Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
  • A61K9/122—Foams; Dry foams
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
  • A61K8/04—Dispersions; Emulsions
  • A61K8/042—Gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
  • A61K8/04—Dispersions; Emulsions
  • A61K8/044—Suspensions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
  • A61K8/04—Dispersions; Emulsions
  • A61K8/046—Aerosols; Foams
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/10—Washing or bathing preparations

Definitions

• the present invention relates to adapalene-based foam compositions, particularly as topical dermatological compositions, especially for the treatment of dermatoses, such as acne.
• retinoids for the topical treatment of various diseases related to the skin or mucous membranes, in particular acne.
• the commonly developed dosage forms are in the form of aqueous gels, emulsions (lotions or creams) poorly adapted to the treatment of acne.
• adapalene is a naphthoic acid derivative having retinoid and anti-inflammatory properties. This molecule has been developed for the topical treatment of acne vulgaris and retinoid-sensitive dermatoses.
• Adapalene is marketed under the Differin® brand at a concentration of 0.1% by weight, in the form of a so-called alcoholic lotion solution, an aqueous gel and a cream. These compositions are intended for the treatment of acne.
• the patent application FR2837101 describes adapalene compositions at a weight concentration of 0.3%, for the treatment of acne.
• An object of the present invention is therefore to provide novel foam compositions particularly well suited to topical administration, comprising adapalene in dispersed form.
• These foam compositions are obtained from intermediate compositions in the form of gels or suspensions and comprising the active ingredient.
• the formulation in the form of a retinoid-containing foam is advantageous for topical treatments, such as that of acne, because it allows a patient-friendly, easy, unique and effective application of adapalene at the level of the skin.
• this type of formulation has a very good cosmetics for patients.
• WO2007 / 007198 discloses foam-like compositions obtained from retinoid-containing emulsions. These compositions have a significant proportion of organic vehicle representing from 2 to 50% by total weight of the composition. This important content of organic vehicle is not suitable for the treatment of acne because it gives a greasy feel.
• emulsions are fat-rich compositions that are incompatible with the treatment of acne, which on the contrary requires aqueous, refreshing and non-greasy compositions. These compositions leave a greasy feel on the skin after application.
• compositions in the form of existing foams do not therefore have all the properties required for the treatment of acne as described above.
• foam-type dermatological composition obtained from an intermediate composition in the form of a gel and / or suspension for topical application providing a very good stability, a non-greasy feel cosmetically acceptable (absence of fatty phase), good maintenance of the asset in dispersed form within the formulation, a viscosity allowing easy application to the skin, targeted to the lesions.
• Foam-type compositions obtained from gel-type intermediate compositions according to the invention do not contain a fatty phase and have a viscosity greater than 8000cps after preparation at room temperature (25 ° C.), measured according to the conditions defined in the example 1 of this application ("Example 1: Characterization of intermediate formulations of the gel type and suspensions").
• Foam-type compositions obtained from suspension-type intermediate compositions according to the invention do not contain a fatty phase and have a viscosity of between 8000cps and 32000cps after preparation at room temperature (25 ° C.), measured according to the conditions defined in Example 1 of the present application ("Example 1: Characterization of intermediate formulations of gel type and suspensions").
• intermediate composition in the form of gel and / or suspension
• intermediate formulation intermediate formulation and gel-type formulation and or suspension
• formulation intermediate formulation and or suspension
• composition or “foam-type composition” or “foam” represent the final composition in the form of foam.
• the active agent is present in dispersed form.
• gel By gel is meant a semi-solid preparation containing a gelling agent which provides rigidity to a colloidal solution or dispersion (Lucinda Buhse et al., “Topical Drug Classification”, International Journal of Pharmaceutics, 2005 (295), 101 -1 12).
• suspension a liquid preparation containing solid particles dispersed in a compatible liquid vehicle for dermal application (CDER Data Standards Manual, version 008, April 14, 1992).
• a liquid flows with little or no external forces and shows Newtonian or pseudoplastic behavior (Lucinda Buhse et al, Topical Drug Classification, International Journal of Pharmaceutics, 2005 (295), 101-112).
• the Applicant has in particular made a foam from a gel-type intermediate composition comprising:
• a chelating agent optionally, a chelating agent,
• At least one humectant and / or emollient optionally, at least one humectant and / or emollient
• Adapalene being in dispersed form in said composition.
• the Applicant has also produced a foam from a suspension-type intermediate composition comprising:
• At least one suspending and / or viscosizing agent at least one suspending and / or viscosizing agent
• a chelating agent optionally, a chelating agent,
• At least one humectant and / or emollient optionally, at least one humectant and / or emollient
• Adapalene being in dispersed form in said composition.
• the present invention comprises adapalene.
• the adapalene is used at concentrations of between 0.001 and 10% by weight relative to the total weight of the intermediate composition, and preferably between 0.01 and 5%, more preferably, between 0.05% and 0.5% and most preferably from 0.1% to 0.3% by weight relative to the total weight of the intermediate composition.
• the particle size of the adapalene is such that at least 90% by number of the particles, and preferably at least 90% by number of the particles, have a diameter of less than 10 ⁇ and at least 99% by number of the particles. particles have a diameter less than 50 ⁇ , the particle sizes being preferably measured by optical microscopy.
• the adapalene is in dispersed form.
• active in dispersed form according to the invention is meant an active ingredient in the form of solid particles, suspended in a given vehicle. Such particles preferably have a size greater than ⁇ ⁇ .
• the suspensive power of the dispersed active agent such as the adapalene of our gel and suspension-type compositions is optimized by the addition of at least one gelling agent and in the presence or absence of at least one suspending agent and / or or viscose.
• the aqueous phase of the gel or of the suspension may be present in a content of between 40 and 90% by weight relative to the total weight of the intermediate composition, preferably between 65% and 85% by weight.
• the gelling agent (s) and / or pH-independent gelling agents present in the gel or the suspension serve to increase the viscosity of the aqueous phase. This makes it possible in particular to improve the stabilization of this phase and its binder nature, which leads to both a good homogeneity of the distribution of the active ingredient in the intermediate composition and to the production of foams having the texture and stability sought.
• the gelling agent (s) and / or pH-independent gelling agents may especially be chosen from:
• non-electrolyte sensitive carbomers sold by way of non-limiting example under the name Carbopol Ultrez-20®, Carbopol 1382® or
• xanthan gum sold under the name Xantural 180® by the company Kelco or Satiaxane UCX91 1® by Cargill
• guar gum sold under the name N-Hance® by IMCD
• locust bean gum sold under the name Viscogum® by Cargill
• gum tragacanth seed extract quince
• alginates such as sodium alginate sold under the name Satialgine® by Cargill
• Modified starches such as modified potato starch sold under the name Solanace® Structure or mixtures thereof;
• Acrylic polymers coupled to hydrophobic chains such as the 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 moles of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexylisocyanate) (SMDI), 35% by weight in a mixture of propylene glycol (39%) and water (26%));
• Aculyn 44® polycondensate comprising at least as elements, a polyethylene glycol with 150 or 180 moles of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexylisocyanate) (SMDI), 35% by weight in a mixture of propylene glycol (39%) and water (26%)
• SMDI methylene bis (4-cyclohexylisocyanate
• Polyacrylamides such as the Acrylamide / Sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 mixture sold under the name Sepineo P600® (or Simulgel 600PHA®) by Seppic, the polyacrylamide / isoparaffin C13-14 / laureth-7 mixture, for example, that sold under the name Sepigel 305® by the company Seppic, the mixture hydroxyethylacrylate / sodium acryloyldimethyl Taurate Copolymer sold under the name Sepinov EMT 10® by the company Seppic; and
• the gelling agent and / or gelling pH-independent as described above can be used at preferred concentrations ranging from 0.1% to 10% by weight relative to the total weight of the intermediate composition and, more preferably, from 0 , 2 to 5%.
• preferred gelling agent mention may be made of polysaccharides such as xanthan gum (Xantural 180®) and guar gum (N-Hance®), celluloses such as hydroxyethylcellulose (Natrosol 250HHX®), polyacrylamides such as Acrylamide / Sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 (Sepineo P600® (or Simulgel 600PHA®)) and the hydroxyethylacrylate / sodium acryloyldimethyl Taurate Copolymer (Sepinov EMT 10®) blend.
• polysaccharides such as xanthan gum (Xantural 180®) and guar gum (
• the suspension agent (s) present in the suspension serve to keep in suspension the active agent present in the intermediate compositions without, however, increasing the viscosity.
• Viscarin® by way of non-limiting example Viscarin GP-379NF® and Viscarin GP-209NF®
• Gelcarin® by way of non-limiting example the Gelcarin GP-379NF®
• the suspending agent and / or viscose as described above can be used at preferential concentrations ranging from 0.1% to 10% by weight relative to the total weight of the intermediate composition and, more preferably, from 0 , 2 to 5%.
• a preferred suspending and / or viscosizing agent mention may be made of microcrystalline cellulose and sodium carboxymethyl cellulose sold under the name Avicel CL-61 1®, carrageenans with, for example, Viscarin GP-209NF. ®, clays with Veegum HS® for example, polysaccharides with Amigel® as an example.
• the gels and suspensions of the present invention contain surfactants, amphiphilic molecules, which will make it possible to form the foam and to stabilize it (A.Arzhavitina, "Foams for pharmaceutical and cosmetics application", International Journal of Pharmaceutics, 394 (2010), 1 -17).
• the surfactants are amphiphilic compounds which have a hydrophobic part having an affinity for the oil and a hydrophilic part having an affinity for water thus creating a link between the two phases.
• the polarity of the surfactant is defined by the HLB (Hydrophile / Lipophilic Balance).
• High HLB indicates that the hydrophilic moiety is predominant, and conversely, low HLB indicates that the lipophilic moiety is predominant.
• HLB values greater than about 10 correspond to hydrophilic surfactants.
• Surfactants can be classified, according to their structure, under the generic terms “ionic” (anionic, cationic, amphoteric) or "nonionic".
• Nonionic surfactants are surfactants that do not dissociate into ions in water and are therefore insensitive to pH changes.
• the surfactants present in the intermediate composition provide a surface modification at the liquid / gas type interfaces, which makes it possible to ensure the formation of the foam (Dominique Langevin, "Aqueous foams: a field of investigation at the frontier between chemistry and physics”).
• anionic surfactants mention may be made of sodium lauryl sulphates (sodium lauryl sulfate sold under the name Texapon K12P PH® by Cognis) of ammonium or triethanolamine, sodium lauryl ether sulphates (sodium laureth sulfate sold under the name Texapon N70® by Cognis), magnesium, ammonium, TEA (triethylamine), sodium lauroyl sarcosinate sold under the name Protelan LS901 1® by the company Zschimmer & Schwarz company, sodium olefinsulfonates, sulfoacetates, sulfosuccinates, sodium taurates, sodium cocoyl glutamate & disodium cocoyl glutamate sold under the name Amisoft CS-22® by the company Ajinomoto.
• sodium lauryl sulphates sodium lauryl sulfate sold under the name Texapon K12P PH® by
• Nonlimiting examples of cationic surfactants include quaternary ammoniums, alkylpyridinium chlorides, alkylammonium saccharinates and aminoxides.
• amphoteric surfactants are betaines and their derivatives with, for example, cocamidopropylbetaine sold under the name Amonyl 380BA® by Seppic, cocobetaine sold under the name Amonyl. 265BA® by Seppic or Dehyton AB 30® by Cognis, the disodium cocoamphoacetate sold under the name Rewoteric AM2 C NM® by Evonik.
• Non-limiting examples of nonionic surfactants include sorbitan esters such as POE (20) sorbitan monooleate, sold under the name Tween 80®, POE (20) sorbitan monostearate sold under the name of Tween 60®, sorbitan monostearate sold under the name Span 60® by Uniqema, glycerol esters such as glycerol monostearate sold under the name Cutina GMSVPH® by Cognis, polyethylene glycol esters such as PEG-6 isostearate sold under the name Olepal isostearic® by the company Gattefossé, fatty alcohol ethers such as POE (21) stearyl ether sold under the name Brij 721® by the company Uniqema, or the ceteareth 20 sold under the name Eumulgin B2PH® by Cognis, polyoxyethylene glycol esters such as glyceryl stearate and PEG 100 stearate sold under the name Arlacel
• the surfactant as described above is preferably comprised at a content of between 0.2 and 15% by weight relative to the total weight of the intermediate composition, preferably between 0.5 and 10%. .
• the particularly preferred surfactants are chosen from anionics (Texapon N70®, Protelan LS901 1®), amphoters (Amonyl 380BA®, Amonyl 265BA®), nonionics (Tween 80 ®, Surfhope C1215L®, Sisterna L70C®, Oramix NS10®, Eumulgin HRE40PH®).
• composition of the gel or suspension type according to the invention also comprises at least one wetting agent.
• the wetting agents have the role of reducing the surface tension and to allow greater spreading of the liquid. Without using this list, a wetting agent may be used, which may preferably have an HLB of 10 to 14.
• wetting agents that can be used according to the invention, mention may be made of compounds of the Poloxamers family with Poloxamer 124 sold under the the name of Synperonic PE / L44® by Uniquema or Lutrol L44® sold by BASF, poloxamer 182 sold under the name Synperonic PE / L62® by Uniquema or Lutrol L62® by BASF, compounds of the family of glycols with propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol, ethoxydiglycol.
• the wetting agents are in liquid form so as to be easily incorporated into the gel-like composition or suspension without the need to heat it.
• the wetting agent as described above may be used at preferential concentrations ranging from 0.05% to 10% by weight relative to the total weight of the intermediate composition and, more preferably, ranging from 0.1% to 8% by weight. %.
• the particularly preferred wetting agent is propylene glycol and Lutrol L44® sold by BASF.
• chelating agents mention may be made, by way of non-limiting examples, of ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid and acetic acid (DTPA), ethylene diamine-di (O-hydroxyphenyl acetic acid) (EDDHA), hydroxy-2-ethylenediamine triacetic acid (HEDTA), ethyldiamine-di (O-hydroxy-p-methyl) acid phenyl) acetic acid (EDDHMA) and ethylene diamine di (5-carboxy-2-hydroxyphenyl) acetic acid (EDDCHA).
• EDTA ethylene diamine tetraacetic acid
• DTPA diethylene triamine pentaacetic acid and acetic acid
• EEDHA ethylene diamine-di (O-hydroxyphenyl acetic acid)
• HEDTA hydroxy-2-ethylenediamine
• the chelating agent as described above may be used at preferential concentrations ranging from 0% to 1.5% by weight relative to the total weight of the intermediate composition and, more preferably, ranging from 0% to 1%.
• concentration is preferably between 0.01% and 1%.
• EDTA ethylene diamine tetraacetic acid
• composition of gel or suspension type according to the invention may also contain humectants which function to hydrate the skin and facilitate the application of the formulation.
• humectants and / or emollients preferentially, without this list being limiting, compounds such as glycerine and sorbitol, sugars (for example glucose, lactose), PEGs (for example Lutrol E400), urea, amino acids (for example serine, citrulline, arginine, asparagine, alanine). These agents are taken alone or combined in the composition.
• the humectant and / or emollient agent as described above may be used at preferential concentrations ranging from 0% to 20% by weight relative to the total weight of the intermediate composition and, more preferably, ranging from 0 to 15%. .
• concentration is preferably between 0.01% and 15%.
• glycerin As a humectant and / or emollient preferred agent, mention may be made of glycerin.
• the intermediate compositions of the invention may furthermore optionally comprise any additive usually used in the cosmetics or pharmaceutical field, such as conventional or inorganic or organic base or acidic neutralizing agents, sunscreens, antioxidants, fillers, solvents and the like. electrolytes, preservatives, dyes, perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, soothing and protective agents for the skin, propenetrating agents, or a mixture thereof.
• any additive usually used in the cosmetics or pharmaceutical field such as conventional or inorganic or organic base or acidic neutralizing agents, sunscreens, antioxidants, fillers, solvents and the like. electrolytes, preservatives, dyes, perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds, soothing and protective agents for the skin, propenetrating agents, or a mixture thereof.
• electrolytes preservatives, dyes, perfumes,
• additives as described above can be used at preferential concentrations ranging from 0% to 20% by weight relative to the total weight of the intermediate composition and, more preferably, ranging from 0 to 15%.
• concentration is preferably between 0.01% and 15%.
• the invention thus relates to a pharmaceutical composition based on adapalene, characterized in that it is in the form of a foam obtained from an intermediate composition of gel or suspension type, in particular for a topical application, intended to the treatment of acne.
• the invention relates to a pharmaceutical composition characterized in that it is in the form of a foam obtained from an intermediate composition of gel or suspension type, said composition comprising, by weight relative to total weight of the composition:
• compositions between 60 and 98% by weight relative to the total weight of the composition, a gel or a suspension, preferably between 80 and 96%,
• composition Between 2 and 40% by weight relative to the total weight of the composition and preferably between 4 and 20% of at least one propellant.
• the intermediate composition in gel form comprises (% by weight relative to the total weight of the gel composition):
• Adapalene being in dispersed form in said gel.
• the intermediate composition in the form of suspension comprises (% expressed by weight relative to the total weight of the suspension-type composition):
• the invention relates to a pharmaceutical composition based on adapalene, characterized in that it is in the form of a foam obtained from an intermediate composition of gel or suspension type which comprises:
• Said gel comprising (% expressed by weight relative to the total weight of the gel-type composition):
• Said adapalene being in dispersed form in said gel.
• Said suspension comprising (% expressed by weight relative to the total weight of the suspension-type composition):
• Said benzoyl peroxide being in dispersed form in said suspension.
• the invention also relates to the use of the new foam-type composition as described above in cosmetics and dermatology. Due to the marked activity of adapalene in the fields of cell differentiation and proliferation, the compositions of the invention are particularly suitable in the following therapeutic areas:
• the compounds can also be used in certain inflammatory conditions that do not have a keratinization disorder, such as folliculitis,
• compositions or gels and suspensions according to the invention are particularly suitable for the treatment, in a preventive or curative manner, of acne vulgaris.
• compositions according to the invention also find application in the cosmetic field, in particular for the treatment of acne-prone skin, to combat the oily appearance of the skin or hair.
• compositions according to the invention are administered topically.
• the invention also relates to a process for preparing a composition of the gel or suspension type as described above.
• the process for preparing the intermediate gel or suspension composition according to the invention comprises, by way of example, the following steps:
• Step a preparation of the active phase:
• Step b Preparation of the aqueous phase
• purified water is introduced with stirring, if necessary hot, and the gelling agent (s) and / or the one or more independent pH-gelling agents (with the exception of polyacrylamide), the hydrophilic surfactant (s). and optionally the suspending agent (s) and / or viscosity agent (s), the chelating agent, the preserving agent (s), the stabilizing agent (s), the humectant (s) and / or emollient (s).
• the gelling agent (s) and / or the one or more independent pH-gelling agents with the exception of polyacrylamide
• the hydrophilic surfactant (s). optionally the suspending agent (s) and / or viscosity agent (s), the chelating agent, the preserving agent (s), the stabilizing agent (s), the humectant (s) and / or emollient (s).
• Step c Preparation of the gel or suspension
• step a) The active phase obtained in step a) is then introduced with stirring into the aqueous phase.
• Step d Add polyacrylamide (optional)
• Step e Neutralization step (optional)
• the neutralizing agent of the gelling agent is introduced if necessary into the gel or into the suspension.
• Step f Water adjustment (optional)
• Additives if present in the gel or the suspension are added to the aqueous phase.
• the subject of the invention is a process for preparing a composition in the form of an adapalene-based foam by mixing a gel or a suspension with at least one propellant gas.
• Foams are defined as a dispersion of a gas in a liquid or a solid (A.Arzhavitina, "Foams for pharmaceutical and cosmetics application", International Journal of Pharmaceutics, 394 (2010), 1 -17).
• the European Pharmacopoeia 6th Edition 2010 describes a "medicinal foam” as a preparation consisting of the dispersion of a large volume of gas in a liquid preparation generally containing one or more active ingredients, at least one surfactant ensuring their formation, and various other excipients.
• the US Pharmacopoeia USP Chapter ⁇ 1 151> lists the foams in the "Aerosol Foam” section. It is a composition containing one or more active ingredients, one or more surfactants, aqueous or non-aqueous liquids and propellants.
• the foam compositions of the present invention are obtained by introducing the gel and / or suspension type intermediate composition into an aerosol container containing at least one propellant gas under pressure.
• the aerosol consists of 3 elements "Pharmaceutical Dosage Forms, USP ⁇ 1 151>": - the waterproof case; the valve ensuring the closure and allowing the communication of the container with the atmosphere to distribute the product; the diffuser or push button comprises the opening of the valve and allows to act on the flow; By releasing the formulation of the gel or suspension type of the container by means of the push button, a foam is obtained.
• the aerosol container used in the context of this embodiment is preferably a shaving foam bomb container, namely a closed, pressure vessel comprising an outlet nozzle connected to the gel or suspension and containing at least one a propellant, a valve and a push-button adapted to the distribution of the foam.
• the aerosol differs from some pump sprayers that act only by the action of a mechanical spring (no propellant). It should be noted that an aerosol always contains a propellant that hunt and disperse the product (Martini TM, Aesthetics-cosmetics, Volume 2, “Cosmetology”, Editions Masson, Paris, 2002).
• propellants that can be used in our invention are of two types: compressed gases, liquefied gases.
• Compressed gases are gaseous at room temperature.
• nitrogen gaseous at room temperature.
• carbon dioxide gaseous at room temperature
• nitrous oxide and their mixtures.
• Liquefied gases are liquid at room temperature.
• butane propane and isobutane, and mixtures thereof.
• the propellants used according to the present invention are in proportions ranging from 2 to 40%, and preferably ranging from 4% to 20% by weight of the composition.
• the aerosol containers for the delivery of a foam comprising a gel or a suspension and at least one pressurized propellant gas constitute another specific object of the present invention.
• the physical stability of the intermediate formulations of the gel or suspension type is controlled by a macroscopic and microscopic observation, stored at room temperature (RT) and 40 ° C after T + 1 month or T + 2 month or T + 3 month.
• Adapalene is observed in fluorescent light.
• Characterization of the gel and the suspension is completed by a measurement of the viscosity and the realization of a rheological profile.
• the apparent viscosity of the gel and the suspension is measured using Brookfield RVDVII + and LVDVII + viscometers at room temperature (25 ° C.).
• the ranges of measurable viscosity with these two types of Brookfield are as follows:
• RVDVII + Viscometer 100 cP - 40 McP
• a HAAKE rheometer of type VT550 with a measurement mobile SVDIN is used.
• the rheograms are produced at 25 ° C and imposed speed from 0 to 100 s "1.
• the viscosity values are written to the shear values and shear rate constants of 4 s" 1, 20s “1 100s” 1 ( y), and measuring the shear stress.
• flow threshold ⁇ 0 expressed in Pascal
• the flow threshold is equivalent to the value found at the shear rate of 4s -1 .
• the quality of the foam at the outlet of the container is evaluated according to a classification on a scale of 1 to 5, with "1" representing a foam with fine bubbles and "5" representing a foam with large bubbles.
• the measurement of the density of the foam is carried out according to the protocol described in the European Pharmacopoeia 6th Edition 2010:
• Protocol Keep the container at a temperature of 25 ° C for at least 24 hours.
• a rigid tube with a length of 70 mm to 100 mm and an inside diameter of about 1 mm, shake the container to homogenize the liquid phase and expel at a loss 5ml to 10ml of foam.
• Tare a flat-bottomed crystallizer with a volume of approximately 60 ml and a height of approximately 35 mm. Place the end of the rigid tube into the corner of the bottom of the crystallizer and, to fill it evenly, press the push button in a circular motion. After complete expansion of the foam, level off the excess with a blade. Weigh. Determine the mass of the same volume of water R by filling the same crystallizer with water R. The density of the foam is equal to the ratio: m / e
• the device consists of a burette of 50ml, with an internal diameter of 15 mm, graduated 0.1 ml in 0.1 ml and provided with a single-way valve 4mm.
• the graduation corresponding to 30ml is at least 210 mm from the axis of the tap.
• the lower part of the burette is connected, via a plastic tube with a maximum length of 50mm and an inside diameter of 4mm, to the foam generator container equipped with a push button adapted to this connection.
• Connect the push-button to the output of the burette.
• foams obtained from gels and / or suspensions which are introduced into an aerosol container containing at least one propellant gas under pressure:

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• 2010
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