 BENZALKONIUM 
                 CHLORIDE 
               
               
                 SORBATE DE 
                 POTASSIUM SORBATE 
                 0.20 
               
               
                 POTASSIUM 
               
               
                 EAU PURIFIEE 
                 PURIFIED WATER 
                 QSP 100.00 
               
               
                   
               
             
          
           
               
                 CHARACTERISATION 
                 MACROSCOPIC 
                 White, smooth, brilliant 
               
               
                 TO T0 
                 APPEARANCE 
                 cream 
               
               
                   
                 MICROSCOPIC 
                 Absence of crystals. Fine, 
               
               
                   
                 APPEARANCE 
                 homogeneous emulsion 
               
               
                   
                 pH 
                 6.64 
               
               
                   
                 VISCOSITY 
                 Needle 5, Rate 10 32320 cp 
               
               
                   
                 CENTRIFUGING 
                 RAS 
               
               
                   
               
             
          
           
               
                 STABILITY 
                   
                   
                   
                   
               
               
                 MONITORING 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                   
               
             
          
           
               
                 Physical 
                 pH 
                 6.58/6.41 
                 6.44/6.23 
                 NR 
                 6.48/6.17 
               
               
                 stability 
                 TA/40° C. 
               
               
                   
                 Viscosity 
                 309000 cp 
                 251000 cp 
                 287000 cp 
                 300000 cp 
               
               
                   
                 TA 
               
               
                   
                 Needle 5 
               
               
                   
                 Rate 1 
               
               
                   
                 Viscosity 
                 320000 cp 
                 374000 cp 
                 324000 cp 
                 317000 cp 
               
               
                   
                 40° C. 
               
               
                   
                 Needle 5 
               
               
                   
                 Rate 1 
               
               
                   
               
             
          
         
       
     
       Example 3 
     Characterisation of the Formulations by Cutaneous Penetration Studies on Human Skin 
       [0174]    The cutaneous penetration studies enable the formulations to be characterised and the parameters peculiar to each of the formulations to be demonstrated. 
         [0175]    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′,1″]-terphenyl-4-carboxylic acid. 
         [0176]    The reference gel is described as follows: 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Constituents 
                 % 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 COMPOUND A 
                 0.01 
               
               
                   
                 Propylene Glycol 
                 30.00 
               
               
                   
                 Ethanol 95-96% 
                 67.99 
               
               
                   
                 Klucel HF Pharma 
                 2.00 
               
               
                   
                   
               
             
          
         
       
     
       “Single Time” Cutaneous Penetration Study: 
       [0177]    In this study the Formula is applied for 16 hours to the surface of the skin. After the application COMPOUND A is quantified in the different compartments of the skin: stratum corneum, epidermis, dermis and receiving liquid according to the validated bioanalysis method. 
         [0178]    The details of the cutaneous application are given in the table below. 
         [0000]    
       
         
               
             
               
               
             
               
             
               
               
             
               
             
               
               
             
               
             
               
               
               
               
               
             
               
               
               
             
           
               
                   
               
             
             
               
                 Skin: 3 donors, 2 samples per donor 
               
               
                   
               
             
          
           
               
                 Source 
                 Entire abdominal human skin 
               
               
                 Thickness 
                 0.79-1.22 mm 
               
               
                 Age 
                 39-64 years. 
               
               
                 Franz cells 
                 2 cm 2   
               
               
                 Volume of receiving liquid 
                 3 mL 
               
               
                 Barrier function 
                 Evaluated by determination of the 
               
               
                   
                 Insensitive Loss in Water, acceptable 
               
               
                   
                 except where contraindicated 
               
               
                   
               
             
          
           
               
                 Formulations 
               
               
                   
               
             
          
           
               
                 A: Reference gel containing 100 μg/g 
                 B: Oil in water emulsion with emulsifier, 
               
               
                 of COMPOUND A 
                 containing 100 μg/g of COMPOUND A 
               
               
                   
                 (Formula 3) 
               
               
                   
               
             
          
           
               
                 Application 
               
               
                   
               
             
          
           
               
                 Application 
                 ~2 mg/cm 2   
               
               
                 Quantity of active ingredient applied 
                 142~241 ng/cm 2   
               
               
                 Exposure time 
                 16 h 
               
               
                   
               
             
          
           
               
                 Samples taken 
               
               
                   
               
             
          
           
               
                 Donor compartment lavage 
                   
                   
                   
                   
               
               
                 Kleenex (enabling the 
               
               
                 surplus product 
                 {close oversize brace}   
                 “Excess”/Unabsorbed dose 
                 {close oversize brace}   
                 Mass balance 
               
               
                 to be removed) 
               
               
                 1 st  strip 
               
               
                 Stratum corneum (2-15 strips max) 
               
               
                 Epidermis 
                 {close oversize brace}   
                 Total skin 
                 {close oversize brace}   
                 Total penetration 
               
               
                 Dermis 
               
             
          
           
               
                 Receiving Liquid 
                 } 
                 Absorbed dose 
               
               
                   
               
             
          
         
       
     
         [0179]    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. 
         [0180]    The conditions of LC/MS/MS developed enabled up to 0.1% of the doe applied in each of the compartments to be detected (unabsorbed dose, stratum, epidermis, dermis and receiving liquid). 
         [0181]    The technical conditions are given in the table below. 
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 LC column 
                 Hypersil gold 50 * 2.1 mm (UPLC) 
               
               
                 Mobile phase 
                 Phase A: ACN + 0.1% Formic Acid 
               
               
                   
                 Phase B: H 2 O + 0.1% Formic acid 
               
               
                 Lavage 
                 CAN 
               
               
                 Needle 
               
               
                 Lavage 
                 ACN/H 2 O 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 &gt; 318.20 
                 0.100 
                 50.0 
                 40.0 
                 1.58 
                 COMPOUND A 
               
               
                   
                 1: 464.06 &gt; 372.10 
                 0.100 
                 55.0 
                 40.0 
                 1.58 
                 Deuterated 
               
               
                   
                   
                   
                   
                   
                   
                 Internal Standard 
               
               
                   
               
               
                 Volume 
                 5 μL 
               
               
                 Injection 
               
               
                 Run time 
                 4 minutes 
               
               
                   
               
             
          
         
       
     
         [0182]    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)       
 
       FIG. 1 
       [0185]    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 precipitation in the epidermis, and very low penetration in the dermis. Compound A is not detected in the receiving liquid. 
         [0186]    Penetration values in the epidermis+dermis compartment:
       The penetration values for the oil in water type emulsion without emulsifier, containing 100 μg/g (0.01%) of compound A are between 6.8 ng/cm 2  and 10.6 ng/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.       
 
       Penetration Kinetics Study: 
       [0188]    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. 
         [0189]    The details of the cutaneous application are given in the table below: 
         [0000]    
       
         
               
               
             
               
               
               
               
               
             
               
               
             
           
               
                   
               
             
             
               
                 Skin 
                 3 donors, 2 samples per donor per time, n = 6 
               
               
                   
               
               
                 Source 
                 Abdominal human skin dermatomed from corpse 
               
               
                 Thickness 
                 500 μm 
               
               
                 Age 
                 Not Indicated 
               
               
                 Franz cells 
                 1-2 cm 2   
               
               
                 Volume of Receiving Liquid 
                 Not Indicated 
               
               
                 Barrier Function 
                 Evaluated by tritiated water 
               
               
                   
               
               
                 Products 
               
               
                   
               
               
                 Reference gel 100 μg/g 
                 Oil in water type emulsion without emulsifier 
               
               
                   
                 100 μg/g (Formula 1) 
               
               
                 Formula Application 
                 ~2 mg/cm 2   
               
               
                 Quantity of active ingredient 
                 Between 100-200 ng/cm 2   
               
               
                 applied 
               
               
                 Exposure time 
                 Up to 24 h 
               
               
                   
               
               
                 Samples taken 
               
               
                   
               
               
                 Exposure time 
                 0.5, 1, 3, 6, 24 h 
               
             
          
           
               
                 Lavage of donor compartment 
                   
                   
                   
                   
               
               
                 Kleenex (enabling the surplus 
                 {close oversize brace}   
                 “Excess”/Unabsorbed dose 
               
               
                 product to be removed) 1 st  strip 
               
               
                 Stratum corneum (2-15 strips max) 
                   
                   
                   
                  Mass balance 
               
               
                 Epidermis 
                 {close oversize brace}   
                 Total Skin 
                 {close oversize brace}   
               
               
                 Dermis 
               
             
          
           
               
                 Analyses 
                 LC/UV and LC/MS 
               
               
                 Limit of quantification 
                 1 ng/ml 
               
               
                   
               
             
          
         
       
     
         [0190]    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. 
         [0191]    In this type of study the parameters considered are:
       c. The penetration kinetics profile in the epidermis (qualitative data)   d. The initial rate of penetration in the epidermis   e. The maximum quantity that has penetrated the epidermis
 
a. Penetration kinetics profile in the epidermis:
       
 
       FIG. 2 
       [0195]    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. 
         [0196]    As seen in Section 1 (“Single time” cutaneous penetration study), these two formulae have different penetration levels at 16 h, 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. 
         [0197]    Initial rate of the kinetics:
       The initial value of the rate of the kinetics or gradient in the first 3 hours is 4.2 ng/cm 2 /h.       
 
         [0199]    Maximum quantity in the epidermis:
       The maximum quantity in the epidermis is 18.7 ng/cm 2 .       
 
       Example 4 
     Tolerance Study 
       [0201]    In this study:
       10 subjects received 2 grams of gel (reference gel) applied to 1000 cm 2  for 4 weeks.       
 
         [0203]    A reference gel is understood to mean a gel described as follows: 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 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. 
           
         
       
     
         [0205]    During the study the investigators had the opportunity of changing the area of application where irritation was excessive. 
         [0206]    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. 
         [0207]    Development of the percentage of subjects for whom there is no change of area of application 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Gel 
                   
                 Gel 
                   
                   
               
               
                   
                 50 μg/g 
                 Cream B 
                 50 μg/g 
                 Gel 
                 Gel 
               
               
                   
                 1000 
                 50 μg/g 
                 2000 
                 100 μg/g 
                 25 μg/g 
               
               
                   
                 cm 2   
                 1000 cm 2   
                 cm 2   
                 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 
                 N (%) 
                 — 
                 1 (10) 
                 — 
                 — 
                 1 (10) 
               
               
                 change 
               
               
                 in the 
               
               
                 course 
               
               
                 of the 
               
               
                 study 
               
               
                   
               
             
          
         
       
     
       FIG. 3 
       [0208]    FIG. 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. 
         [0209]    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. 
         [0210]    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.