Abstract:
A composition in the form of a gel, preferably hydroglycolic, is described. The composition can include in a physiologically acceptable medium, at least one particular retinoid. Also described, is a method for the preparation thereof and the cosmetic and dermatological use of the same.

Description:
CROSS-REFERENCE TO PRIOR APPLICATIONS 
     This application is a National Stage of PCT/EP2013/061200, filed May 30, 2013, and designating the United States (published Dec. 5, 2013, as WO 2013/178759 A1), which claims priority under 35 U.S.C. §119 to U.S. Provisional Application No. 61/654,702, filed Jun. 1, 2012, and French Patent Application No. 1255092, filed Jun. 1, 2012, each hereby expressly incorporated by reference in its entirety and each assigned to the assignee hereof. 
    
    
     The invention relates to a composition of aqueous gel type, preferably aqueous-glycolic gel type, and which comprises, in a physiologically acceptable medium, at least one retinoid of general formula (I) 
                                
wherein
         R 1  is a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms or a —CF 3  radical;   R 2  is a hydrogen atom, an alkyl or alkoxy radical having from 1 to 4 carbon atoms or a chlorine atom;   R 3  is a hydrogen atom, or a linear or branched alkyl or alkoxy radical having from 1 to 10 carbon atoms, optionally substituted with a methoxy group;   R 4  is a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms;   R 5  is a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms;   or else R 4  and R 5  form, together with the —N—C(═Y)— bond, a ring of pyrrolidine, pyrrolidinone, piperidine or piperidinone type;   Y represents two hydrogen atoms or a heteroatom such as oxygen or sulfur;   Ar represents a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring;   X represents an oxygen atom optionally substituted with an alkyl or alkylamine chain or a C—C single bond;   A represents a hydrogen atom or the formula below:       

     
       
                 
         
             
             
         
      
         
         
           
              wherein
           Q is an oxygen atom or the —NH— bond;   R 6  represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, a cycloalkyl radical having from 3 to 6 carbon atoms, or a —C(O)CH 2  or —C(O)CH 2 CH 3  radical;   R 7  and R 7 ′ represent, independently of one another, a hydrogen atom or a hydroxyl group, on the condition that R 7  and R 7 ′ are not simultaneously a hydroxyl group;   
         
             n is 0, 1, 2, 3, 4 or 5. 
           
         
       
    
     These compounds, described in patent EP 1 831 149, are powerful retinoids which modulate the nuclear retinoic acid receptor (RAR), more specifically the gamma subtype of this receptor (RARγ). 
     RAR receptors activate transcription by binding to DNA sequence elements, called RAR response elements (RAREs), in the form of a heterodimer with retinoid X receptors (called RXRs). 
     Three subtypes of human RARs have been identified and described: RARα, RARβ et RARγ. 
     Since RAR-gamma receptors are located in the epidermis, it is important for the release of the compounds described by general formula (I) to take place in this part of the skin in order to have a clinical efficacy. 
     However, the topical application of retinoids can cause skin irritation, dryness and erythema. Many articles describe this irritant 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. 
     Many techniques are used to obtain topical preparations for pharmaceutical use containing retinoids, in particular emulsions, for instance patent EP-826366 which describes emulsions that can contain retinoids, or else patent EP-989846 which describes emulsions containing retinoids and at least one emulsifier. 
     However, emulsifiers belong to the chemical family of amphiphilic molecules which are often irritant. Emulsifier-free compositions are as a result less irritant than compositions containing emulsifier. 
     Not using emulsifier in compositions containing retinoids would therefore make it possible to limit the skin irritation caused by the presence of molecules of this class. 
     The prior art describes O/W emulsions with or without emulsifier. Mention may in particular be made of U.S. Pat. No. 5,851,538 which describes formulations with or without emulsifier with porous microspheres containing a virtually continuous network of pores open to the exterior and comprising retinoids. 
     There is consequently a need to have stable and well-tolerated pharmaceutical compositions containing compounds described by general formula (I). 
     The development of pharmaceutical forms of aqueous-glycolic gel type which generally do not contain emulsifier will therefore provide an advantage in terms of skin tolerance. 
     According to the FDA, a gel is a semi-solid pharmaceutical form which contains a gelling agent conferring consistency on a colloidal dispersion or solution. An aqueous-glycolic gel is therefore a gel according to this definition, the gelled phase of which contains water and one or more glycols. 
     A first subject according to the invention relates to a pharmaceutical composition comprising at least one compound of general formula (I) 
                                
wherein
         R 1  is a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms or a —CF 3  radical;   R 2  is a hydrogen atom, an alkyl or alkoxy radical having from 1 to 4 carbon atoms or a chlorine atom;   R 3  is a hydrogen atom, or a linear or branched alkyl or alkoxy radical having from 1 to 10 carbon atoms, optionally substituted with a methoxy group;   R 4  is a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms;   R 5  is a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms;   or else R 4  and R 5  form, together with the —N—C(═Y)— bond, a ring of pyrrolidine, pyrrolidinone, piperidine or piperidinone type;   Y represents two hydrogen atoms or a heteroatom such as oxygen or sulfur;   Ar represents a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring;   X represents an oxygen atom optionally substituted with an alkyl or alkylamine chain or a C—C single bond;   A represents a hydrogen atom or the formula below:       

     
       
                 
         
             
             
         
      
         
         
           
              wherein
           Q is an oxygen atom or the —NH— bond;   R 6  represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, a cycloalkyl radical having from 3 to 6 carbon atoms, or a —C(O)CH 2  or —C(O)CH 2 CH 3  radical;   R 7  and R 7 ′ represent, independently of one another, a hydrogen atom or a hydroxyl group, on the condition that R 7  and R 7 ′ are not simultaneously a hydroxyl group;   
         
             n is 0, 1, 2, 3, 4 or 5;
 
water, at least one gelling agent, at least one hydrophilic solvent of the compound of formula (I) and at least one hydrophilic cosolvent of the compound of formula (I).
 
           
         
       
    
     Preferentially, the composition is an aqueous-glycolic gel characterized in that the active agent of general formula (I) is solubilized. 
     A second subject according to the invention relates to a pharmaceutical composition as described above, for use as a medicament. 
     A third subject according to the invention relates to a pharmaceutical composition as described above, for use in the treatment of pathological conditions such as: 
     1) dermatological conditions associated with a keratinization disorder relating to cell differentiation and proliferation, in particular for treating common acne, comedonal acne, polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne, secondary acne such as solar acne, acne medicamentosa or occupational acne;
 
2) keratinization disorders, in particular ichthyosis, ichthyosiform conditions, lamellar ichthyosis, Darier&#39;s disease, palmoplantar keratoderma, leukoplakia, pityriasis rubra pilaris and leukoplakiform conditions, cutaneous or mucosal (buccal) lichen;
 
3) dermatological conditions with an inflammatory immunoallergic component, with or without a cell proliferation disorder, and in particular all forms of psoriasis, whether cutaneous, mucosal or ungual, and even psoriatic arthritis, or else atopic dermatitis and the various forms of eczema;
 
4) skin disorders caused by exposure to UV radiation, and also for repairing or combating skin aging, whether it is photo-induced or chronological, or for reducing actinic keratoses and pigmentations, or any pathological conditions associated with chronological or actinic aging, such as xerosis, pigmentations and wrinkles;
 
5) any condition associated with benign dermal or epidermal proliferations, whether or not they are of viral origin, such as common warts, flat warts, molluscum contagiosum and epidermodysplasia verruciformis, or oral or florid papillomatoses;
 
6) dermatological disorders such as immune dermatoses, for instance lupus erythematosus, bullous immune diseases and collagen diseases, such as scleroderma;
 
7) stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy;
 
8) healing disorders, or for preventing or repairing stretch marks, or else for promoting healing;
 
9) in the treatment of any condition of fungal origin at the cutaneous level, such as tinea pedis and tinea versicolor;
 
10) pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation or vitiligo;
 
11) cutaneous or mucosal cancerous or precancerous conditions, such as actinic keratoses, Bowen&#39;s disease, in-situ carcinomas, keratoacanthomas and skin cancers such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous lymphomas such as T lymphoma.
 
     A fourth subject according to the invention relates to a method for preparing a pharmaceutical composition as previously described and comprising the following steps:
         a) Solubilization of the hydrophilic additives in water with stirring.   b) Solubilization, with stirring, of the retinoid of general formula (I) in the preferred solvent.   c) Addition of ethanol and propylene glycol.   d) Gelling of the aqueous phase by adding the gelling agent.   e) Addition of the active phase (b) to (d).       

     A fifth subject according to the invention relates to compositions of aqueous-glycolic gel type comprising a compound of general formula (I) 
                                
and at least one polyacrylamide gelling agent, characterized in that the maximum amount of active ingredient absorbed in the dermis and the epidermis 16 hours after application is between 5 ng/cm 2  and 15 ng/cm 2 .
 
     A sixth subject according to the invention relates to compositions of aqueous-glycolic gel type comprising a compound of general formula (I) 
                                
and at least one polyacrylamide gelling agent, characterized in that the maximum amount of active ingredient absorbed in the epidermis is obtained between 1 and 6 hours after application.
 
    
    
     
       The invention will be described in greater detail in the description and the examples which follow, and also in the appended figures in which: 
         FIGS. 1 and 2  show the results of a study of the kinetics of penetration into the epidermis of a composition according to the invention and of a reference gel. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     For the purposes of ease of reading, general formula (I) and compound A will be considered, in the rest of the text, as being described as follows: 
     General Formula (I): 
                                
wherein
         R 1  is a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms or a —CF 3  radical;   R 2  is a hydrogen atom, an alkyl or alkoxy radical having from 1 to 4 carbon atoms or a chlorine atom;   R 3  is a hydrogen atom, or a linear or branched alkyl or alkoxy radical having from 1 to 10 carbon atoms, optionally substituted with a methoxy group;   R 4  is a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms;   R 5  is a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms;   or else R 4  and R 5  form, together with the —N—C(═Y)— bond, a ring of pyrrolidine, pyrrolidinone, piperidine or piperidinone type;   Y represents two hydrogen atoms or a heteroatom such as oxygen or sulfur;   Ar represents a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring;   X represents an oxygen atom optionally substituted with an alkyl or alkylamine chain or a C—C single bond;   A represents a hydrogen atom or the formula below:       

     
       
                 
         
             
             
         
      
         
         
           
              wherein
           Q is an oxygen atom or the —NH— bond;   R 6  represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, a cycloalkyl radical having from 3 to 6 carbon atoms, or a —C(O)CH 2  or —C(O)CH 2 CH 3  radical;   R 7  and R 7 ′ represent, independently of one another, a hydrogen atom or a hydroxyl group, on the condition that R 7  and R 7 ′ are not simultaneously a hydroxyl group;   
         
             n is 0, 1, 2, 3, 4 or 5. 
           
         
       
    
     Compound A: as being 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic acid. 
     In the light of the physicochemical characteristics of the active agent, the applicant has had to face a certain number of constraints regarding the use of the compounds described by general formula (I). These compounds:
         are insoluble in water,   are particularly soluble in two solvents determined from the pre-formulation studies as described in example 1,   are stable in only two cosolvents of compound A, determined from the pre-formulation studies as described in example 1.       

     In addition, the maximum concentrations of the main solvents in the pharmaceutical compositions are preferably limited in order to optimize tolerance. Thus, the composition according to the invention preferably contains a maximum amount of 1% by weight of phenoxyethanol. It also preferably contains a maximum amount of 30% percent by weight of ethanol. 
     A first subject according to the present invention relates to pharmaceutical compositions containing at least one active agent which is a compound of general formula (I), these compositions being in the form of an aqueous gel, preferably an aqueous-glycolic gel, and the active agent being solubilized in said compositions. 
     Such gels exhibit good physical and chemical stability, a rapid penetration speed and a high level of penetration into the epidermis. 
     According to the FDA, a gel is a semi-solid pharmaceutical form which contains a gelling agent conferring consistency on a colloidal dispersion or solution. An aqueous-glycolic gel is therefore a gel according to this definition, the gelled phase of which contains water and one or more glycols. 
     In the invention, the compositions contain the active agent described by general formula (I) at concentrations preferably ranging from 0.00001% to 1% by weight, more preferentially from 0.0001% to 0.1% by weight and more preferentially from 0.001% to 0.1% by weight, relative to the total weight of the composition. 
     Preferentially, the active agent described by general formula (I) is compound A. 
     In the invention, the compositions contain at least one hydrophilic solvent of compound A. 
     The term “solvent” is intended to mean a liquid which has the property of dissolving, diluting or extracting substances without causing chemical modification of these substances and without itself being modified. 
     According to the invention, the hydrophilic solvent is such a liquid, in which the compounds of general formula (I) (and more particularly compound A) have a solubility, at ambient temperature and atmospheric pressure, greater than or equal to 0.1% by weight. 
     In the light of the pre-formulation results (example 1), the hydrophilic solvent can be advantageously selected from the list comprising methylpyrrolidone, ethoxydiglycol, benzyl alcohol, polyethylene glycol 400, phenoxyethanol and ethanol. 
     The solvent preferentially comprises the phenoxyethanol sold, for example, under the name phenoxetol by Clariant, and which can be used in a content ranging from 0.2% to 5% by weight and more preferentially from 0.5% to 2% by weight, relative to the total weight of the composition. The solvent can also comprise ethanol which can be used from 5% to 50% by weight and preferentially from 15% to 30% by weight, relative to the total weight of the composition. 
     In the invention, the compositions contain at least one cosolvent. 
     The term “cosolvent” is intended to mean a substance which acts as a solvent in combination with another substance. 
     In the light of the pre-formulation results (example 1), the cosolvent can be chosen from glycols, such as monopropylene glycol and dipropylene glycol, and can be used in the contents ranging from 2% to 50% by weight and preferentially from 10% to 40% by weight, relative to the total weight of the composition. 
     In the invention, the compositions contain at least one gelling agent. 
     The term “gelling agent” is intended to mean a polymer compound capable of conferring on the composition the texture of a gel. 
     The gelling agent(s) can in particular be chosen from polymers of vegetable origin, gums, pectins, cellulose and its derivatives, polymers of microbiological origin, such as xanthan gum, and gelling polymers of synthetic origin. 
     By way of nonlimiting example of gelling agents which can be part of the compositions, mention may be made of the acrylates/C10-30 alkyl acrylate crosspolymer sold under the name Pemulen TR-1 or Pemulen TR-2 by the company Lubrizol, gelling agents of the polyacrylamide family, such as the sodium acrylamide/acryloyldimethyl taurate copolymer/isohexadecane/polysorbate 80 mixture sold under the name Simulgel 600PHA by the company SEPPIC, and the polyacrylamide/isoparaffin C13-14/laureth-7 mixture sold under the name Sepigel 305 by the company SEPPIC, the carbomers sold under the name Ultrez 20®, Ultrez 10®, Carbopol 1382® or Carbopol ETD202ONF®, Carbopol 981 or else Carbopol 980 by the company Lubrizol, polysaccharides with, by way of nonlimiting examples, xanthan gum, such as Xantural180® sold by the company Kelco, the gellan gum sold under the name Kelcogel by the company Kelco, guar gum, cellulose and its derivatives, such as the microcrystalline cellulose and sodium carboxymethylcellulose sold under the name Avicel CL-611 by the company FMC Biopolymer, hydroxypropylmethylcellulose, in particular the product sold under the name Methocel E4M premium by the company Dow Chemical, or hydroxyethylcellulose, in particular the product sold under the name Natrosol HHX 250® by the company Ashland, sodium carboxymethylcellulose, in particular Blanose cellulose gum 7F sold by the company Ashland, the family of aluminum magnesium silicates, such as Veegum K sold by the company Vanderbilt, the family of acrylic polymers coupled to hydrophobic chains, such as the PEG-150/decyl/SMDI copolymer sold under the name Aculyn 44 (polycondensate comprising at least as elements a polyethylene glycol comprising 150 or 180 mol of ethylene oxide, decyl alcohol and methylenebis(4-cyclohexylisocyanate) (SMDI), at 35% by weight in a mixture of propylene glycol (39%) and water (26%)), the family of modified starches, such as the modified potato starch sold under the name Structure Solanace, or else mixtures thereof, the family of carrageenans, in particular divided up into four major families: κ, λ, β, ω, such as the Viscarin® products and the Gelcarin® products sold by the company IMCD. 
     Preferentially, a gelling agent of polyacrylamide type such as Simulgel 600 PHA® is used, at concentrations ranging from 0.005% to 5% by weight and preferentially ranging from 1% to 4% by weight, alone or combined with at least one of the gelling agents mentioned above at concentrations ranging from 0.005% to 3% by weight. 
     In the invention, the compositions can contain additives among which mention may be made of the following categories (used alone or in combination):
         Preserving agents, such as methyl paraben, propyl paraben, benzalkonium chloride, phenoxyethanol sold under the name phenoxetol by Clariant, benzyl alcohol sold under the name benzyl alcohol by Merck, potassium sorbate sold under the name 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 Bronopol by Jan Dekker International, chlorhexidine sold under the name Chlorhexidine digluconate 20% solution by Arnaud Pharmacie, chlorocresol and its derivatives, sodium benzoate sold under the name Probenz SP by Unipex, ethyl alcohol and diazolidinylurea. These preservatives can be used alone or in combination in order to efficiently protect the formulae against any bacterial contamination.   Agents for improving the properties of the formulae on application, such as cyclomethicone (St-Cyclomethicone 5NF) or dimethicone (Q7 9120 silicon fluid having a viscosity of 20 cst to 12500 cst from Dow Corning).   Chelating agents such as EDTA (ethylenediaminetetraacetic acid) and its derivatives or salts, dihydroglycerol, citric and tartaric acids, the gluconolactone sold under the name glucono-delta-lactone SG by Jungbunzlauer, or mixtures thereof.   Antioxidants such as vitamin E and its derivatives, for instance DL-alpha-tocopherol or tocopheryl acetate from Roche, vitamin C and its derivatives, for instance ascorbyl palmitate from Roche, the butylhydroxytoluene sold under the name Nipanox BHT by Clariant.   Soothing agents and/or anti-irritants, such as the PPG-12/SMDI copolymer sold by the company Bertek Pharmaceuticals under the trade name Polyolprepolymer-2, glycyrrhetinic acid or its derivatives, for instance Enoxolone sold by the company BASF, hyaluronic acid as it is or in its sodium hyaluronate form sold under the trade name Hyal. Na PWD PH 15-41-45 by the company Contipro, the allantoin sold under the name Ronacare Allantoine by Merck.   Any other additives normally used in the pharmaceutical and cosmetics field which make it possible to confer specific properties on said preparation.       

     The composition according to the invention advantageously has the following general composition, the percentages being expressed by weight relative to the total weight of the composition:
         from 0.00001% to 1% by weight, preferentially from 0.0001% to 0.1% by weight, more preferably from 0.001% to 0.1% by weight, of compound A,   water,   from 0.005% to 10% by weight and preferentially from 1% to 4% by weight of gelling agent,   from 0.2% to 50% by weight and preferentially from 0.5% to 30% by weight of hydrophilic solvent,   from 2% to 50% by weight and preferentially from 10% to 40% by weight of cosolvent,   optionally, from 0 to 15% by weight and preferentially from 0.1% to 10% by weight of one or more additives.       

     Another subject according to the invention relates to a method for preparing a pharmaceutical composition as previously described and comprising the following steps: 
     A) Preparation of the aqueous phase: solubilize the hydrophilic additives in water with stirring. 
     B) Preparation of the active phase: 
     Solubilize, with stirring, compound A in the hydrophilic solvent (for example, phenoxyethanol), if necessary under hot conditions. 
     At ambient temperature, add the cosolvent(s) (for example, ethanol and propylene glycol). 
     C) Mixing of the two phases: 
     Gel the aqueous phase by adding the thickener (for example, Simulgel 600PHa) with stirring, then add the active phase. 
     Once this mixture is homogeneous, add the cyclomethicone-5 (if present in the formula) with stirring. 
     EXAMPLES 
     Example 1 
     Pre-Formulation 
     In order to produce an aqueous-glycolic gel containing an amount of ethanol of less than 30%, in which compound A is solubilized, pre-formulation studies were carried out in order to reveal the excipients enabling good solubilization and also good stability of the active agent.
         (1) List of the hydrophilic excipients or mixture of hydrophilic excipients in which maximum solubility was determined by HPLC:       

     
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 Trade name 
                 INCI name 
                 Maximum solubility as % 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Pharmasolve 
                 Methyl Pyrolidone 
                 4.84 
               
               
                 Transcutol 
                 Ethoxy diglycol 
                 4.17 
               
               
                 Benzyl Alcohol 
                 Benzoyl Alcohol 
                 2.3880 
               
               
                 PEG 400 
                 Peg-8 
                 1.52 
               
               
                 Phenoxetol 
                 Phenoxyethanol 
                 1.957 
               
               
                 Ethanol 95-96% 
                 Ethanol 
                 0.92 
               
               
                 Hydrolite 5P 
                 Pentylene glycol 
                 0.482 
               
               
                 Arlasolve DMI 
                 Dimethyl Isosorbide 
                 0.4 
               
               
                 Hexylene Glycol 
                 Hexylene Glycol 
                 0.4 
               
               
                 Dipropylene Glycol 
                 Dipropylene Glycol 
                 0.4 
               
               
                 Care 
               
               
                 Propylene Glycol 
                 Propylene Glycol 
                 0.111 
               
               
                 Glycerine 
                 Glycerin 
                 0.002 
               
               
                   
               
             
          
         
       
     
     This study shows that 6 solvents can be considered to be “principal solvents” of compound A (Pharmasolve, Transcutol, benzyl alcohol, PEG 400, Phenoxetol and ethanol), it being possible for the others to be used as “cosolvents”, apart from the glycerine, in which compound A is virtually insoluble.
         (2) Stability of compound A in its principal solvents, determined by HPLC       

     
       
         
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 Excipients 
                 Compound A 
                   
               
             
          
           
               
                 Trade name 
                 INCI name 
                 % 
                 Stability results 
               
               
                   
               
               
                 Pharmasolve 
                 Methyl Pyrolidone 
                 0.03% 
                 Unstable 
               
               
                 Transcutol 
                 Ethoxy diglycol 
                 0.03% 
                 Unstable 
               
               
                 Benzyl Alcohol 
                 Benzoyl Alcohol 
                 0.01% 
                 Unstable 
               
               
                 PEG 400 
                 Poly Ethylene 
                  0.3% 
                 Unstable 
               
               
                   
                 Glycol 
               
               
                 Phenoxetol 
                 Phenoxyethanol 
                 0.05% 
                 Stable 
               
               
                 Ethanol 95-96% 
                 Ethanol 
                 0.005%  
                 Stable 
               
               
                   
               
             
          
         
       
     
     These stability studies show that, among the “principal solvents” identified, compound A is stable only in phenoxyethanol and ethanol.
         (3) Stability of compound A in its cosolvents, determined by HPLC       

     
       
         
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 Excipients 
                 COMPOUND A 
                 Stability 
               
             
          
           
               
                 Trade name 
                 INCI name 
                 % 
                 results 
               
               
                   
               
               
                 Hydrolite 5P 
                 Pentylene glycol 
                 0.03% 
                 Unstable 
               
               
                 Arlasolve DMI 
                 Dimethyl Isosorbide 
                 0.03% 
                 Unstable 
               
               
                 Hexylene Glycol 
                 Hexylene Glycol 
                 0.001%  
                 Unstable 
               
               
                 Dipropylene Glycol 
                 Dipropylene Glycol 
                  0.3% 
                 Stable 
               
               
                 Care 
               
               
                 Propylene Glycol 
                 Propylene Glycol 
                 0.05% 
                 Stable 
               
               
                   
               
             
          
         
       
     
     These stability studies show that, among the “cosolvents” identified, compound A is stable only in dipropylene glycol and propylene glycol. 
     Example 2 
     Formulations 
     In the following examples, the formulae produced are characterized at T 0 . The physical and chemical stability of the formulations is determined after storage at ambient temperature (AT) and +40° C. after T+1 Month and/or T+2 Months or T+3 Months or T+6 Months. The material and the methods used for these characterizations are described below. 
     Chemical Assaying of Compound A:
         Material: HPLC   Expression of the results: the titer of the active agent is expressed as relative % with respect to the initial % performed at T 0 . The limits set for good stability are 95%-105%.       

     Macroscopic Observation:
         The macroscopic observation makes it possible to guarantee the physical integrity of the products at T 0  and afterwards stability.       

     Microscopic Observation:
         The microscopic observation makes it possible to evaluate the good solubilization of COMPOUND A as early as T 0 , the non-recrystallization over time and also the size of the globules of the oily phase.   Material: Zeiss Axio microscope       

     pH:
         Material: Mettler Toledo SevenMulti pH meter   Method: Measurements carried out at ambient temperature after stabilization of all the samples for 24 h in a chamber at 25° C.       

     Viscosity:
         The viscosity measurement makes it possible to evaluate the consistency of the formulae produced.   Material: Brookfield RV DVII+Pro   Method: Measurements carried out at ambient temperature after stabilization of all the samples for 24 h in a chamber at 25° C. The value is read after 1 minute. The choice of the spindle and of the speed will be described in each composition example. The values obtained are expressed in centipoises (Cps).       

     Centrifugation:
         The centrifugation makes it possible to evaluate the resistance of the formulae to a mechanical stress.   Material: Galaxy 14D VWR   Method: 30 minutes at 5000 rpm   A result which complies signifies that there is neither phase separation nor exudate.       

     Formula No. 1 
     
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 TRADE NAME 
                 INCI NAME 
                 % 
               
               
                   
               
               
                   
                 COMPOUND A 
                 COMPOUND A 
                 0.010 
               
               
                   
                 PROPYLENE GLYCOL 
                 Propylene glycol 
                 38.000 
               
               
                   
                 ETHANOL 95-96% 
                 Ethanol 
                 30.000 
               
               
                   
                 RONACARE ALLANTOIN 
                 Allantoin 
                 0.200 
               
               
                   
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS Copolymer Dispersion 
                 4.000 
               
               
                   
                   
                 40%/Isohexadecane/polysorbate 80 
                   
               
               
                   
                 ST-CYCLOMETHICONE 5NF 
                 Cyclopentasiloxane 
                 2.000 
               
               
                   
                 PHENOXETOL 
                 Phenoxyethanol 
                 1.000 
               
               
                   
                 PURIFIED WATER 
                 Purified water 
                 QS 100.000 
               
               
                   
               
             
          
           
               
                   
                 CHARACTERIZATION 
                 MACROSCOPIC APPEARANCE 
                 Shiny, smooth, white gel 
               
               
                   
                 AT T0 
                 MICROSCOPIC APPEARANCE 
                 Absence of crystals. 
               
               
                   
                   
                 pH 
                 Not able to be done 
               
               
                   
                   
                 VISCOSITY 
                 Not done 
               
               
                   
                   
                 CENTRIFUGATION 
                 Complies 
               
               
                   
               
             
          
           
               
                 MONITORING OF 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                 STABILITY 
                   
                   
                   
                   
               
               
                 Microscopic appearance 
                 Complies, no 
                 Complies, no 
                 Complies, no 
                 Complies, no 
               
               
                   
                 recrystallization 
                 recrystallization 
                 recrystallization 
                 recrystallization 
               
               
                 Macroscopic appearance 
                 Complies 
                 Complies 
                 Complies 
                 Complies 
               
               
                   
               
             
          
           
               
                   
                 Chemical 
                 Assay 
                 AT 
                 98.40 
                 98.70 
                 97.50 
                 101.210 
               
               
                   
                 stability 
                 Compound A 
                 40° C. 
                 98.30 
                 98.60 
                 96.40 
                 100.50 
               
               
                   
                   
                 initial % 
               
               
                   
               
             
          
         
       
     
     These results show good physical and chemical stability of the active agent and of the composition as a whole over time. 
     Formula No. 2 
     
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 TRADE NAME 
                 INCI NAME 
                 % 
               
               
                   
               
               
                   
                 COMPOUND A 
                 COMPOUND A 
                 0.010 
               
               
                   
                 PROPYLENE GLYCOL 
                 Propylene glycol 
                 40.000 
               
               
                   
                 ETHANOL 95-96% 
                 Ethanol 
                 30.000 
               
               
                   
                 RONACARE ALLANTOIN 
                 Allantoin 
                 0.200 
               
               
                   
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS Copolymer Dispersion 
                 4.000 
               
               
                   
                   
                 40%/Isohexadecane/polysorbate 80 
                   
               
               
                   
                 PHENOXETOL 
                 Phenoxyethanol 
                 1.000 
               
               
                   
                 PURIFIED WATER 
                 Purified water 
                 QS 100.000 
               
               
                   
               
             
          
           
               
                   
                 CHARACTERIZATION 
                 MACROSCOPIC 
                 Shiny, smooth, white gel 
               
               
                   
                 AT T0 
                 APPEARANCE 
                   
               
               
                   
                   
                 MICROSCOPIC APPEARANCE 
                 Absence of crystals. 
               
               
                   
                   
                 pH 
                 Not able to be done 
               
               
                   
                   
                 VISCOSITY 
                 Not done 
               
               
                   
                   
                 CENTRIFUGATION 
                 Complies 
               
               
                   
               
             
          
           
               
                 MONITORING OF STABILITY 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                 Microscopic appearance 
                 Complies, no 
                 Complies, no 
                 Complies, no 
                 Complies, no 
               
               
                   
                 recrystallization 
                 recrystallization 
                 recrystallization 
                 recrystallization 
               
               
                 Macroscopic appearance 
                 Complies 
                 Complies 
                 Complies 
                 Complies 
               
               
                   
               
             
          
           
               
                   
                 Chemical 
                 Assay 
                 AT 
                 99.90 
                 101.80 
                 103.20 
                 99.70 
               
               
                   
                 stability 
                 COMPOUND 
                 40° C. 
                 97.50 
                 99.60 
                 96.80 
                 95.90 
               
               
                   
                   
                 A initial % 
               
               
                   
               
             
          
         
       
     
     These results show good physical and chemical stability of the active agent and of the composition as a whole over time. 
     Formula No. 3 
     
       
         
               
               
               
               
             
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                   
                 TRADE NAME 
                 INCI NAME 
                 % 
               
               
                   
               
               
                   
                 COMPOUND A 
                 COMPOUND A 
                 0.010 
               
               
                   
                 PROPYLENE GLYCOL 
                 Propylene glycol 
                 40.000 
               
               
                   
                 ETHANOL 95-96% 
                 Ethanol 
                 20.000 
               
               
                   
                 RONACARE ALLANTOIN 
                 Allantoin 
                 0.200 
               
               
                   
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS Copolymer Dispersion 
                 3.000 
               
               
                   
                   
                 40%/Isohexadecane/polysorbate 80 
                   
               
               
                   
                 ST-CYCLOMETHICONE 5NF 
                 Cyclopentasiloxane 
                 2.000 
               
               
                   
                 PHENOXETOL 
                 Phenoxyethanol 
                 1.000 
               
               
                   
                 PURIFIED WATER 
                 Purified water 
                 QS 100.000 
               
               
                   
               
             
          
           
               
                   
                 CHARACTERIZATION 
                 MACROSCOPIC 
                 Shiny, smooth, white gel 
               
               
                   
                 AT T0 
                 APPEARANCE 
                   
               
               
                   
                   
                 MICROSCOPIC APPEARANCE 
                 Absence of crystals. 
               
               
                   
                   
                 pH 
                 Not able to be done 
               
               
                   
                   
                 VISCOSITY 
                 Not done 
               
               
                   
                   
                 CENTRIFUGATION 
                 Complies 
               
               
                   
               
             
          
           
               
                 MONITORING OF STABILITY 
                 1 Month 
                 2 Months 
                 3 Months 
                 6 Months 
               
               
                 Microscopic appearance 
                 Complies, no 
                 Complies, no 
                 Complies, no 
                 Complies, no 
               
               
                   
                 recrystallization 
                 recrystallization 
                 recrystallization 
                 recrystallization 
               
               
                 Macroscopic appearance 
                 Complies 
                 Complies 
                 Complies 
                 Complies 
               
               
                   
               
             
          
           
               
                   
                 Chemical 
                 Assay 
                 AT 
                 100.10 
                 96.60 
                 97.90 
                 97.10 
               
               
                   
                 stability 
                 COMPOUND 
                 40° C. 
                 101.10 
                 95.50 
                 97.00 
                 93.90 
               
               
                   
                   
                 A initial % 
               
               
                   
               
             
          
         
       
     
     These results show good physical and chemical stability of the active agent and of the composition as a whole over time. 
     Formula No. 4 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 TRADE NAME 
                 INCI NAME 
                 % 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 COMPOUND A 
                 COMPOUND A 
                 0.010 
               
               
                 DIPROPYLENE GLYCOL CARE 
                 Dipropylene glycol 
                 40.000 
               
               
                 ETHANOL 95-96% 
                 Ethanol 
                 20.000 
               
               
                 RONACARE ALLANTOIN 
                 Allantoin 
                 0.200 
               
               
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS 
                 3.000 
               
               
                   
                 Copolymer Dispersion 
               
               
                   
                 40%/Isohexadecane/ 
               
               
                   
                 polysorbate 80 
               
               
                 ST-CYCLOMETHICONE 5NF 
                 Cyclopentasiloxane 
                 2.000 
               
               
                 PHENOXETOL 
                 Phenoxyethanol 
                 1.000 
               
               
                 PURIFIED WATER 
                 Purified water 
                 QS 100.000 
               
               
                   
               
             
          
         
       
     
     Formula No. 5: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 TRADE NAME 
                 INCI NAME 
                 % 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 COMPOUND A 
                 COMPOUND A 
                 0.020 
               
               
                 DIPROPYLENE GLYCOL CARE 
                 Dipropylene glycol 
                 40.000 
               
               
                 ETHANOL 95-96% 
                 Ethanol 
                 20.000 
               
               
                 RONACARE ALLANTOIN 
                 Allantoin 
                 0.200 
               
               
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS 
                 3.000 
               
               
                   
                 Copolymer Dispersion 
               
               
                   
                 40%/Isohexadecane/ 
               
               
                   
                 polysorbate 80 
               
               
                 PHENOXETOL 
                 Phenoxyethanol 
                 2.000 
               
               
                 PURIFIED WATER 
                 Purified water 
                 QS 100.000 
               
               
                   
               
             
          
         
       
     
     Formula No. 6: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 TRADE NAME 
                 INCI NAME 
                 % 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 COMPOUND A 
                 COMPOUND A 
                 0.005 
               
               
                 DIPROPYLENE GLYCOL CARE 
                 Dipropylene glycol 
                 40.000 
               
               
                 ETHANOL 95-96% 
                 Ethanol 
                 20.000 
               
               
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS 
                 3.000 
               
               
                   
                 Copolymer Dispersion 
               
               
                   
                 40%/Isohexadecane/ 
               
               
                   
                 polysorbate 80 
               
               
                 ST-CYCLOMETHICONE 5NF 
                 Cyclopentasiloxane 
                 2.000 
               
               
                 PURIFIED WATER 
                 Purified water 
                 QS 100.000 
               
               
                   
               
             
          
         
       
     
     Formula No. 7: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 TRADE NAME 
                 INCI NAME 
                 % 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 COMPOUND A 
                 COMPOUND A 
                 0.005 
               
               
                 PROPYLENE GLYCOL 
                 Propylene Glycol 
                 40.000 
               
               
                 ETHANOL 95-96% 
                 Ethanol 
                 20.000 
               
               
                 RONACARE ALLANTOIN 
                 Allantoin 
                 0.200 
               
               
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS 
                 3.000 
               
               
                   
                 Copolymer Dispersion 
               
               
                   
                 40%/Isohexadecane/ 
               
               
                   
                 polysorbate 80 
               
               
                 PHENOXETOL 
                 Phenoxyethanol 
                 1.000 
               
               
                 PURIFIED WATER 
                 Purified water 
                 QS 100.000 
               
               
                   
               
             
          
         
       
     
     Formula No. 8: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 TRADE NAME 
                 INCI NAME 
                 % 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 COMPOUND A 
                 COMPOUND A 
                 0.010 
               
               
                 DIPROPYLENE GLYCOL CARE 
                 Dipropylene glycol 
                 40.000 
               
               
                 ETHANOL 95-96% 
                 Ethanol 
                 20.000 
               
               
                 RONACARE ALLANTOIN 
                 Allantoin 
                 0.200 
               
               
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS 
                 4.000 
               
               
                   
                 Copolymer Dispersion 
               
               
                   
                 40%/Isohexadecane/ 
               
               
                   
                 polysorbate 80 
               
               
                 ST-CYCLOMETHICONE 5NF 
                 Cyclopentasiloxane 
                 1.000 
               
               
                 PURIFIED WATER 
                 Purified water 
                 QS 100.000 
               
               
                   
               
             
          
         
       
     
     Formula No. 9: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 TRADE NAME 
                 INCI NAME 
                 % 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 COMPOUND A 
                 COMPOUND A 
                 0.01 
               
               
                 DIPROPYLENE GLYCOL CARE 
                 Dipropylene glycol 
                 30.000 
               
               
                 ETHANOL 95-96% 
                 Ethanol 
                 15.000 
               
               
                 RONACARE ALLANTOIN 
                 Allantoin 
                 0.200 
               
               
                 SIMULGEL 600 PHA 
                 Acrylamide, AMPS 
                 3.000 
               
               
                   
                 Copolymer Dispersion 
               
               
                   
                 40%/Isohexadecane/ 
               
               
                   
                 polysorbate 80 
               
               
                 ST-CYCLOMETHICONE 5NF 
                 Cyclopentasiloxane 
                 1.000 
               
               
                 PURIFIED WATER 
                 Purified water 
                 QS 100.000 
               
               
                   
               
             
          
         
       
     
     Example 3 
     Characterization of the Formulations by Means of Cutaneous Penetration Studies on Human Skin 
     The cutaneous penetration studies make it possible to characterize the formulations, and to demonstrate parameters specific to each of the formulations. 
     Two types of cutaneous penetration studies on human skin ex vivo were carried out. 
     In these studies, compound A corresponds to 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic acid. 
     The reference gel being described as follows: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Constituents 
                 % 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Compound A 
                 0.01 
               
               
                   
                 Propylene Glycol 
                 30.00 
               
               
                   
                 Ethanol 95-96% 
                 67.99 
               
               
                   
                 Klucel HF Pharma 
                 2.00 
               
               
                   
                   
               
             
          
         
       
     
     In these 2 studies, the “optimized gel” composition corresponding to formula 3 is evaluated in comparison to a “reference gel” composition. 
     1—“Single Time” Cutaneous Penetration Study: 
     In this study, the formula is applied for 16 h at the surface of the skin. At the end of the application, compound A is quantified in the various skin compartments: stratum corneum, epidermis, dermis and receiving liquid according to a validated bioanalysis method. 
     The details of the cutaneous application are given in the table below. 
     
       
         
               
             
           
               
                   
               
             
             
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
     The bioanalysis was carried out by positive electrospray ionization tandem mass spectrometry, and using a Xevo apparatus (Waters). The quantification limit for compound A is 1 ng/ml. 
     The LC/MS/MS conditions developed made it possible to detect up to 0.1% of the dose applied in each of the compartments (dose nonabsorbed, stratum, epidermis, dermis and receiving liquid). 
     The technical conditions are given in the table below. 
     
       
         
               
               
             
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
             
             
               
                 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 
               
               
                 Washing of 
                 ACN 
               
               
                 needle 
                   
               
               
                 Washing of 
                 ACN/H 2 O 50:50 
               
               
                 septum 
               
               
                   
               
             
          
           
               
                   
                 T (min) 
                 flow rate 
                 % A 
                 % B 
                 Curve 
               
               
                   
               
               
                 Gradient 
                 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 
               
               
                   
               
               
                 Column 
                   
                   
                   
                   
                   
               
               
                 temperature 
                   
                   
                   
                   
                   
               
             
          
           
               
                 MSMS detection 
                 ESI+ MRM (Positive Electrospray) 
               
               
                   
               
             
          
           
               
                   
                 Reaction Channel 
                 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 
               
               
                   
                   
                   
                   
                   
                   
                 Reference 
               
               
                 Injection 
                 5 μl 
                   
                   
                   
                   
                   
               
               
                 Volume 
                   
                   
                   
                   
                   
                   
               
               
                 Run time 
                 4 minutes 
               
               
                   
               
             
          
         
       
     
     a—Profile of Distribution in the Various Compartments (Qualitative Data): 
     The distribution between the various compartments is of the same type for the 2 formulae evaluated: accumulation in the stratum corneum and lower degree of penetration in the epidermis. Compound A is not detected in the receiving liquid and is very weakly present in the dermis. 
     b—Values for Penetration in the Epidermis+Dermis Compartment: 
     The penetration values for the optimized gel (example 3) containing 100 μg/g (0.01%) of compound A are around 9 ng/cm 2 . The levels of penetration of compound A after application of the optimized gel (example 3) tend to be higher than those obtained after application of the reference gel. 
     1—Penetration Kinetics Study— FIG. 1 : 
     In this type of study, the penetration of the active agent is quantified in each compartment of the skin after 0.5 h, 1 h, 3 h, 6 h and 24 h of application. Kinetics of penetration into each compartment are then determined and characterized. 
     The details of the cutaneous application are given in the table below: 
     
       
         
               
             
           
               
                   
               
             
             
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
     The amount of active agent in each compartment at each time was determined by LC/UV or by LC/MS. The bioanalysis method was validated so as to detect at least 0.1% of the dose applied in each compartment. 
     In this type of study, the parameters retained are:
         a. The profile of the kinetics of penetration into the epidermis (qualitative data).   b. The initial rate of the penetration into the epidermis.   c. The maximum amount penetrated into the epidermis.       

     a. Profile of the Kinetics of Penetration into the Epidermis— FIG. 2 : 
     The compound A release kinetics obtained for the optimized gel (example 3) shows a steep initial slope, followed by a maximum during which the penetration of compound A no longer increases over time. The reference formula (gel) shows the same profile with a rapid release over the first hours, with a plateau then being reached. 
     As seen in section 1 (“Single time” cutaneous penetration study), these two formulae have penetration levels at 16 h which are different; the penetration of compound A into the epidermis after application of the optimized gel (example 3) tends to be greater than that obtained after application of the reference gel. 
     b. Initial Rate of the Kinetics: 
     The value of the initial rate of the kinetics or slope over the first three hours is 4.12 ng/cm 2 /h. 
     c. Maximum Amount in the Epidermis: 
     The maximum amount in the epidermis is 12.07 ng/cm 2 . 
     Example 4 
     Cosmetic Study of Improved Feel 
     Tests for Improved Feel: 
     In order to obtain an acceptable feel for acne (non-greasy, non-tacky) while at the same time keeping good solubility of compound A in the formula, tests introducing ST-cyclomethicone 5 were carried out, in the knowledge that ST-cyclomethicone 5NF is a nonsolvent of compound A and that this addition may therefore cause recrystallization of compound A: 
     
       
         
               
               
               
               
             
           
               
                   
               
               
                 ST- 
                   
                   
                   
               
               
                 Cyclomethicone 
               
               
                 5NF 
                 0% 
                 2% 
                 5% 
               
               
                   
               
             
             
               
                 Feel 
                 Tacky feel 
                 Acceptable feel 
                 Acceptable feel 
               
               
                 Recrystallization 
                 No 
                 No 
                 Re- 
               
               
                 of 
                 recrystallization 
                 recrystallization 
                 crystallization 
               
               
                 COMPOUND A 
               
               
                   
               
             
          
         
       
     
     These tests allowed us to optimize the amount of ST-cyclomethicone 5NF at 2% in order to obtain a cosmetically acceptable feel.