EP3076945A1 - Microcapsules lipidiques comprenant de preference un retinoide et composition les contenant, leur procede de preparation et leur utilisation en dermatologie - Google Patents
Microcapsules lipidiques comprenant de preference un retinoide et composition les contenant, leur procede de preparation et leur utilisation en dermatologieInfo
- Publication number
- EP3076945A1 EP3076945A1 EP14808978.2A EP14808978A EP3076945A1 EP 3076945 A1 EP3076945 A1 EP 3076945A1 EP 14808978 A EP14808978 A EP 14808978A EP 3076945 A1 EP3076945 A1 EP 3076945A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- oily
- phase
- composition
- microcapsules
- emulsion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- 239000003094 microcapsule Substances 0.000 title claims abstract description 127
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 76
- 239000008346 aqueous phase Substances 0.000 claims description 75
- 239000004480 active ingredient Substances 0.000 claims description 67
- -1 lipid compound Chemical class 0.000 claims description 67
- 239000006185 dispersion Substances 0.000 claims description 55
- MFBCDACCJCDGBA-UHFFFAOYSA-N 4-[3-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)-4-(2-hydroxyethoxy)phenyl]benzoic acid Chemical compound CC(C)(C)C1=CC(C=2C(=CC=C(C=2)C=2C=CC(=CC=2)C(O)=O)OCCO)=CC=C1N1CCCC1 MFBCDACCJCDGBA-UHFFFAOYSA-N 0.000 claims description 52
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- DGUXYDRSGSIRKZ-UHFFFAOYSA-N 4-[2-[3-tert-butyl-4-(diethylamino)phenyl]-2-hydroxyiminoethoxy]-2-hydroxybenzoic acid Chemical compound C1=C(C(C)(C)C)C(N(CC)CC)=CC=C1C(=NO)COC1=CC=C(C(O)=O)C(O)=C1 DGUXYDRSGSIRKZ-UHFFFAOYSA-N 0.000 claims description 2
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- NCYCYZXNIZJOKI-OVSJKPMPSA-N Retinaldehyde Chemical compound O=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 claims description 2
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- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 claims description 2
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Definitions
- Lipid microcapsules preferably comprising a retinoid and composition containing them, process for their preparation and their use in dermatology
- the present invention relates to lipid microcapsules having an oily internal phase and a nonpolymeric envelope obtained from at least one lipid compound chosen from amphiphilic lipids.
- the invention relates to microcapsules comprising an irritating active ingredient and more particularly a retinoid compound, said irritant active ingredient being present in lubilized form in oily heart microcapsules.
- the invention also relates to the primary emulsion composed of oily heart microcapsules dispersed in an aqueous phase and to the pharmaceutical composition comprising, within a pharmaceutically acceptable vehicle, the primary emulsion.
- the invention also relates to the process for preparing the primary emulsion, and the pharmaceutical composition comprising the lipid microcapsules. Finally, the invention relates to a composition for its use in the treatment of dermatological conditions, in particular acne.
- compositions that maintain the bio logical activity of the active ingredient while minimizing its irritating nature.
- Retinoids are active agents commonly used in dermatology but known to be mostly irritating active ingredients, so it is important, while maintaining the pharmaceutical activity, to improve the tolerance of this family of anti-acne molecule.
- the prior art has several formulation patents to improve the tolerance of the irritating active ingredients, especially in the retinoids, topically, by adding antiirritant compounds to the composition.
- Won et al, US 5, 955, 109 incorporate a retinoid in porous microspheres (Microsponge®) to decrease retinoid release in the skin layers, resulting in decreased level of irritation by kinetic control. release of the active ingredient through the skin.
- Mirosponge® porous microspheres
- a retinoid in an oil-in-water microemulsion in order to improve the bioavailability.
- This microemulsion is composed of a phospholipid and a sodium hyaluronate or modified hyaluronic acid.
- Saurai et al in the patent FR 2 865 65 proposes the combination of a retinoid with one or more hyaluronate fragments in a formulation for dermatological use in the case of treatment for which it will be necessary to improve the state of the skin.
- Cattaneo in US Patent 2005/028 1886 presents in its invention microparticles and nanoparticles of chitosan containing a retinoid. These microparticles and nanoparticles generated by a high viscosity chitosan reduce the irritating effect of retinoids.
- Microencapsulation is defined as the set of technologies that make it possible to obtain the preparation of individualized microparticles, consisting of a coating material containing an active material.
- microcapsules implies entities whose diameter is between 1 and 1000 ⁇ .
- nanocapsules is reserved for capsules whose size is less than one micron.
- the encapsulated material may be in the form of fine particles of split liquid, a liquid, or a gaseous compound.
- the microcapsule makes it possible to preserve the encapsulated substance in the form of a finely divided state, and to release it in the desired conditions.
- Microparticles obtained by microencapsulation can be presented under two different types of morphology:
- Microspheres which are particles consisting of a continuous macromolecular or lipidic network forming a matrix in which the active material is finely dispersed.
- the latter may be in the form of fine solid particles or droplets of solutions.
- Microcapsules which are reservoir particles consisting of a core of liquid or solid active material, surrounded by a continuous solid envelope of encapsulating material.
- the different microencapsulation methods can be classified according to different criteria.
- Richard and Benoit (Microencapsulation, 2000, Engineering Techniques, J2210, 1 - 20) propose four different ways of classifying encapsulation methods:
- the nature of the dispersing medium can also serve as a basis for a classification: it can be liquid (interfacial polycondensation, coacervation), gaseous (spray drying, embedding in a fluidized bed), or in the supercritical state (phase separation)
- the family to which the compound used to obtain the capsule belongs can also make it possible to classify the encapsulation modes: preformed polymers (coacervation), lipids (spray-freezing), or monomers (interfacial polycondensation, polymerization in dispersed medium)
- Nebulization / drying (spray 1 - 200 ⁇ Mechanical microspheres drying / atomization)
- microcapsules While mechanical processes only make it possible to obtain microspheres, the microcapsules are generally obtained by physicochemical or chemical methods. These methods require the use of preformed coating agents such as polymers or monomers which in situ via a specific polymerization mechanism allow formation of the coating material.
- the microcapsules and methods for obtaining them have the advantage over the prior art of not containing volatile organic polymer or solvent, and not to I had temperature cycles.
- any solvent considered unstable, i.e. having a boiling point strictly below 100 ° C.
- any solvent having a boiling point greater than or equal to 100 ° C. will be considered as non-extensible according to the invention.
- the active substances are initially maintained and protected in the microcapsule core for a defined period of time, and in a second time are either progressively released through the membrane according to a certain speed of release, are liberated massively at one time.
- the release is triggered by a method providing specific release.
- the problem that the present invention proposes to solve here is therefore to design a physically and chemically stable composition capable of containing at least one irritant active ingredient, in particular a retinoid, for the treatment of dermatological pathologies, particularly acne, said active ingredient being in solubilized form, the composition according to the invention for improving the tolerance of the active ingredient while having an ease of use and acceptable cosmetics for application to all areas of the body that may be affected by the pathology .
- physical stability according to the invention is meant a composition whose physical properties such as organoleptic characteristics, microcapsule size, pH and viscosity are stable over time and under different temperature conditions, 4 ° C, temperature ambient, 40 ° C.
- chemical stability is meant a composition in which the active ingredient is chemically stable over time and this whatever the temperature condition: 4 ° C., ambient temperature, 40 ° C.
- ambient temperature is meant a temperature of between 15 and 25 ° C.
- the irritant active ingredient preferably the retinoid
- the irritant active ingredient must be in a form lubilized in a stable composition.
- many retinoids often have solubilization difficulties.
- the retinoids according to the invention, and in particular the retinoid preferentially used have a low solubility, thus limiting the incorporation of these into the vehicles mentioned in the preceding patents, and making it difficult to obtain a stable composition.
- the addition of soiling agent in topical formulations often increases the irritating power of the formulations.
- the Applicant has surprisingly discovered that a composition which makes it possible to modify the structure of the The interface between the solubilization medium of the active ingredient and the aqueous phase had an influence on the stability and tolerance of the active ingredient in the composition.
- the active ingredient is solubilized in the oily heart of lipid microcapsules.
- lipid microcapsules a vesicular system of micrometric size that is to say greater than one micrometer consisting of a non-polymeric lipid envelope surrounding a liquid or semi-liquid oily heart at room temperature.
- oily heart, or internal lipid phase is meant the internal phase of lipid microcapsules of micrometric size containing a lipophilic solvent immiscible with water.
- the present invention thus relates to the formulation of lipid microcapsules of micrometric size which can improve the cutaneous tolerance of irritant active principles, especially retinoids, in the treatment of dermatological pathologies, in particular acne.
- the oily heart of the lipid microcapsules of micrometric size of the present invention is lipophilic allowing the solubilization of hydrophobic active ingredients in greater quantity.
- the present invention is a system for implementing lipid microcapsules of micrometric size without the use of organic solvents vo latil often used for the formation of the envelope, thus limiting the risks of toxicity and intolerance and in particular irritation .
- the composition comprises lipid microcapsules of micrometric size and not lipid microspheres.
- lipid microspheres are matrix particles, i.e. the whole of the mass is solid at room temperature.
- the lipid microcapsules of micrometric size according to the invention are particles whose core is composed of one or more fats liquid (s) or semi-liquid (s) at room temperature in which is preferably the solubilized active ingredient, and whose envelope is of a lipidic and nonpolymeric nature.
- lipid microcapsules of micrometric size according to the invention do not require any polymer and therefore no in situ polymerization.
- lipid microcapsules of micrometric size not requiring the use of polymer or organic solvent vo latil, which are capable of comprising at least one irritant active ingredient, preferably a retinoid, in solubilized form.
- lipid microcapsules of micrometric size make it possible to guarantee the stability of at least one irritant active ingredient, preferably a retinoid, in the solubilized form within the lipid microcapsules, as well as a good tolerance of the composition obtained from these microcapsules.
- compositions according to the invention can also promote skin penetration of the active agent, which is useful in the treatment of dermatological conditions, in particular acne.
- the present invention therefore has for first obj and a lipid microcapsule of micrometric size containing an oily internal phase, a non-polymeric envelope obtained from at least one lipid compound selected from amphiphilic lipids.
- the lipid microcapsule of micrometric size according to the invention preferably contains an irritant active ingredient lubilized in the oily internal phase.
- the lipid microcapsules of micrometric size according to the invention preferably consist of:
- At least one irritant active ingredient preferably a retinoid.
- the invention relates in particular to lipid microcapsules of micrometric size made without organic solvents vo latil.
- the present invention also relates to a primary emulsion composed of lipid microcapsules of micrometric size dispersed in an aqueous phase.
- primary emulsion is therefore meant the lipid system composed of micron-sized lipid microcapsules with a solid or semi-solid interface dispersed in an aqueous phase. continuous, said microcapsules containing an oily heart in which is preferably the irritant active ingredient, and in particular the retinoid, which is lubilized, and an envelope obtained from a lipid compound, forming the semi-solid interface or so lide between the oily internal phase and the continuous aqueous phase.
- This primary emulsion is therefore an oil-in-water type emulsion.
- Said primary oil-in-water emulsion according to the invention may be incorporated into a pharmaceutically acceptable vehicle, such as a gel, a solution or an emulsion such as a cream or a lotion.
- a pharmaceutically acceptable vehicle such as a gel, a solution or an emulsion such as a cream or a lotion.
- the present invention therefore also relates to a composition, in particular a pharmaceutical composition, said composition comprising, within a pharmaceutically acceptable vehicle, the primary emulsion according to the invention.
- the present invention therefore relates to a pharmaceutical composition, said composition comprising, within a pharmaceutically acceptable vehicle, the primary emulsion composed of lipid microcapsules of micrometric size preferably consisting of:
- At least one irritant active ingredient preferably a retinoid
- said lipid microcapsules of micrometric size being dispersed in an aqueous phase.
- composition according to the invention is therefore meant the primary emulsion, incorporated in a pharmaceutically acceptable vehicle, such as an excipient or a mixture of excipients which can form a composition in the form of a gel, a solution or an emulsion such as a cream or a lotion that can be sprayable or not.
- a pharmaceutically acceptable vehicle such as an excipient or a mixture of excipients which can form a composition in the form of a gel, a solution or an emulsion such as a cream or a lotion that can be sprayable or not.
- compositions according to the invention have the advantage of being stable physically and chemically.
- Lipid microcapsules of micrometric size according to the present invention means lipid microsystems whose size is preferably between 1 ⁇ and ⁇ ⁇ ⁇ .
- 50% of the lipid microcapsules have at least an average size of between 1 and 80 ⁇ m and preferably between 1 and 50 ⁇ m. In a particularly preferred embodiment, the microcapsules according to the invention have an average size of between 1 and 20 ⁇ .
- the lipid microcapsules of micrometric size are present in the composition according to the invention in an amount of between 0.1 and 30% by weight relative to the total weight of the composition, preferably between 0.5 and 20%, and more particularly between 1 and 30% by weight. and 10%.
- microcapsules each consist of a liquid or semi-liquid core at room temperature, preferably containing the active ingredient, and an envelope obtained from at least one lipid compound.
- the present invention relates to lipid microcapsules of micrometric size containing exclusively phosphatidylcho lines without any other additional lipophilic or hydrophilic co-surfactant.
- the envelope encapsulating the oily liquid or semiliquid heart at room temperature is preferably composed of a rigid material at room temperature, non-polymeric and whose transition temperature or melting is high. To be rigid at room temperature, the transition or melting temperature must be greater than 35 ° C, preferably greater than 40 ° C and ideally greater than 45 ° C.
- the envelope consists of at least one lipid compound of amphiphilic type.
- the envelope consists of a single lipid compound, advantageously chosen from amphiphilic lipids. More preferably, the lipid compound is selected from the family of phospholipids, and more specifically, phosphatidylcho lines or lecithins. Phosphatidylcho lines or lecithins show good compatibility with the skin with a very low irritating potential.
- lecithins there may be mentioned in particular soy or egg lecithins, natural or synthetic or derived.
- the first type of lecithin is phosphatidylcholine (PC).
- lecithin including phosphatidylglycerol, phosphatidylinositol, sphingomyelin and phosphatidylethanolamine.
- lecithins having a transition temperature greater than 35 ° C. mention may be made more particularly of dipalmitoylphosphatidylcholine (DPPC), phosphatidylcholine distearoyl (DSPC), phosphatidylcholine dibehenyl (DBPC), palmitoylstearoyl phosphatidylcholine (PSPC). palmitoyl-behenyl phosphatidylcholine (PSPC), stearoyl-behenyl phosphatidylcholine (SBPC), as well as all saturated lecithins with long chains of fatty acids and their derivatives.
- DPPC dipalmitoylphosphatidylcholine
- DSPC phosphatidylcholine distearoyl
- DBPC phosphatidylcholine dibehenyl
- PSPC palmitoylstearoyl phosphatidylcholine
- SBPC stearoyl-behenyl phosphat
- the lecithins especially used in the present invention are soluble at room temperature, which favors the formation of a semi-solid interface around the liquid or semi-liquid core.
- This formulation allows the encapsulation of the active ingredient solubilized in the oily heart, more particularly the retinoid.
- the lipid microcapsules of micrometric size according to the invention more particularly contain a semi-solid or solid interface between the internal phase and the aqueous continuous phase, thanks to the use as a single lipid compound of a preferably hydrogenated lecithin.
- the hydrogenated lecithin used according to the invention has a high percentage of saturated phosphatidylcholine. By high percentage is meant an amount greater than 85% hydrogenated phosphatidylcho line (or saturated) relative to the total weight of lecithin.
- lecithin preferentially used according to the invention, mention may be made of certain hydrogenated lecithins with a content of hydrogenated phosphatidylcho line greater than 85%, for example Lipoid® grade P 1 00-3, Phospho lipon® grade 90H sold by Lipoid, Epikuron® grade 200 SH marketed by Cargill, or Emulmetik® 950 sold by Lucas Meyer.
- the lecithin used as the sole lipid compound is Phospholipon® 90H for which the content of hydrogenated phosphatidylcho line is greater than 90%>, whose transition temperature is about 54 ° C.
- the lipid compound surrounding the liquid or semiliquid heart as defined above is present in an amount of between 0.01 and 10% by weight, preferably between 0.05 and 5% by weight, and more preferably between 0.1 and 1. % by weight relative to the total weight of the microcapsule.
- the lipid compound, especially hydrogenated lecithin, according to the invention alone allows encapsulation of the retinoid, which prevents the contact of this active agent with the aqueous phase, and thus ensures chemical stability.
- the lipid microcapsule, and in particular the envelope is free of any co-surfactant, in particular lipophilic or hydrophilic co-surfactant.
- Lipid microcapsules of micrometric size are in particular free of organic solvent vo latil.
- lipid microcapsules of micrometric size are free of polymer.
- composition according to the invention therefore preferably comprises, within the microcapsules, at least one active ingredient known to those skilled in the art for presenting an irritating character.
- the irritant active ingredients that can be used preferentially according to the invention are retinoids.
- Retinoids which can be used in the context of the invention include in particular all-trans retinoic acid or tretinoin, 13-cis-retinoic acid or isotretinoin, acitretin, arotinoic acid, retinol, adapalene, tazarotene, retinaldehyde, etretinate and the compounds protected in patent application WO2006 / Such as 3 "-tert-butyl-4 * - (2-hydroxyethoxy) -4" -pyrrolidin-1-y-1 [1, 3 ', 1 "] -terphenyl-4-carboxylic acid; or Trifarotene, the compounds of the patent application FR0512367 including 2-hydroxy-4- [3-hydroxy
- the composition according to the invention preferably comprises between 0.00001 and 1% of at least one retinoid by weight relative to the total weight of the composition, preferably from 0.0001 to 0.5% and, preferably, the composition according to the invention contains from 0.001% to 0.05% of a retinoid by weight relative to the total weight of the composition.
- the composition comprises between 0.001 and 0.05% of Trifarotene, more particularly between 0.003 and 0.03% by weight relative to the total weight of the composition.
- the irritant active ingredient in particular the retinoid, and more particularly the trifarotene, is thus solubilized in the core of the lipid microcapsules of micrometric size according to the invention.
- Said core, or oily internal phase comprises at least one liquid or semi-liquid fatty substance at ambient temperature.
- the composition of the internal phase of the microcapsules is essential for the stability of the active ingredient.
- the oily internal phase must of course be compatible with the asset to be solubilized, and so lubilizing asset when the latter is present in the microcapsules.
- soiling phase of the asset is meant a phase in which the active ingredient is stable and has a solubility strictly greater than 0. 1% by weight, especially at room temperature.
- stability of the active ingredient in the oily phase is meant in the sense of the invention that the active ingredient is chemically stable over time and this whatever the temperature condition: 4 ° C, room temperature, 40 ° C.
- the stability of the active ingredient in the oily phase is evaluated in particular by liquid chromatography coupled to a UV detector (HPLC-UV).
- liquid or semi-liquid fatty substance at ambient temperature means an oily solvent.
- oily solvent means any material immiscible with water of origin, natural, animal or synthetic at room temperature.
- This oily internal phase therefore comprises at least one oily solvent, chosen from triglycerides and oils containing them, mineral oils, fatty acid esters, carboxylic acid esters, polyethoxylated fatty acids, fatty alcohols and esters. corresponding polyethylene glycol ethers, amides or glyco ls.
- the oily solvent constituting the oily internal phase does not comprise fatty acids which are not esterified or polyethoxylated. More particularly, the oily solvent may be a mineral oil, a triglyceride, a fatty acid ester, a carboxylic acid ester, a fatty alcohol, or polyethylene glycol ether.
- mineral oils there may be mentioned, without limitation, paraffin oil.
- oils containing triglycerides include without limitation, the octanoic acid triglycerides or triglycerides of caprylic / capric acids such as those sold by Stéarineries Dubois or those sold under the name Miglyol ® 810, 812 , and 818 by the company Sasol.
- fatty acid esters mention may be made, without limitation, of diisopropyl adipate, such as the commercial product Crodamol® DA sold by Croda or Schercemol DIA Ester® sold by Lubrizol, or cetearyl isononanoate sold under the name Cetiol SN® by BASF.
- diisopropyl adipate such as the commercial product Crodamol® DA sold by Croda or Schercemol DIA Ester® sold by Lubrizol, or cetearyl isononanoate sold under the name Cetiol SN® by BASF.
- alkyl benzoate C 12-15
- Crodamol® AB sold by Croda
- propylene glycol caprylate sold under the name Capryol. 90® by the company Gattefossé.
- fatty alcohols non-limiting mention may be made of octyl dodecanol or octyl dodecanol octanoate.
- ethers of polyethylene glycols mention may be made, without limitation, of the PPG-15 stearyl ether sold under the name Arlamol PS11E-LQ by the company Croda.
- the solvents used in the oily internal phase are alkyl benzoate (C 12-15 ), propylene glycol caprylate or caprylic / capric acid triglycerides.
- the preferred oily internal solvent phase of the active ingredient is diisopropyl adipate or PPG-15-stearyl ether.
- oily solvent (s) adapted according to the irritating active ingredient to be solubilized.
- preferred oily solvents for solubilizing trifarotene are diisopropyl adipate or PPG-stearyl ether.
- the oily internal phase may also contain one or more non-oily co-solvents or other non-organic organic solvents, in particular N-methyl-2-pyrrolidone or dimethylisobsorbide or else dimethylsulfoxide. .
- the internal phase does not require any solvents / cosolvent of alcoholic type to solubilize the active ingredient.
- the blends of solvents selected according to the invention are sufficient to obtain the required solubility and stability of the active ingredient within the microcapsules without resorting to any alcoholic solvent.
- the internal phase may also include one or more liquid or semi-liquid fatty substances at room temperature unsolubilizing asset.
- non-solubilising fatty substance of the active is meant a compound for which the active ingredient, preferably the retinoid, has a solubility of less than or equal to 0. 1%.
- the solvent will be present in an amount of between 50 and 99.997% by weight relative to the total weight of the internal phase; preferably in an amount of between 70 and 99.997% by weight relative to the total weight of the internal phase, preferably between 95 and 99.997%).
- the optional fatty or cosolvent is present in an amount of between 0 and 50% by weight relative to the total weight of the internal phase; preferably in an amount of between 0.1 and 25% by weight relative to the total weight of the internal phase, preferably between 0.5 and 10%.
- the internal phase may also comprise one or more compounds such as, for example, antioxidants or preservatives.
- the invention also relates to a primary emulsion composed of lipid microcapsules of size micrometric dispersed in an aqueous phase as described above.
- the oil-in-water emulsion according to the invention comprises lipid microcapsules of micrometric size as described above, preferably comprising an irritant active ingredient solubilized within the oily heart.
- the oily internal phase of the microcapsules is present in an amount of between 0.1 and 50% by weight relative to the total weight of the primary emulsion, preferably in an amount of between 0.5 and 35. % by weight relative to the total weight of the primary emulsion.
- the ratio between the internal oily phase and the amount of hydrogenated lecithin is between 5 and 10 to 1.
- this ratio in the emulsion is between 6 to 8 for 1 and preferably 7 to 1.
- the ratio between the water and the internal oily phase is between 1.25 to 5 to 1.
- this ratio between the water and the internal oily phase is between 2 to 4 to 1 and preferably 2 to 3 to 1.
- the microcapsules are dispersed in an aqueous phase.
- the continuous aqueous phase comprises water.
- This water can be demineralised water, floral water, or natural thermal or mineral water,
- the water may be present in a content of between 55 and 95% by weight relative to the total weight of the composition, preferably between 60 and 95% by weight.
- the present invention therefore has for object and a composition, in particular a pharmaceutical composition, said composition comprising the primary emulsion containing the lipid microcapsules of micrometric size defined above in the text of the present invention in a pharmaceutically acceptable vehicle, such as a gel. a solution or emulsion such as a cream or lotion.
- a pharmaceutically acceptable vehicle such as a gel.
- a solution or emulsion such as a cream or lotion.
- the primary emulsion is dispersed in an aqueous phase which comprises at least one gelling agent.
- This gelling agent may be a cellulose derivative chosen from semi-synthetic cellulosic gelling agents.
- the gelling agent may also be chosen from natural gums, in particular xanthan gum (known for example under the name Stiaxane and sold by Cargill), starch and its derivatives, and crosslinked polyacrylic acid polymers such as carbomers such as Carbopol 980, Carbopol Ultrez 10 and among their alkylated derivatives such as copolymers of acrylates / C 10-30 alkyl acrylates such as Carbopol ETD2020, Pemulen TR I, Pemulen TR2, carboxyvinyl polymers, polyvinyl pyrrolidones and their derivatives, polyvinyl alcohols.
- natural gums in particular xanthan gum (known for example under the name Stiaxane and sold by Cargill), starch and its derivatives, and crosslinked polyacrylic acid polymers such as carbomers such as Carbopol 980, Carbopol Ultrez 10 and among their alkylated derivatives such as copolymers of acrylates / C 10-30
- the gelling agent may also be chosen from emulsifying polymers such as Sepigel 305 consisting of a polyacrylamide / isoparaffin C 13 -C 14 / laureth-7 mixture, or Simulgel® 600PHA or Sepineo® P600, namely sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80. These two products being marketed by Seppic.
- emulsifying polymers such as Sepigel 305 consisting of a polyacrylamide / isoparaffin C 13 -C 14 / laureth-7 mixture, or Simulgel® 600PHA or Sepineo® P600, namely sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80.
- the pharmaceutically acceptable carrier is a solution
- the primary emulsion is dispersed in a vehicle composed of an aqueous phase.
- aqueous phase which constitutes the pharmaceutically acceptable vehicle is meant any aqueous phase as defined above in the present invention.
- the pharmaceutically acceptable vehicle is a cream or a lotion
- the primary emulsion is dispersed in a vehicle composed of an aqueous phase and a fatty phase comprising or not at least one surfactant or emulsifier.
- the composition according to the invention therefore comprises a fatty phase.
- This fatty phase may include, for example, vegetable, mineral, animal or synthetic oils, silicone oils, and mixtures thereof.
- the emulsion is in the form of an oil-in-water (O / W) emulsion.
- This emulsion may not comprise or comprise at least one emulsifying agent.
- the cream or the lotion according to the invention also comprises an aqueous phase.
- aqueous phase which constitutes the pharmaceutically acceptable vehicle, alone or within an emulsion, is meant any aqueous phase as defined above in the present invention.
- composition according to the invention may also contain, within the primary emulsion or the pharmaceutically acceptable vehicle, additives or combinations of additives, such as:
- UV-A and UV-B filters are UV-A and UV-B filters
- ingredients of the pharmaceutically acceptable vehicle and in particular, the aqueous phases, the fatty phases, the emulsifiers and the optional compound (s) to be added to these compositions, in such a way that the advantageous properties intrinsically attached to the present invention are not or substantially unaffected by the choice of ingredients.
- composition according to the invention therefore comprises, in a pharmaceutically acceptable vehicle, by weight relative to the total weight of the composition, microcapsules composed: a) a non-polymeric envelope obtained from 0.01 to 10% of lipid compound chosen from amphiphilic lipids;
- composition according to the invention thus preferably comprises, in a pharmaceutically acceptable vehicle, by weight relative to the total weight of the composition, microcapsules composed of: a) 0.1% to 5% of lipid compound chosen from amphiphilic lipids, preferably hydrogenated lecithin;
- liquid or semi-liquid fat at room temperature preferably fatty acid esters or polyethylene glycol ethers
- c) between 0.00001 and 0, 1%> of at least one retinoid, preferably Trifarotene.
- the composition may comprise from 1 to 20% by weight of liquid or semi-liquid fatty substance at ambient temperature, preferably fatty acid esters or polyethylene glycol ethers.
- the composition comprises, in a pharmaceutically acceptable vehicle, by weight relative to the total weight of the composition:
- composition that can be used according to the invention is intended for the treatment of the skin and can be administered topically, parenterally or orally.
- the pharmaceutical composition may be in liquid or pasty form, and more particularly in the form of capsules, dragees, or syrups.
- the composition may be in the form of suspensions for infusion or for injection.
- the composition is in a form suitable for topical administration.
- Topical administration we mean an application on the skin, the mucous membranes, the hair or the scalp.
- the composition may be in liquid or pasty form, and more particularly in the form of creams, milks, ointments, soaked swabs, syndets, wipes, gels, sprays, foams, lotions, sticks, shampoos, or washing bases.
- the subject of the invention is also a process for the preparation of the compositions according to the invention.
- the object of the invention is the process for the preparation of compositions comprising at least one retinoid, preferably Trifarotene.
- the process according to the invention does not involve phase inversion phenomena characterized by a Phase Inversion Temperature (TIP) (used in particular in Patents FR 2 805 761 and FR 2 840 53 1), and therefore does not require a cycle (s) of rise and fall in temperature.
- TIP Phase Inversion Temperature
- the process according to the invention does not use a high pressure homogenizer (HHP) and therefore does not require a prehomogenization step.
- HHP high pressure homogenizer
- the process according to the invention therefore has the advantage of not having successive heating and cooling cycles, of not using organic solvents, polymer, of not requiring a gelling step. of the emulsion and no prehomogenization step.
- the process as presented according to the invention and proposed for producing lipid microcapsules of micrometric size as described above uses equipment allowing emulsification at high shear rate.
- rotor / stator mixers such as a Polytron (Kinematica) or the Magic Lab (Ika).
- sonication can be used with eg a Branson type probe.
- the method consists of producing a primary emulsion, which is then diluted in a pharmaceutically acceptable vehicle.
- This primary emulsion makes it possible to vary the mode of introduction of hydrogenated lecithin which can be introduced completely into the oily phase (100% oily phase) or into the aqueous phase (100% aqueous phase) or introduced in different ratios, for example a 50/50 ratio in the oily phase and in the aqueous phase.
- production of the primary emulsion comprises 3 steps:
- the preparation of the aqueous phase and the oily phase may be dependent on the choice of the dispersion mode of the hydrogenated lecithin:
- the lipid compound preferably hydrogenated lecithin
- the lipid compound used is dispersed throughout the aqueous phase heated to about 75 ° C, using a high shear rotor / stator mixer such as Ultra Turrax (Ika), Polytron (Kinematica) or Magic Lab (Ika), with stirring between 5,000 and 10,000 rpm, for a defined time period will not exceed 30 minutes.
- a preservative and an antioxidant can be added at this stage.
- the active ingredient in a suitable container and using a magnetic bar, is solubilized in the internal oily phase heated to about 75 ° C., comprising, inter alia, the oil which solubilizes the active ingredient.
- a preservative and an antioxidant can be added to this phase after solubilization of the active ingredient.
- all of the aqueous phase is heated to 75 ° C. A preservative and an antioxidant can be added at this stage.
- the active ingredient if present, is solubilized in the internal oily phase heated to about 75 ° C., comprising, inter alia, the oil which solubilizes the active ingredient.
- a preservative and an antioxidant may be added at this stage after lubilization of the active ingredient.
- the lipid compound, preferably hydrogenated lecithin, used is dispersed in this oily phase always at about 75 ° C. using a high shear rotor / stator mixer such as an Ultra Turrax (Ika), or a Polytron (Kinematica) with stirring between 5,000 to 10,000 rpm, for a defined time that will not exceed 30 minutes.
- a high shear rotor / stator mixer such as an Ultra Turrax (Ika), or a Polytron (Kinematica) with stirring between 5,000 to 10,000 rpm, for a defined time that will not exceed 30 minutes.
- all of the aqueous phase is heated to 75 ° C.
- About half of the lipid compound, preferably hydrogenated lecithin, used is dispersed in this aqueous phase still heated to about 75 ° C., using a high shear rotor / stator mixer such as a Ultra Turrax (Ika), a Polytron (Kinematica), or the Magic Lab (Ika) with stirring between 5,000 to 10,000 rpm, for a defined time that will not exceed 30 minutes.
- a preservative and an antioxidant can be added at this stage.
- the active ingredient in a suitable container and using a magnetic bar, is solubilized in the internal oily phase heated to about 75 ° C., comprising, inter alia, the oil which solubilizes the active ingredient.
- the other part of the lipid compound preferably hydrogenated lecithin, is dispersed in this oily phase still heated to about 75 ° C., using a high shear rotor / stator mixer such as an Ultra Turrax (Ika) or a Polytron (Kinematica), with stirring between 5,000 to 10,000 rpm, for a defined time that will not exceed 30 minutes.
- a preservative and an antioxidant may be added at this stage after lubilization of the active ingredient.
- the aqueous and oily phases are mixed by incorporation of the oily phase into the aqueous phase.
- the operating mode is dependent on the type of device used. Three types of apparatus are preferentially used to effect the mixing of the two phases resulting in the primary emulsion according to the invention: the method with Polytron, the method with Magic Lab, the method with sonication probe. According to the different types of agitators, the emulsion is produced as described: ⁇ Process with Polytron under temperature regulation at
- lipid compound preferably hydrogenated lecithin
- the primary emulsion obtained above is then introduced into a pharmaceutically acceptable vehicle previously produced, of the solution, cream, lotion and gel type.
- a pharmaceutically acceptable vehicle previously produced, of the solution, cream, lotion and gel type.
- the gelling step is carried out instantaneously at the end of the production of the primary emulsion:
- Stirring can be generated by using a light deflocculator attached to an IKA or Rayneri type stirring motor.
- a gentle stirring corresponds to a speed which makes it possible to obtain a homogeneous gel after 20 minutes without generating excessive aeration of the formulation, for example a speed around 200 rpm.
- a quantity of primary emulsion can be removed and then diluted in one part of water. This mixture is then thickened by the addition of a gelling agent.
- compositions according to the invention comprises the following steps:
- step (e) stirring mixture of the oily and aqueous phases obtained at the end of step (d);
- the Applicant has surprisingly discovered that the mode of introduction of the lipid compound, and more particularly of hydrogenated lecithin, had an influence on the stability over time of the microcapsules dispersed within the pharmaceutically acceptable vehicle.
- the microcapsules and processes making it possible to obtain them as described above have the advantage over the prior art of using processes that are alternative to processes using rise and fall cycles. in temperature, or high pressure homogenizers.
- the lipid compound is introduced either at 100% in the oily phase or at 100% in the aqueous phase depending on the nature of the oily core chosen to solubilize the active ingredient, in particular Trifarotene, within the microcapsule. .
- the hydrogenated lecithin is introduced either at 100%) in the oily phase or at 100% in the aqueous phase depending on the nature of the oily core chosen to solubilize the Trifarotene within the microcapsule.
- the preferred apparatus is the Magic Lab.
- the preferred mode of dispersion of the lipid compound, and more preferably of hydrogenated lecithin is 100% in the fatty phase, in the case of the use of oily solvents such as triglycerides and acid esters such as diisopropyl adipate.
- the preferred mode of dispersion of the lipid compound, and more preferably of hydrogenated lecithin is 100% in the aqueous phase, especially in the case of the use of oily solvents of the following type.
- polyethylene glycol ethers such as, for example, PPG-15-stearyl ether.
- oily solvent (s) adapted according to the irritant active ingredient to be solubilized when the latter is present and thus the mo of dispersion of the lipid compound.
- the process for preparing a composition according to the invention comprises the following steps:
- the process for preparing a composition according to the invention comprises the following steps:
- these preparation processes are carried out in the absence of organic solvent vo latil.
- composition according to the invention is usable as a medicament.
- the subject of the invention is also the composition as defined above for its use for treating dermatological conditions, in particular human affections, as defined hereinafter.
- dermatological disorders related to a keratinization disorder relating to differentiation and cell proliferation in particular to treat vulgar, comedonal, polymorphic, rosacea acne, nodulocystic acne, conglobata, senile acnes, secondary acnes such as acne soothing, medicated or professional;
- disorders of keratinization including ichthyosis, ichthyosiform states, lamellar ichthyosis, Darrier's disease, palmoplantar keratoderma, leukoplakia, pityriasis rubra pilaire and leucoplasiform states, cutaneous or mucosal lichen (oral) ;
- dermatological disorders such as immune dermatoses such as lupus erythematosus, oily immune diseases and collagen diseases, such as scleroderma;
- disorders of pigmentation such as hyperpigmentation, melasma, hypopigmentation or vitiligo
- cancerous or precancerous, cutaneous or mucosal states such as actinic keratoses, Bowen's disease, in-situ carcinomas, keratoacanthoma and skin cancers such as basal cell carcinoma (BCC), spinal cell carcinoma (SCC) and cutaneous tek lymphoma than T-cell lymphoma.
- the invention relates to the composition for use in the treatment of acne, ichthyos, ichthyosiform states, palmoplantar hyperkeratosis or psoriasis.
- the invention relates to the composition according to the invention for its use as a medicament in the treatment of dermatological conditions, especially human, as previously defined.
- the composition according to the invention will comprise trifarotene for treating acne, ichthyos, ichthyosiform states, palmoplantar hyperkeratosis or psoriasis.
- the invention relates to the use of the composition according to the invention for the treatment of dermatological conditions, in particular human affections, as previously defined.
- the composition is used for the treatment of acne, ichthyos, ichthyosiform states, palmoplantar hyperkeratosis or psoriasis.
- compositions comprising a retinoid
- the objective of this pre-formulation study is to identify oily, solubilizing phases in which Trifarotene has a solubility of greater than 0.1% w / w and in which it is chemically stable.
- the stability of the asset was evaluated by liquid chromatography coupled to a UV detector (HPLC-UV).
- propylene glycol monocaprylate propylene glycol mono laurate, diisopropyl adipate, PPG-stearyl ether and macrogolate are suitable for solubilizing the Trifarotene.
- compositions of the primary emulsions A to G containing such microcapsules are therefore as follows:
- Methyl paraben 1.12 0.56 0.28 1.12 1.12 1.12
- lipid microcapsules have been prepared and contain in the oily heart the trifarotene solubilized in an oil or a mixture of oils. so lvantes.
- the primary emulsions were preferably made using Trifarotene as the solvent, either diisopropyl adipate or PPG-stearyl ether.
- compositions of the primary emulsions A 1 and B 1 are therefore as follows:
- the macroscopic observation is carried out on the formulation in its original packaging.
- the primary emulsions A1 obtained have the same appearance.
- the primary emulsions A 1 obtained have the same appearance as the dispersion mode of the hydrogenated lecithin either in 100% in aqueous phase or 100% in oily phase.
- EXAMPLE 5 Characterization of the Granulometric Distribution of the Primary Emulsion of the Composition Al of Example 3, Containing the Trifarotene, Obtained with the Magic Lab
- the primary emulsions Al were carried out with the Magic Lab in dispersing the hydrogenated lecithin either 100% in the aqueous phase or 100% in the fatty phase.
- the particle size distribution of the lipid microcapsules within the primary emulsion Al was determined using a Mastersizer 3000 type granulometer (Malvern). The composition is diluted before analysis (1 g in 9 g of purified water). On the same preparation, five successive measurements are made.
- the particle size distribution is presented by expressing D 10 , D 50 and D 90:
- - D50 is the particle size below which 50%> of the sample is located
- - D90 is the particle size below which 90%> of the sample is located.
- the data show that the lipid microcapsules obtained have a size greater than one micrometer.
- EXAMPLE 6 Examples of Gel-type Compositions According to the Invention Made from the Placebo Primary Emulsions of Compositions A to E of Example 2
- various amounts of Primary emulsions prepared according to Example 2 were removed and diluted in a gel base.
- IIG gel 100 gram gel
- composition B of Example 2 35.855 grams of the primary placebo emulsion of composition B of Example 2 are added to the formulation.
- gel-type compositions obtained according to the invention are therefore the following:
- compositions (% m / m)
- compositions (% m / m)
- compositions of gel type IG 'to IVG' according to the invention, a corresponding quantity of primary emulsion prepared according to Example 3 was taken and diluted in a gel base.
- gel-type compositions obtained according to the invention are therefore the following:
- compositions A, D and E respectively of Example 2 are added to the formulation.
- cream compositions Ia to IIIc obtained according to the invention are therefore the following:
- compositions (% m / m)
- Example 9 Examples of cream-type formulations compositions according to the invention made from primary emulsions Al and Bl of Example 3 containing Trifarotene.
- cream-type compositions obtained according to the invention are therefore the following:
- EXAMPLE 10 Characterization of the IG Composition of Example 7 of the Gel Type According to the Invention, Made from Primary Emulsions Containing Trifarotene, Obtained by the Three Methods.
- the hydrogenated lecithin is dispersed at 100% in the fatty phase.
- the measurement of the viscosity is carried out using a Brookfield RVDVII + type apparatus. The measurements are carried out after 1 min, in the original packaging.
- the gels have the same characteristics.
- the measurement of the viscosity is carried out using a Brookfield RVDVII + type apparatus. The measurements are carried out after 1 min, in the original packaging.
- the gels containing the microcapsules are stable for 3 months at room temperature and at 40 ° C.
- Example 12 Characterization of the compositions le. IVc, and VG of Example 6 of the gel type according to the invention, made from primary emulsions placedbo, obtained according to two different modes of introduction of hydrogenated lecithin.
- the equipment which has been used for producing the primary emulsions is the Magic Lab.
- gel No. 1 corresponds to the IG, IVG and VG gels of Example 6 in which the lecithin was dispersed at 100% in the aqueous phase.
- gel No. 2 corresponds to the IG, IVG and VG gels of Example 6 in which the lecithin was dispersed at 100% in the oily phase.
- the dispersion mode of the hydrogenated lecithin may generate different characteristics.
- FIGS. 1 and 2 represent the images obtained under the microscope (objective 40 and ⁇ 252 magnification) of the microcapsules in No. 1 and No. 2 gels, respectively, which were made from the primary emulsion D containing the PPG-15 stearyl ether as an oil (gels corresponding to the IVG gel in Example 6).
- FIGS. 3 and 4 represent the images obtained under a microscope (objective 40 and x252 magnification) of the microcapsules in gels Nos. 1 and 2, respectively, which were produced from the primary emulsion E containing triglycerides of capric acids / caprylic as oil (gels corresponding to the VG gel in Example 6). Microscopic observation of the microcapsules reveals that the microcapsules within the No. 1 and No. 2 gels do not differ in terms of polydispersity and shape.
- the dispersion mode of hydrogenated lecithin does not affect the physical appearance of the microcapsules.
- a mode of dispersion of hydrogenated lecithin may be preferred for each type of oil.
- the preferred mode of dispersion of hydrogenated lecithin is 100% in the fatty phase.
- the preferred dispersion mode of hydrogenated lecithin is 100% in the aqueous phase.
- Example 6 Capric / caprylic acid triglycerides
- Figures 5 and 6 show microscope images (objective 40 and magnification 252) and microcapsules in No. 1 and No. 2 gels, which were made from IVG compositions containing PPG-stearyl ether in as oil after 6 months of storage at a temperature of 40 ° C.
- the microcapsules are more regular and more uniform in size (FIG. 5).
- Figures 7 and 8 show the images obtained under a microscope (objective 40 and magnification 252) microcapsules containing capric / caprylic acid triglycerides after 6 months of storage at a temperature of 40 ° C.
- microcapsules are generally uniform and uniform in size, after 6 months of stability at 40 ° C. (FIGS. 7 and 8).
- the equipment that was used to make the primary emulsions is the Magic Lab.
- the preferred dispersion mode for hydrogenated lecithin with diisopropyl adipate is 100% in the fat phase.
- the preferred dispersion mode for lecithin hydrogenated with PPG-stearyl ether is 100% in the aqueous phase.
- Gel No. IG is represented in FIG. 9. It has been characterized by scanning electron microscopy after cryo-fracture according to the following protocol:
- the preferred dispersion mode for hydrogenated lecithin with diisopropyl adipate is 100% in the fat phase.
- Example 17 Stability Study of the Gels of Example 16
- Composition IXG (Diisopropyl Gel No. 2 (Carbomer)
- the equipment that was used to produce the primary emulsions is the Magic Lab.
- the preferred dispersion mode for hydrogenated lecithin with diisopropyl adipate is the 100% dispersion in the fat phase.
- the preferred dispersion mode for lecithin hydrogenated with PPG-stearyl ether is the 100% dispersion in the aqueous phase.
- composition IIIG '
- oil PPG 1 stearyl ether
- the preferred dispersion mode for hydrogenated lecithin with diisopropyl adipate is the 100% dispersion in the oily phase.
- the gel No. 1 corresponds to the gel IIG in which the diisopropyl adipate was dispersed in the fatty phase and to the gel III G in which the diisopropyl adipate was dispersed in the fatty phase.
- Example 21 Stability Study of the Gels of Example 20
- the equipment that was used to make the primary emulsions is the Magic Lab.
- the preferred dispersion mode for hydrogenated lecithin with diisopropyl adipate is the 100% dispersion in the fat phase.
- the preferred dispersion mode for lecithin hydrogenated with PPG-stearyl ether is the 100% dispersion in the aqueous phase.
- Example 23 Stability study of the creams of Example 20
- Composition Ic (Diisopropyl adipate),
- Example 24 Study of in vitro cutaneous penetration of the encapsulated Trifarotene in microcapsules according to Example 14 dispersed in a gel Conditions of the study:
- Trifarotene is quantified in the different compartments of the skin: stratum corneum, epidermis, dermis and liquid receptor according to a validated bioanalysis method carried out by tandem mass spectrometry by positive electrospray ionization, and using a Xevo device (Waters).
- the limit of quantification for Trifarotene is I ng / mL.
- the LC / MS / MS conditions developed detected up to 0.1% of the dose applied in each of the compartments (unabsorbed dose, stratum, epidermis, dermis and receptor fluid).
- Example 14 (100% fatty phase dispersion) containing 100 ⁇ g / g Trifarotene Gel No.
- the formula of the reference gel is as follows Ingredients / Names INCI Composition (% m / m)
- Hydroxypropylcellulo is 2.00
- Results The results presented in Figure 10 show the amount penetrated as a percentage of the applied dose (% applied dose) according to the different skin compartments.
- Trifarotene The total penetration of Trifarotene from the different gels containing the encapsulated Trifarotene is lower than the reference in which the Trifarotene is solubilized but not encapsulated:
- the amount penetrated is of the order of 4.86%
- the amount penetrated varies from 3.17 to 3.25%
- Trifarotene The epidermal and dermis tissue distribution of Trifarotene is similar whether encapsulated or not.
- Trifarotene is similar regardless of the mode of dispersion of hydrogenated phosphatidylcholine. Also, the encapsulation of Trifarotene decreases the amount penetrated at the level of the stratum corneum without modifying the tissue distribution of the latter.
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FR1362117 | 2013-12-04 | ||
PCT/EP2014/076658 WO2015082659A1 (fr) | 2013-12-04 | 2014-12-04 | Microcapsules lipidiques comprenant de preference un retinoide et composition les contenant, leur procede de preparation et leur utilisation en dermatologie |
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EP14808978.2A Pending EP3076945A1 (fr) | 2013-12-04 | 2014-12-04 | Microcapsules lipidiques comprenant de preference un retinoide et composition les contenant, leur procede de preparation et leur utilisation en dermatologie |
EP14806333.2A Pending EP3076944A1 (fr) | 2013-12-04 | 2014-12-04 | Microcapsules lipidiques comprenant de preference un actif lipophile et composition les contenant, leur procede de preparation et leur utilisation en dermatologie et en cosmetique |
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WO2015082659A1 (fr) | 2013-12-04 | 2015-06-11 | Galderma Research & Development | Microcapsules lipidiques comprenant de preference un retinoide et composition les contenant, leur procede de preparation et leur utilisation en dermatologie |
AU2015238224B2 (en) | 2014-03-28 | 2020-05-14 | Galderma Research & Development | Non-rinse chemical mousse containing benzoyl peroxide |
EP3302421B1 (fr) | 2015-05-29 | 2021-07-07 | Galderma Research & Development | Compositions comprenant au moins un principe actif disperse et des microcapsules lipidiques |
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- 2014-12-04 CN CN202110898887.0A patent/CN113559083A/zh active Pending
- 2014-12-04 EP EP14808978.2A patent/EP3076945A1/fr active Pending
- 2014-12-04 AU AU2014359194A patent/AU2014359194B2/en not_active Ceased
- 2014-12-04 US US15/101,721 patent/US10772807B2/en active Active
- 2014-12-04 WO PCT/EP2014/076659 patent/WO2015082660A1/fr active Application Filing
- 2014-12-04 KR KR1020167017931A patent/KR20160093069A/ko not_active Application Discontinuation
- 2014-12-04 EP EP14806333.2A patent/EP3076944A1/fr active Pending
- 2014-12-04 US US15/101,331 patent/US10857080B2/en active Active
- 2014-12-04 MX MX2016006896A patent/MX2016006896A/es unknown
- 2014-12-04 KR KR1020167017802A patent/KR20160093065A/ko not_active Application Discontinuation
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- 2014-12-04 JP JP2016536542A patent/JP2016539150A/ja active Pending
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US20160303005A1 (en) | 2016-10-20 |
KR20160093065A (ko) | 2016-08-05 |
AU2014359194A1 (en) | 2016-07-14 |
KR20160093069A (ko) | 2016-08-05 |
AU2014359195B2 (en) | 2020-02-27 |
WO2015082660A1 (fr) | 2015-06-11 |
US10772807B2 (en) | 2020-09-15 |
JP2016539161A (ja) | 2016-12-15 |
CN113559083A (zh) | 2021-10-29 |
CN105939704A (zh) | 2016-09-14 |
AU2014359194B2 (en) | 2020-02-06 |
WO2015082659A1 (fr) | 2015-06-11 |
JP2016539150A (ja) | 2016-12-15 |
EP3076944A1 (fr) | 2016-10-12 |
AU2014359195A1 (en) | 2016-06-23 |
US20160310439A1 (en) | 2016-10-27 |
US10857080B2 (en) | 2020-12-08 |
MX2016007067A (es) | 2016-08-11 |
MX2016006896A (es) | 2016-08-17 |
CN105934239A (zh) | 2016-09-07 |
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