EP1915133A1 - Oil-in-water-type emulsion for topical application in dermatology - Google Patents

Oil-in-water-type emulsion for topical application in dermatology

Info

Publication number
EP1915133A1
EP1915133A1 EP06794313A EP06794313A EP1915133A1 EP 1915133 A1 EP1915133 A1 EP 1915133A1 EP 06794313 A EP06794313 A EP 06794313A EP 06794313 A EP06794313 A EP 06794313A EP 1915133 A1 EP1915133 A1 EP 1915133A1
Authority
EP
European Patent Office
Prior art keywords
emulsion according
weight
water
emulsion
therapeutic agent
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.)
Withdrawn
Application number
EP06794313A
Other languages
German (de)
French (fr)
Inventor
Sandrine Segura-Orsoni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galderma SA
Original Assignee
Galderma SA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Galderma SA filed Critical Galderma SA
Publication of EP1915133A1 publication Critical patent/EP1915133A1/en
Withdrawn legal-status Critical Current

Links

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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/113—Multiple emulsions, e.g. oil-in-water-in-oil
    • 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
    • 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
    • A61P17/06—Antipsoriatics

Definitions

  • Oil-in-water emulsion for topical application in dermatology Oil-in-water emulsion for topical application in dermatology
  • the present invention relates to a novel topical composition in the form of an oil-in-water emulsion, with a high proportion of oily phase in the internal phase of the emulsion, combining the occlusive and emollient properties of an ointment without having the disadvantages of greasy feel, while promoting the therapeutic properties of the biologically active agent present in said composition.
  • the use of an ointment is widely preferred.
  • the ointment is mainly composed of fatty substances that bring emollience to the skin and limit desquamation.
  • this dosage form has the disadvantage, by its nature, to have a greasy and sticky touch, resulting in discomfort for the patient's everyday life (unpleasant sensations, greasy spots on clothes, etc.).
  • these ointments are based on a high percentage of petrolatum.
  • compositions for topical application to the skin in which the fatty phase represents from 60% to 70% by weight.
  • aqueous continuous phase emulsions which offer the advantage of a non-greasy touch, a great ease of spreading, etc.
  • the emollient power of such emulsions is very often insufficient or even unsatisfactory.
  • compositions having both the benefits of ointments (occlusivity, emollience) and emulsions in aqueous continuous phase (non-greasy feel, cosmetically acceptable, ease of spreading, no residues), while avoiding disadvantages related to these two types of formulation.
  • compositions should promote the therapeutic properties of the biologically active agent, to ensure its effectiveness in this new dosage form.
  • these compositions should have bioequivalence in terms of vasoconstriction with major products on the market, especially for topical compositions containing corticosteroids.
  • the inventors have now discovered a new emulsion of oil-in-water type, containing a very high proportion of fat phase, corresponding to the proportions generally encountered in water-in-oil type emulsions.
  • This new emulsion also called lipocreme, could be obtained using an oil-in-water type nonionic emulsifier system combined with one or more propenetrating agents.
  • the aqueous continuous phase emulsion according to the invention has the advantage of a non-greasy feel while providing satisfactory emollient power brought by the high percentage of fat phase.
  • this new formulation has a therapeutic activity equivalent to that expected in the case of ointments with a high concentration of petrolatum.
  • the present invention relates first of all to an oil-in-water type emulsion containing at least one therapeutic agent for topical application and further comprising: a) from 25% to 60% by weight of a fatty phase; b) from 1% to 15% by weight of a nonionic emulsifier system; c) from 1% to 30% by weight of at least one propenetrating agent; and d) from 5% to 50% by weight of water.
  • the emulsion according to the present invention comprises a quantity of fat phase of between 35% and 50% by weight.
  • fatty phase is understood to mean one or more compounds chosen from emollients, waxes and fatty alcohols, alone or as mixtures of two or more of them.
  • the emollients will advantageously be the emollients commonly used for the formulations referred to in the present invention and well known to those skilled in the art.
  • vegetable oils such as cottonseed oil, or almond oil
  • esters such as isopropyl palmitate, and isopropyl myristate
  • mineral oils such as light mineral oils, volatile or non-volatile silicone oils, for example dimethicone and cyclomethicone
  • petrolatum such as light mineral oils, volatile or non-volatile silicone oils, for example dimethicone and cyclomethicone.
  • the waxes which can also be used as constituents of the emulsion fatty phase according to the present invention are the waxes commonly used by those skilled in the art in this field, among which, for example, beeswax can be mentioned, carnauba wax, ozokerite, paraffin and dimethiconol behenate.
  • the fatty phase may contain one or more fatty alcohols known to those skilled in the art, and as such, there may be mentioned in particular, and not limited to, cetyl alcohol and stearyl alcohol.
  • the fatty phase will preferably contain one or more of the following ingredients: isopropyl palmitate, a mineral oil, petrolatum, dimethicone.
  • the fatty phase is emulsified by means of a nonionic emulsifying system.
  • HLB hydrophilic-lipophilic balance
  • ionic anionic, cationic, amphoteric
  • nonionic Nonionic surfactants are surfactants that do not dissociate into ions in water and are therefore insensitive to pH changes.
  • Nonionic surfactants are particularly well suited for the preparation of the oil-in-water type emulsion, object of the present invention.
  • the emulsifying system, component of the emulsion of the invention comprises at least one nonionic surfactant, hydrophilic predominant fraction, that is to say having a high HLB, greater than about 10.
  • said high HLB nonionic surfactants have an HLB between 10 and 18.
  • low HLB nonionic surfactants examples include sorbitan esters, such as sorbitan monostearate (sold as Span 60 by Unichema), glycerol esters (sold under the name Cutina GMSVPH by Cognis). ) such as glycerol monostearate (Cutina GMS from Cognis), low HLB sucrose esters such as sucrose distearate.
  • said nonionic surfactants exhibiting low HLB have an HLB of less than 10.
  • the nonionic surfactants may be used alone or in a mixture of two or more of them to form the emulsifying system comprising the emulsion of the invention.
  • one or more pairs of "high HLB nonionic surfactant” / "low HLB nonionic surfactant” will be used as the emulsifying system. It may in particular be a nonionic emulsifying system comprising at least one nonionic surfactant having an HLB greater than about 10 and at least one nonionic surfactant having an HLB of less than about 10.
  • the emulsifying system is composed of the glycerol monostearate / ceteareth 20 surfactant couple.
  • the ratio of each of the two surfactants forming the aforementioned pair is most often determined by the calculation of the required HLB of the fat phase used.
  • the search for the optimal emulsification of a fat or a mixture of fat passes through the preliminary determination of its required HLB. Indeed, each fat has a defined required HLB. We can not operate in all cases with the same emulsifier.
  • the HLB required by the fat phase corresponds to the HLB value of the emulsifier or the pair of emulsifiers that will provide the most stable emulsion with the fatty substances considered.
  • the emulsion of the present invention comprises one or more propenetrating agents in preferential concentrations ranging from 1 to 30%, preferably from 5% to 25%, and more preferably ranging from 15%. at 20% by weight relative to the total weight of the composition.
  • the propenetrating agents must generally be non-solubilizing therapeutic agents at the percentage used, not cause harmful exothermic reactions for the various components, help the good dispersion of said therapeutic agents and have anti-foam properties.
  • the pro-penetrating agents are preferably used, without this list being limiting, of compounds selected from those known to those skilled in the art, such as propylene glycol, dipropylene glycol, Transcutol ® (ethoxydiglycol), propylene glycol dipelargonate glycol, lauroglycol, urea, acetone, oleic acid.
  • Propenetrating agents may be well understood in mixtures of two or more of them.
  • the propenetrating agent is chosen from propylene glycol, dipropylene glycol and propylene glycol dipelargonate. More preferably, the propenetrating agent is propylene glycol.
  • propenetrating agent will depend on the nature of the therapeutic agent included in the emulsion of the invention.
  • the aqueous phase of the emulsion according to the invention comprises water, purified or not, demineralized or not, and in particular a floral water such as cornflower water, or a natural thermal or mineral water, for example chosen among the water of Vittel, the waters of the Vichy basin, the water of Uriage, the water of the Roche-Posay, the water of the Bourboule, the water of Enghien-les-Bains, the water of Saint Gervais-les-Bains, the water of Neris-Bains, the water of Allevard-les-Bains, the water of Digne, the water of Maizines, the water of Neyrac-les- Baths, the water of Lons-le-Saunier, the Eaux Bonnes, the water of Rochefort, the water of Saint Christau, the water of the Fumades and the water of Tercis-les-Bains, the water of Avène or the water of Aix les Bains.
  • a floral water such as cornflower water
  • the emulsion according to the present invention comprises a substantial amount of water, of between 5% and 50%, advantageously about 30% by weight. emulsion.
  • the oil-in-water emulsion of the present invention is particularly suitable for the treatment and / or prevention of skin diseases.
  • the therapeutic agent included in said emulsion will therefore preferably be a therapeutically active compound in the treatment and / or prevention of this type of disease.
  • the emulsions of the present invention have proved particularly effective for the topical application to the skin of therapeutic agents of the class of corticosteroids, already known and marketed.
  • the therapeutic agents of the corticosteroid class will be chosen from clobetasol 17-propionate, desonide, betamethasone, betamethasone acetate, betamethasone valerate, betamethasone dipropionate and dipropionate monohydrate.
  • betamethasone the diflucortolone valerate, fluticasone valerate, 17-butyrate hydrocortisone, mometasone fuorate, halobetasol propionate, desoximetasone, clobetasone butyrate, hydrocortisone, cortisone, prednisolone, miconazole, prednisone, triamcinolone acetonide, methylprednisolone, fluometholone, fluocinolone acetonide, desonide.la dexamethasone, dexamethasone dipropionate, aclasone, dexamethasone 17, 21 -dipropionate, mometasone furoate, diflorasone diacetate, or mixtures thereof.
  • the therapeutic agents of the class of corticosteroids will preferably be chosen from clobetasol 17-propionate, desonide and betamethasone valerate, clobetasol 17-propionate being the preferred therapeutic agent.
  • the emulsions of the present invention can also be used for formulations for cutaneous topical applications of vitamin D and its analogs.
  • vitamin D analogs By way of non-limiting example of vitamin D analogs, mention may be made of ergocalciferol, alfacalcidol, calcifediol, calcipotriol, calcitriol, cholecalciferol, tacalcitol, 6- (3-hydroxy acid). -5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylselanyl) -nicotinic acid, 4- [6-ethyl-4 '- (1-ethyl-1-hydroxy) propyl) -2'-propyl-biphenyl-3-loxymethyl] -2-hydroxymethyl-phenyl ⁇ -methanol, or mixtures thereof.
  • the emulsions of the present invention may also be used for formulations for topical cutaneous applications of retinoids.
  • Retinoid means any compound binding to the RAR and / or RXR receptors.
  • the retinoid is a compound chosen from the family of benzonaphthalene retinoids as described in the patent application EP 0 199 636.
  • adapalene (6- [3- (1-adamantyl) acid) is preferred.
  • 4-methoxyphenyl] -2-naphthhanoic as well as its precursors and / or derivatives.
  • Tretinoin and isotretinoin can also be used.
  • retinoid precursors are meant their immediate biological precursors or substrates, as well as their chemical precursors.
  • Derivatives of retinoids include both their metabolic derivatives and their chemical derivatives.
  • retinoids can be chosen from those described in the following patents or patent applications: 118 4,666,941, US 4,581,380, EP 0 210 929,
  • EP 0 823 903 EP 0 832 057, EP 0 832 081, EP 0 816 352, EP 0 826 657,
  • oil-in-water emulsion of the present invention may be made with a combination of different therapeutic agents selected from the different categories defined above.
  • One of the main objectives of the invention is to provide a system for topical application having the advantages of a fat cream, with regard to the properties of penetration through the epidermis, as well as the advantages of an aqueous emulsion, from the point of view of comfort and ease of use, as well as the stability of said formulation.
  • the emulsion described here and object of the present invention may further comprise any additive usually used in the cosmetic or pharmaceutical field, such as sequestering agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants conventional, inorganic or organic pH buffers, dyes, bases or acids, perfumes, essential oils, cosmetic active agents, moisturizers, vitamins, sphingolipids, self-tanning compounds, such as DHA, gelling agents, soothing and skin-protecting agents such as Pallantoin.
  • any additive usually used in the cosmetic or pharmaceutical field such as sequestering agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants conventional, inorganic or organic pH buffers, dyes, bases or acids, perfumes, essential oils, cosmetic active agents, moisturizers, vitamins, sphingolipids, self-tanning compounds, such as DHA, gelling agents, soothing and skin-protecting agents such as Pallantoin.
  • EDTA ethylenediamine tetracetic acid
  • preservatives examples include benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinyl urea, parabens, or mixtures thereof.
  • antioxidants mention may be made, by way of nonlimiting examples, of ascorbic acid and its salts, tocopherols and sulphite salts, such as sodium metabisulphite, sodium sulphite, butylhydroxyanisole, beta-butylhydroxytoluene and propyl gallate,
  • the oxidizing agent is selected from DL-alpha tocopherol, butylhydroxyanisole, butylhydroxytoluene and propyl gallate.
  • humectants examples include glycerin and sorbitol, and as pH buffers, citric acid and sodium citrate.
  • the emulsion according to the invention may also contain, as additive, one or more compounds falling within the category of gelling agents, that is to say capable of conferring a sufficient viscosity on the emulsion to maintain the suspension in suspension. various components of said emulsion.
  • gelling agents may advantageously be chosen from the gelling agents currently used, and especially chosen from, by way of non-limiting examples, among carbomer, hydroxyethylcellulose, methylcellulose, guar gum, xanthan gum, hectorite, pectin, magnesium aluminum silicate, gelling agents of the family of polyacrylamides such as the mixture sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 sold under the name Simulgel 600 ® by the company SEPPIC, the polyacrylamide / isoparaffin C13 14 / laureth-7 as, for example, the one sold under the name Sepigel 305 ® by Seppic, the family of acrylic polymers coupled to hydrophobic chains, such as the copolymer PEG-150 / decyl / SMDI sold under the name Aculyn 44 ® (polycondensate comprising at least, as components, a polyethylene glycol containing 150 or 180 mol of
  • the preferred gelling agents are xanthan gum, magnesium aluminum silicate (Vanderbilt Veegum K), magnesium silicate and aluminum / aluminum / Titanium Dioxide (Vanderbilt Veegum ULTRA) or mixtures thereof.
  • the oil-in-water emulsion of the present invention comprises: a. from 35% to 45% by weight of a fatty phase; b. from 5% to 15% by weight of a nonionic emulsifier system; vs. from 15% to 20% by weight of at least one propenetrating agent; d. from 0.01% to 0.5% by weight of at least one therapeutic agent; e. from 5% to 50% by weight of water; and F. additives, preferably between 0.2% to 25% by weight.
  • the present invention relates to a process for preparing the oil-in-water type emulsion as defined above, characterized in that it comprises the steps of: a. dissolution and / or dispersion in water, with stirring, of at least one pro-penetrating agent and the optional additive (s), at a temperature of between 60 ° C. and 95 ° C., until a phase is obtained homogeneous aqueous; b. incorporation, with stirring, of the aqueous phase in the fatty phase, in which the pair of emulsifiers, previously heated to a temperature of between 60 ° C. and 95 ° C., has been solubilized; and vs. incorporation, with stirring and at a temperature below 4O 0 C, of the therapeutic agent, may be dissolved beforehand in a suitable solvent.
  • solvent any solvent capable of solubilizing the therapeutic agent (s), and / or of dissolving the therapeutic agent (s), when these are in solid form, in order to allow their perfect incorporation into the fatty phase emulsion. aqueous phase.
  • the present invention relates to a physiologically acceptable galenic formulation which is compatible with topical application to the skin, superficial body growths or mucous membranes, comprising at least one oil-in-water type emulsion, as it comes from to be defined in this presentation.
  • the dosage form is an oil-in-water emulsion itself.
  • the invention also relates to the use of the emulsion described above or the aforementioned formulation for application to the skin, superficial body growths or mucous membranes of at least one therapeutic agent belonging to the class of corticosteroids, in particular in view of their use for the prevention and / or treatment of dermatological diseases.
  • Said therapeutic agents are particularly suitable in the following treatment areas:
  • the oil-in-water emulsion of the present invention has proved to be entirely suitable for the prevention and treatment of all forms of psoriasis, whether cutaneous, mucous or ungual. .
  • the fat phase is weighed in a receiving beaker which is then placed in a waterbath at 78 ° C.
  • the aqueous phase is weighed in a beaker and then the citric acid is added.
  • the sodium citrate is then dispersed with vigorous stirring.
  • the gelling agents are then added and, after homogenization, propylene glycol, by heating at 78 ° C. with Rayneri stirring.
  • the hot fatty phase is then stirred Rayneri.
  • the aqueous phase is poured into the fatty phase with stirring (1000 rpm) and heating at 78 ° C for 10 min. It is left stirring (1000 rpm), without heating.
  • the therapeutic agent is prepared by adding it, under magnetic stirring, in a beaker, to propylene glycol, until complete dissolution.
  • This active phase is then incorporated into the emulsion, below 40 ° C.
  • the macroscopic observation makes it possible to guarantee the physical integrity of the products and the microscopic observation makes it possible to verify that there is no recrystallization of the solubilized active ingredient and no significant evolution of the size of the blood cells of the emulsion.
  • a HAAKE ® rheometer VT500 type with a measurement mobile SVDIN is used.
  • the rheograms were performed at 25 0 C by varying the shear rate over time, and measuring the stress.
  • flow threshold (tau 0) is meant the force required (minimum shear stress) to overcome Van der Waals cohesive forces and cause flow.
  • the flow threshold is equivalent to the value found at 4 s -1 .
  • Chemical stability is an assay, by HPLC, of the active and preservatives at room temperature (Ta) and at 45 ° C.
  • This formulation is in accordance with the object of the present invention: no recrystallization of the therapeutic agent was observed after 3 months at 4 ° C.
  • the evaluation tests are carried out on the formulations 2, 3 and 4 of Examples 3, 4 and 5, and, for comparison with the commercial products Temovate Cream ® and Temovate Emollient Cream ® .
  • the study was conducted on 7 healthy subjects, male or female, aged 18 to 70 years.
  • the study is carried out over 2 days. The three formulations and the two reference products were applied to each volunteer.
  • An area not receiving product served as a control area.
  • the obtained variables were subjected to a variant analysis and each formulation was compared to the untreated site and the reference product at each measurement time.
  • Temovate Cream ® induces the most important whitening. Statistically, 1 AUC of Temovate Cream ® is significantly different from the AUC of the untreated zone and formulation 2 of Example 3 for the parameter a *. For parameter L *, the AUC of Temovate Cream ® is significantly different from the AUC all other test areas, except those treated with Temovate Emollient Cream ® .
  • Temovate Emollient Cream ® Temovate Emollient Cream ®
  • formulation 3 of Example 4 formulation 2 of Example 3 are quite close to each other.
  • the AUCs of these 3 products are all significantly different from the 1 AUC of the untreated zone for parameter a *.
  • parameter L * only the AUC of the Formulation of Example 3 is not different from the untreated zone.
  • the AUC of formulation 2 of Example 3 appears to be the weakest for both the parameter a * and the parameter L *. Statistically, I 1 AUC of the latter appears as significantly different from the untreated zone for the parameter a * but not for the parameter L *.
  • Student's t-test was performed with a significance threshold of less than 0.1.
  • This test evaluates the irritating potential of Formulation 2 and Formulation 3 in various irritation tests in healthy volunteers.
  • METHODOLOGY The study was conducted over 15 days for each volunteer. The volunteers presented themselves every day at the test center, except at D4, D8, D16, D11 and D12 where the applications were performed at home.

Abstract

The invention relates to a novel topical composition in the form of an oil-in-water-type emulsion having a high proportion of oil phase in the internal phase, which combines the occlusive and emollient properties of an ointment without feeling greasy, while promoting the therapeutic properties of the biologically-active agent present in the composition.

Description

Émulsion de type huile-dans-eau pour application topique en dermatologieOil-in-water emulsion for topical application in dermatology
La présente invention concerne une nouvelle composition topique sous forme d'émulsion de type huile-dans-eau, à forte proportion de phase huileuse en phase interne de l'émulsion, alliant les propriétés occlusives et émollientes d'un onguent sans présenter les inconvénients de toucher gras, tout en favorisant les propriétés thérapeutiques de l'agent biologiquement actif présent dans ladite composition.The present invention relates to a novel topical composition in the form of an oil-in-water emulsion, with a high proportion of oily phase in the internal phase of the emulsion, combining the occlusive and emollient properties of an ointment without having the disadvantages of greasy feel, while promoting the therapeutic properties of the biologically active agent present in said composition.
Pour les pathologies visées où la peau est sèche et desquamée, l'utilisation d'un onguent est largement préférée. En effet, l'onguent est principalement composé de corps gras qui apportent de l'émollience à la peau et limitent la desquamation. Cependant cette forme galénique a l'inconvénient, de par sa nature, d'avoir un toucher gras et collant, d'où un inconfort pour la vie courante du patient (sensations désagréables, taches grasses sur les vêtements, etc.)- La majorité de ces onguents sont à base d'un fort pourcentage de vaseline.For targeted diseases where the skin is dry and flaky, the use of an ointment is widely preferred. Indeed, the ointment is mainly composed of fatty substances that bring emollience to the skin and limit desquamation. However this dosage form has the disadvantage, by its nature, to have a greasy and sticky touch, resulting in discomfort for the patient's everyday life (unpleasant sensations, greasy spots on clothes, etc.). these ointments are based on a high percentage of petrolatum.
La demande de brevet EP-A1-0 069 423 décrit par exemple des compositions pour application topique sur la peau, dans lesquelles la phase grasse représente de 60% à 70% en poids.The patent application EP-A1-0 069 423 describes, for example, compositions for topical application to the skin, in which the fatty phase represents from 60% to 70% by weight.
On connaît d'autre part les émulsions à phase continue aqueuse qui offrent l'avantage d'un toucher non gras, d'une grande facilité d'étalement, etc. Cependant, le pouvoir émollient de telles émulsions est très souvent insuffisant, voire non satisfaisant.Also known are aqueous continuous phase emulsions which offer the advantage of a non-greasy touch, a great ease of spreading, etc. However, the emollient power of such emulsions is very often insufficient or even unsatisfactory.
Il existe donc un besoin pour des compositions présentant à la fois les avantages des onguents (occlusivité, émollience) et des émulsions en phase continue aqueuse (toucher non gras, cosmétiquement acceptable, facilité d'étalement, pas de résidus), tout en évitant les inconvénients liés à ces deux types de formulation.There is therefore a need for compositions having both the benefits of ointments (occlusivity, emollience) and emulsions in aqueous continuous phase (non-greasy feel, cosmetically acceptable, ease of spreading, no residues), while avoiding disadvantages related to these two types of formulation.
De plus, en terme d'efficacité, ces compositions devraient favoriser les propriétés thérapeutiques de l'agent biologiquement actif, afin de garantir son efficacité dans cette nouvelle forme galénique.In addition, in terms of efficacy, these compositions should promote the therapeutic properties of the biologically active agent, to ensure its effectiveness in this new dosage form.
De façon avantageuse, lorsqu'elles comprennent au moins un agent thérapeutique de la classe des corticostéroides, ces compositions devraient présenter une bioéquivalence en terme de vasoconstriction avec les produits majeurs sur le marché, notamment pour les compositions topiques à base de corticostéroïdes.Advantageously, when they comprise at least one therapeutic agent of the class of corticosteroids, these compositions should have bioequivalence in terms of vasoconstriction with major products on the market, especially for topical compositions containing corticosteroids.
Les inventeurs ont maintenant découvert une nouvelle émulsion de type huile- dans-eau, contenant une très forte proportion de phase grasse, correspondant aux proportions généralement rencontrées dans les émulsions de type eau-dans-huile.The inventors have now discovered a new emulsion of oil-in-water type, containing a very high proportion of fat phase, corresponding to the proportions generally encountered in water-in-oil type emulsions.
Cette nouvelle émulsion, appelée aussi lipocrème, a pu être obtenue en utilisant un système émulsifiant non ionique de type huile-dans-eau, combiné à un ou plusieurs agents propénétrants.This new emulsion, also called lipocreme, could be obtained using an oil-in-water type nonionic emulsifier system combined with one or more propenetrating agents.
Ladite émulsion utilisant un système émulsifiant non ionique de type huile- dans-eau permettant, malgré la phase interne grasse très importante, de ne pas changer le sens de l'émulsion.Said emulsion using a non-ionic emulsifier system of oil-in-water type, in spite of the very large internal fatty phase, not to change the direction of the emulsion.
Par conséquent, l'émulsion à phase continue aqueuse selon l'invention présente l'avantage d'un toucher non gras tout en offrant un pouvoir émollient satisfaisant amené par le fort pourcentage de phase grasse.Therefore, the aqueous continuous phase emulsion according to the invention has the advantage of a non-greasy feel while providing satisfactory emollient power brought by the high percentage of fat phase.
De manière tout à fait surprenante, cette nouvelle formulation possède une activité thérapeutique équivalente à celle attendue dans le cas d'onguents possédant une forte concentration en vaseline.Quite surprisingly, this new formulation has a therapeutic activity equivalent to that expected in the case of ointments with a high concentration of petrolatum.
Ainsi la présente invention concerne tout d'abord une émulsion de type huile- dans-eau renfermant au moins un agent thérapeutique pour application topique et comprenant en outre : a) de 25% à 60% en poids d'une phase grasse ; b) de 1% à 15% en poids d'un système émulsionnant non ionique ; c) de 1% à 30% en poids d'au moins un agent propénétrant ; et d) de 5% à 50% en poids d'eau.Thus, the present invention relates first of all to an oil-in-water type emulsion containing at least one therapeutic agent for topical application and further comprising: a) from 25% to 60% by weight of a fatty phase; b) from 1% to 15% by weight of a nonionic emulsifier system; c) from 1% to 30% by weight of at least one propenetrating agent; and d) from 5% to 50% by weight of water.
Avantageusement, l'émulsion selon la présente invention comprend une quantité de phase grasse comprise entre 35% et 50% en poids.Advantageously, the emulsion according to the present invention comprises a quantity of fat phase of between 35% and 50% by weight.
Au sens de la présente invention, on entend par phase grasse un ou plusieurs composés choisis parmi les émollients, les cires et les alcools gras, seuls ou en mélanges de deux ou plusieurs d'entre eux. Les émollients seront avantageusement les émollients couramment utilisés pour les formulations visées dans la présente invention et bien connus de l'homme du métier. À titre d'exemples non limitatifs, on peut citer les huiles végétales, telles que l'huilé de graines de coton (cottonseed oil), ou l'huile d'amande douce (almond oil) ; les esters tels que le palmitate d'isopropyle, et le myristate d'isopropyie ; les huiles minérales, telles que les huiles minérales légères (light minerai oil), les huiles de silicone volatiles ou non volatiles, comme par exemple la diméthicone et la cyclométhicone ; et la vaseline.For the purposes of the present invention, the term "fatty phase" is understood to mean one or more compounds chosen from emollients, waxes and fatty alcohols, alone or as mixtures of two or more of them. The emollients will advantageously be the emollients commonly used for the formulations referred to in the present invention and well known to those skilled in the art. By way of non-limiting examples, mention may be made of vegetable oils, such as cottonseed oil, or almond oil; esters such as isopropyl palmitate, and isopropyl myristate; mineral oils, such as light mineral oils, volatile or non-volatile silicone oils, for example dimethicone and cyclomethicone; and petrolatum.
Les cires pouvant être également utilisées comme constituants de la phase grasse de Pémulsion selon la présente invention sont les cires couramment utilisées par l'homme du métier dans ce domaine, parmi lesquelles on peut citer, à titre purement illustratif, la cire d'abeille, la cire de carnauba, l'ozokérite, la paraffine et le béhénate de diméthiconol.The waxes which can also be used as constituents of the emulsion fatty phase according to the present invention are the waxes commonly used by those skilled in the art in this field, among which, for example, beeswax can be mentioned, carnauba wax, ozokerite, paraffin and dimethiconol behenate.
De même, la phase grasse pourra contenir un ou plusieurs alcools gras connus de l'homme du métier, et à ce titre, on peut citer notamment, et de manière non limitative, l'alcool cétylique et l'alcool stéarylique.Similarly, the fatty phase may contain one or more fatty alcohols known to those skilled in the art, and as such, there may be mentioned in particular, and not limited to, cetyl alcohol and stearyl alcohol.
La phase grasse contiendra de préférence un ou plusieurs des ingrédients suivants : du palmitate d'isopropyl, une huile minérale, de la vaseline, de la diméthicone.The fatty phase will preferably contain one or more of the following ingredients: isopropyl palmitate, a mineral oil, petrolatum, dimethicone.
Selon la présente invention, la phase grasse est mise en émulsion au moyen d'un système émulsionnant non ionique.According to the present invention, the fatty phase is emulsified by means of a nonionic emulsifying system.
Les tensioactifs sont qualifiés de molécules amphiphiles en raison de leur double polarité hydrophile et lipophile. La structure de ces molécules permet de les caractériser : la balance hydrophile - lipophile (HLB) est le rapport entre la partie hydrophile et la partie lipophile. Une HLB élevée indique que la fraction hydrophile est prédominante, et, à l'inverse, une faible HLB indique que la partie lipophile est prédominante. Par exemple, des valeurs de HLB supérieures à environ 10 correspondent à des tensioactifs hydrophiles. Les tensioactifs peuvent être classés, selon leur structure, sous les termes générique "ioniques" (anioniques, cationiques, amphotères) ou "non ioniques". Les tensioactifs non ioniques sont des tensioactifs qui ne se dissocient pas en ions dans l'eau et sont donc insensibles aux variations de pH.Surfactants are termed amphiphilic molecules because of their hydrophilic and lipophilic double polarity. The structure of these molecules makes it possible to characterize them: the hydrophilic-lipophilic balance (HLB) is the ratio between the hydrophilic part and the lipophilic part. High HLB indicates that the hydrophilic moiety is predominant, and conversely, low HLB indicates that the lipophilic moiety is predominant. For example, 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.
Les tensioactifs non ioniques sont particulièrement bien adaptés pour la préparation de l'émulsion de type huile-dans-eau, objet de la présente invention. Ainsi, le système émulsionnant, composant de l'émulsion de l'invention, comprend au moins un tensioactif non ionique, à fraction prédominante hydrophile, c'est-à-dire présentant une HLB élevée, supérieure à environ 10.Nonionic surfactants are particularly well suited for the preparation of the oil-in-water type emulsion, object of the present invention. Thus, the emulsifying system, component of the emulsion of the invention, comprises at least one nonionic surfactant, hydrophilic predominant fraction, that is to say having a high HLB, greater than about 10.
On peut citer, à titre d'exemples de tensioactifs non ioniques présentant une HLB élevée, les esters de sorbitan tels que le POE(20) sorbitan monooléate, vendu sous le nom de « Tween 80 » (HLB=I 5) ; le POE(20) sorbitan monostéarate vendu sous le nom de « Tween 60 » (HLB=14.9) ; les éthers d'alcools gras tels que le POE (21) stéaryl ether (HLB= 15.5), ou le ceteareth 20 vendu sous le nom de « Eumulgin B2 » par Cognis (HLB de 15,5).Examples of nonionic surfactants with high HLB include sorbitan esters such as POE (20) sorbitan monooleate sold as "Tween 80" (HLB = 15); POE (20) sorbitan monostearate sold under the name "Tween 60" (HLB = 14.9); fatty alcohol ethers such as POE (21) stearyl ether (HLB = 15.5), or ceteareth 20 sold under the name "Eumulgin B2" by Cognis (HLB 15.5).
De préférence, lesdits tensioactifs non ioniques de haute HLB, présentent une HLB comprise entre 10 et 18.Preferably, said high HLB nonionic surfactants have an HLB between 10 and 18.
On citera, comme exemples de tensioactifs non ioniques de basse HLB, les esters de sorbitan, tels que le monostéarate de sorbitan (vendu sous le nom de Span 60 par Unichema), les esters de glycérol (vendu sous le nom de Cutina GMSVPH par Cognis) tels que le monostéarate de glycérol (Cutina GMS de chez Cognis), les esters de saccharose de bas HLB comme le distéarate de saccharose.Examples of low HLB nonionic surfactants include sorbitan esters, such as sorbitan monostearate (sold as Span 60 by Unichema), glycerol esters (sold under the name Cutina GMSVPH by Cognis). ) such as glycerol monostearate (Cutina GMS from Cognis), low HLB sucrose esters such as sucrose distearate.
De préférence, lesdits tensioactifs non ioniques présentant de faible HLB, présentent une HLB inférieure à 10.Preferably, said nonionic surfactants exhibiting low HLB have an HLB of less than 10.
Les tensioactifs non ioniques peuvent être utilisés seuls ou en mélange de deux ou plusieurs d'entre eux pour former le système émulsionnant composant l'émulsion de l'invention.The nonionic surfactants may be used alone or in a mixture of two or more of them to form the emulsifying system comprising the emulsion of the invention.
De préférence, on utilisera, en tant que système émulsionnant un ou plusieurs couples "tensioactif non ionique de haute HLB" / "tensioactif non ionique de faible HLB", il pourra en particulier s'agir d'un système émulsionnant non ionique comprenant au moins un tensioactif non ionique présentant une HLB supérieure à environ 10 et au moins un tensioactif non ionique présentant une HLB inférieure à environ 10.Preferably, one or more pairs of "high HLB nonionic surfactant" / "low HLB nonionic surfactant" will be used as the emulsifying system. It may in particular be a nonionic emulsifying system comprising at least one nonionic surfactant having an HLB greater than about 10 and at least one nonionic surfactant having an HLB of less than about 10.
Selon un mode de réalisation particulièrement préféré de la présente invention, le système émulsionnant est composé du couple de tensioactifs monostéarate de glycérol / Ceteareth 20.According to a particularly preferred embodiment of the present invention, the emulsifying system is composed of the glycerol monostearate / ceteareth 20 surfactant couple.
L'utilisation des couples de tensioactifs précités offre l'avantage de rigidifier le film interfacial et par conséquent d'augmenter de manière sensible la stabilité de l'émulsion.The use of the above-mentioned surfactant couples has the advantage of stiffening the interfacial film and consequently of appreciably increasing the stability of the emulsion.
Le ratio de chacun des deux tensioactifs formant le couple précité est déterminé le plus souvent par le calcul de la HLB requise de la phase grasse utilisée.The ratio of each of the two surfactants forming the aforementioned pair is most often determined by the calculation of the required HLB of the fat phase used.
La recherche de l'emulsification optimale d'une matière grasse ou d'un mélange de matières grasses passe par la détermination préalable de son HLB requis. En effet, chaque corps gras possède un HLB requis défini. On ne peut donc pas opérer dans tous les cas avec le même émulsionnant. Le HLB requis par la phase grasse correspond à la valeur de HLB de l'émulsionnant ou du couple d'emulsionnants qui va fournir avec les corps gras considérés l'émulsion la plus stable.The search for the optimal emulsification of a fat or a mixture of fat passes through the preliminary determination of its required HLB. Indeed, each fat has a defined required HLB. We can not operate in all cases with the same emulsifier. The HLB required by the fat phase corresponds to the HLB value of the emulsifier or the pair of emulsifiers that will provide the most stable emulsion with the fatty substances considered.
Outre le système émulsionnant qui vient d'être décrit, l'émulsion de la présente invention comprend un ou plusieurs agents propénétrants dans des concentrations préférentielles allant de 1 à 30 %, préférentiellement de 5% à 25%, et plus préférentiellement allant de 15% à 20% en poids par rapport au poids total de la composition.In addition to the emulsifying system which has just been described, the emulsion of the present invention comprises one or more propenetrating agents in preferential concentrations ranging from 1 to 30%, preferably from 5% to 25%, and more preferably ranging from 15%. at 20% by weight relative to the total weight of the composition.
Les agents propénétrants doivent être généralement non solubilisant des agents thérapeutiques au pourcentage utilisé, ne pas provoquer de réactions exothermiques néfastes pour les divers composants, aider à la bonne dispersion desdits agents thérapeutiques et avoir des propriétés anti-mousse. Parmi les agents propénétrants, on utilise préférentiellement, sans que cette liste soit limitative, des composés choisis parmi ceux connus de l'homme du métier, tels que le propylène glycol, le dipropylène glycol, le Transcutol® (éthoxydiglycol), le dipélargonate de propylène glycol, le lauroglycol, l'urée, l'acétone, l'acide oléique.The propenetrating agents must generally be non-solubilizing therapeutic agents at the percentage used, not cause harmful exothermic reactions for the various components, help the good dispersion of said therapeutic agents and have anti-foam properties. Among the pro-penetrating agents, are preferably used, without this list being limiting, of compounds selected from those known to those skilled in the art, such as propylene glycol, dipropylene glycol, Transcutol ® (ethoxydiglycol), propylene glycol dipelargonate glycol, lauroglycol, urea, acetone, oleic acid.
Les agents propénétrants peuvent être bien entendus formulés en mélanges de deux ou plusieurs d'entre eux. De préférence, l'agent propénétrant est choisi parmi le propylène glycol, le dipropylène glycol et Ie dipélargonate de propylène glycol. De préférence encore, l'agent propénétrant est le propylène glycol.Propenetrating agents may be well understood in mixtures of two or more of them. Preferably, the propenetrating agent is chosen from propylene glycol, dipropylene glycol and propylene glycol dipelargonate. More preferably, the propenetrating agent is propylene glycol.
Il doit être compris que la nature de l'agent propénétrant dépendra de la nature de l'agent thérapeutique inclus dans l'émulsion de l'invention.It should be understood that the nature of the propenetrating agent will depend on the nature of the therapeutic agent included in the emulsion of the invention.
La phase aqueuse de l'émulsion selon l'invention comprend de l'eau, purifiée ou non, déminéralisée ou non, et en particulier une eau florale telle que l'eau de bleuet, ou une eau thermale ou minérale naturelle, par exemple choisie parmi l'eau de Vittel, les eaux du bassin de Vichy, l'eau d'Uriage, l'eau de la Roche-Posay, l'eau de la Bourboule, l'eau d'Enghien-les-Bains, l'eau de Saint Gervais-les-Bains, l'eau de Néris- les-Bains, l'eau d'Allevard-les-Bains, l'eau de Digne, l'eau de Maizières, l'eau de Neyrac-les-Bains, l'eau de Lons-le-Saunier, les Eaux Bonnes, l'eau de Rochefort, l'eau de Saint Christau, l'eau des Fumades et l'eau de Tercis-les-Bains, l'eau d'Avène ou l'eau d'Aix les Bains.The aqueous phase of the emulsion according to the invention comprises water, purified or not, demineralized or not, and in particular a floral water such as cornflower water, or a natural thermal or mineral water, for example chosen among the water of Vittel, the waters of the Vichy basin, the water of Uriage, the water of the Roche-Posay, the water of the Bourboule, the water of Enghien-les-Bains, the water of Saint Gervais-les-Bains, the water of Neris-Bains, the water of Allevard-les-Bains, the water of Digne, the water of Maizières, the water of Neyrac-les- Baths, the water of Lons-le-Saunier, the Eaux Bonnes, the water of Rochefort, the water of Saint Christau, the water of the Fumades and the water of Tercis-les-Bains, the water of Avène or the water of Aix les Bains.
Ainsi, outre la phase grasse, le système émulsionnant, l'agent propénétrant et l'agent thérapeutique, l'émulsion selon la présente invention comprend une quantité substantielle d'eau, comprise entre 5% et 50%, avantageusement environ 30% en poids de Pémulsion.Thus, besides the fatty phase, the emulsifying system, the propenetrating agent and the therapeutic agent, the emulsion according to the present invention comprises a substantial amount of water, of between 5% and 50%, advantageously about 30% by weight. emulsion.
Selon un aspect préféré, l'émulsion de type huile-dans-eau de la présente invention est tout particulièrement adaptée pour le traitement et/ou la prévention des maladies de la peau. L'agent thérapeutique compris dans ladite émulsion sera par conséquent de préférence un composé thérapeutiquement actif dans le traitement et/ou la prévention de ce type de maladies.In a preferred aspect, the oil-in-water emulsion of the present invention is particularly suitable for the treatment and / or prevention of skin diseases. The therapeutic agent included in said emulsion will therefore preferably be a therapeutically active compound in the treatment and / or prevention of this type of disease.
Les émulsions de la présente invention se sont révélées particulièrement efficaces pour l'application topique sur la peau d'agents thérapeutiques de la classe des corticostéroïdes, déjà connus et commercialisés.The emulsions of the present invention have proved particularly effective for the topical application to the skin of therapeutic agents of the class of corticosteroids, already known and marketed.
A titre d'exemple non limitatif, les agents thérapeutiques de la classe des corticostéroïdes seront choisis parmi le clobétasol 17-propionate, le désonide, la betamethasone, l'acétate de bétaméthasone, le valérate de bétaméthasone, le dipropionate de bétaméthasone, le dipropionate monohydrate de bétaméthasone, le valérate de diflucortolone, le valérate de fluticasone, l'hydrocortisone 17-butyrate, le fuorate de mometasone, le propionate d'halobetasol, la desoximetasone, le butyrate de clobetasone, Phydrocortisone, la cortisone, la prednisolone, le miconazole, la prednisone, la triamcinolone acetonide, la methylprednisolone, la fluometholone, la fluocinolone acetonide, le desonide.la dexamethasone, le dipropionate de dexamethasone, l'aclasone, la dexamethasone 17, 21 -dipropionate, la mometasone furoate, la diflorasone diacetate, ou leurs mélanges.By way of non-limiting example, the therapeutic agents of the corticosteroid class will be chosen from clobetasol 17-propionate, desonide, betamethasone, betamethasone acetate, betamethasone valerate, betamethasone dipropionate and dipropionate monohydrate. betamethasone, the diflucortolone valerate, fluticasone valerate, 17-butyrate hydrocortisone, mometasone fuorate, halobetasol propionate, desoximetasone, clobetasone butyrate, hydrocortisone, cortisone, prednisolone, miconazole, prednisone, triamcinolone acetonide, methylprednisolone, fluometholone, fluocinolone acetonide, desonide.la dexamethasone, dexamethasone dipropionate, aclasone, dexamethasone 17, 21 -dipropionate, mometasone furoate, diflorasone diacetate, or mixtures thereof.
Les agents thérapeutiques de la classe des corticostéroides seront préférentiellement choisis parmi le clobétasol 17-propionate, le désonide et le valérate de bétaméthasone, le clobétasol 17-propionate étant l'agent thérapeutique préféré.The therapeutic agents of the class of corticosteroids will preferably be chosen from clobetasol 17-propionate, desonide and betamethasone valerate, clobetasol 17-propionate being the preferred therapeutic agent.
Bien entendu, la présente invention n'a pas pour objet de se limiter à ces seuls corticostéroides, et bien d'autres agents thérapeutiques, et d'autres applications thérapeutiques peuvent être envisagés dans le cadre d'applications topiques au moyen d'émulsions de type huile-dans-eau.Of course, the present invention is not intended to be limited to these corticosteroids alone, and many other therapeutic agents, and other therapeutic applications can be envisaged in the context of topical applications by means of oil-in-water type.
Ainsi, les émulsions de la présente invention peuvent également être utilisées pour des formulations pour applications topiques cutanées de vitamine D et de ses analogues.Thus, the emulsions of the present invention can also be used for formulations for cutaneous topical applications of vitamin D and its analogs.
A titre d'exemple non limitatif d'analogues de la vitamine D, on peut citer l'ergocalciférol, l'alfacalcidol, le calcifédiol, le calcipotriol, le calcitriol, le cholécalciférol, le tacalcitol, l'acide 6-(3-hydroxy-5,5,8,8-tétraméthyl-5,6,7,8-tétrahydro-naphthalen-2- ylselanyl)-nicotinique, le 4-[6-ethyl-4'-(1 -ethyl-1 -hydroxy-propyl)-2'-propyl-biphenyl-3- loxymethyl]-2-hydroxymethyl-phenyl}-methanol, ou leurs mélanges.By way of non-limiting example of vitamin D analogs, mention may be made of ergocalciferol, alfacalcidol, calcifediol, calcipotriol, calcitriol, cholecalciferol, tacalcitol, 6- (3-hydroxy acid). -5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylselanyl) -nicotinic acid, 4- [6-ethyl-4 '- (1-ethyl-1-hydroxy) propyl) -2'-propyl-biphenyl-3-loxymethyl] -2-hydroxymethyl-phenyl} -methanol, or mixtures thereof.
Les émulsions de la présente invention pourront également être utilisées pour des formulations pour applications topiques cutanées de rétinoïdes.The emulsions of the present invention may also be used for formulations for topical cutaneous applications of retinoids.
Par rétinoide, on entend tout composé se liant aux récepteurs RAR et/ou RXR.Retinoid means any compound binding to the RAR and / or RXR receptors.
Préférentiellement, le rétinoide est un composé choisi dans la famille des rétinoïdes benzonaphtaleniques tels que décrits dans la demande de brevet EP 0 199 636. En particulier, on préférera l'adapalene (l'acide 6-[3-(1-adamantyl)-4- méthoxyphényl]-2-naphthanoique), ainsi que ses précurseurs et/ou dérivés. On peut également utiliser la trétinoine et l'isotrétinoine.Preferably, the retinoid is a compound chosen from the family of benzonaphthalene retinoids as described in the patent application EP 0 199 636. In particular, adapalene (6- [3- (1-adamantyl) acid) is preferred. 4-methoxyphenyl] -2-naphthhanoic), as well as its precursors and / or derivatives. Tretinoin and isotretinoin can also be used.
Par précurseurs de rétinoïdes, on entend leurs précurseurs biologiques immédiats ou substrats, ainsi que leurs précurseurs chimiques. Par dérivés des rétinoïdes, on entend aussi bien leurs dérivés métaboliques que leurs dérivés chimiques.By retinoid precursors are meant their immediate biological precursors or substrates, as well as their chemical precursors. Derivatives of retinoids include both their metabolic derivatives and their chemical derivatives.
D'autres rétinoïdes peuvent être choisis parmi ceux décrits dans les brevets ou demandes de brevet suivants : 118 4,666,941, US 4,581,380, EP 0 210 929,Other retinoids can be chosen from those described in the following patents or patent applications: 118 4,666,941, US 4,581,380, EP 0 210 929,
EP 0232 199, EP 0 260 162, EP 0 292 348, EP 0 325 540, EP 0 359 621,EP 0232 199, EP 0 260 162, EP 0 292 348, EP 0 325 540, EP 0 359 621,
EP 0409 728, EP 0409 740, EP 0 552 282, EP 0 584 191, EP 0 514 264,EP 0409 728, EP 0409 740, EP 0 552 282, EP 0 584 191, EP 0 514 264,
EP 0 514 269, EP 0 661 260, EP 0661 258, EP 0 658 553, EP 0 679 628,EP 0 514 269, EP 0 661 260, EP 0661 258, EP 0 658 553, EP 0 679 628,
EP 0679 631, EP 0 679 630, EP 0708 100, EP 0 709 382, EP 0 722 928,EP 0679 631, EP 0 679 630, EP 0 708 100, EP 0 709 382, EP 0 722 928,
EP 0 728 739, EP 0 732 328, EP 0 740 937, EP 0 776 885, EO 0 776 881,EP 0 728 739, EP 0 732 328, EP 0 740 937, EP 0 776 885, EO 0 776 881,
EP 0 823 903, EP 0 832 057, EP 0 832 081, EP 0 816 352, EP 0 826 657,EP 0 823 903, EP 0 832 057, EP 0 832 081, EP 0 816 352, EP 0 826 657,
EP 0 874 626, EP 0 934295, EP 0 915 823, EP 0 882 033, EP 0 850 909,EP 0 874 626, EP 0 934 295, EP 0 915 823, EP 0 882 033, EP 0 850 909,
EP 0 879 814, EP 0 952 974, EP 0 905 118, EP 0 947 496, WO98/56783, WO99/10322, WO99/50239, WO99/65872.EP 0 879 814, EP 0 952 974, EP 0 905 118, EP 0 947 496, WO98 / 56783, WO99 / 10322, WO99 / 50239, WO99 / 65872.
Selon un autre aspect, l'émulsion huile-dans-eau de la présente invention pourra être réalisée avec une combinaison de différents agents thérapeutiques choisis parmi les différentes catégories définies précédemment.In another aspect, the oil-in-water emulsion of the present invention may be made with a combination of different therapeutic agents selected from the different categories defined above.
Un des principaux objectifs de l'invention est de fournir un système pour application topique possédant les avantages d'une crème grasse, en ce qui concerne les propriétés de pénétration au travers de l'épiderme, ainsi que les avantages d'une émulsion aqueuse, du point de vue du confort et de la facilité d'utilisation, ainsi que de la stabilité de ladite formulation.One of the main objectives of the invention is to provide a system for topical application having the advantages of a fat cream, with regard to the properties of penetration through the epidermis, as well as the advantages of an aqueous emulsion, from the point of view of comfort and ease of use, as well as the stability of said formulation.
L'émulsion décrite ici et objet de la présente invention peut comprendre en outre tout additif usuellement utilisé dans le domaine cosmétique ou pharmaceutique, tel que des séquestrants, des antioxydants, des filtres solaires, des conservateurs, des charges, des électrolytes, des agents humectants, des tampons pH, des colorants, de bases ou d'acides usuels, minéraux ou organiques, des parfums, des huiles essentielles, des actifs cosmétiques, des hydratants, des vitamines, des sphingolipides, des composés autobronzants, tels que la DHA, des gélifiants, des agents apaisants et protecteurs de la peau tels que Pallantoïne.The emulsion described here and object of the present invention may further comprise any additive usually used in the cosmetic or pharmaceutical field, such as sequestering agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants conventional, inorganic or organic pH buffers, dyes, bases or acids, perfumes, essential oils, cosmetic active agents, moisturizers, vitamins, sphingolipids, self-tanning compounds, such as DHA, gelling agents, soothing and skin-protecting agents such as Pallantoin.
Bien entendu l'homme du métier veillera à choisir ce ou ces éventuels composés complémentaires, et/ou leur quantité, de manière telle que les propriétés avantageuses de l'émulsion selon l'invention ne soient pas, ou substantiellement pas, altérées.Of course, a person skilled in the art will take care to choose this or these optional additional compounds, and / or their quantity, in such a way that the properties of the emulsion according to the invention are not, or not substantially, altered.
À titre purement illustratif, on peut citer comme exemple d'agents séquestrants, l'acide éthylènediamine tétracétique (EDTA), ainsi que ses dérivés ou ses sels, la dihydroxyéthylglycine, l'acide citrique, l'acide tartrique, ou leurs mélanges.As a purely illustrative example, there may be mentioned as an example of sequestering agents, ethylenediamine tetracetic acid (EDTA), as well as its derivatives or its salts, dihydroxyethylglycine, citric acid, tartaric acid, or mixtures thereof.
On peut citer comme exemples de conservateurs le chlorure de benzalkonium, le phénoxyéthanol, l'alcool benzylique, la diazolidinylurée, les parabens, ou leurs mélanges.Examples of preservatives include benzalkonium chloride, phenoxyethanol, benzyl alcohol, diazolidinyl urea, parabens, or mixtures thereof.
Parmi les agents antioxydants, on peut citer à titre d'exemples non limitatifs, l'acide ascorbique et ses sels, les tocophérols et les sels de sulfites tels que le métabisulfite de sodium, le sulfite de sodium, le Butylhydroxyanisole, le BButylhydroxytoluène et le propyle gallate,Among the antioxidants, mention may be made, by way of nonlimiting examples, of ascorbic acid and its salts, tocopherols and sulphite salts, such as sodium metabisulphite, sodium sulphite, butylhydroxyanisole, beta-butylhydroxytoluene and propyl gallate,
De préférence, l'agent oxydant est choisi parmi le DL-alpha tocophérol, le butylhydroxyanisole, le butylhydroxytoluène et le propyle gallate.Preferably, the oxidizing agent is selected from DL-alpha tocopherol, butylhydroxyanisole, butylhydroxytoluene and propyl gallate.
On peut citer comme exemples d'agents humectants, la glycérine et le sorbitol, et comme tampons pH, l'acide citrique et le citrate de sodium.Examples of humectants are glycerin and sorbitol, and as pH buffers, citric acid and sodium citrate.
L'émulsion selon l'invention peut également contenir, à titre d'additif, un ou plusieurs composés entrant dans la catégorie des gélifiants, c'est-à-dire capables de conférer une viscosité suffisante à l'émulsion pour maintenir en suspension les divers composants de ladite émulsion.The emulsion according to the invention may also contain, as additive, one or more compounds falling within the category of gelling agents, that is to say capable of conferring a sufficient viscosity on the emulsion to maintain the suspension in suspension. various components of said emulsion.
Ces gélifiants pourront avantageusement être choisis parmi les gélifiants couramment utilisés, et notamment choisis parmi, à titre d'exemples non limitatifs, parmi le carbomer, l'hydroxyéthylcellulose, la méthylcellulose, la gomme de guar, la gomme xanthane, l'hectorite, la pectine, le silicate de magnésium et d'aluminium, les gélifiants de la famille des polyacrylamides tels que le mélange copolymère acryloyldiméthyltaurate de sodium / isohexadécane / polysorbate 80 vendu sous le nom Simulgel 600® par la société Seppic, le mélange polyacrylamide / isoparaffine C13-14 / laureth-7 comme, par exemple, celui vendu sous le nom de Sepigel 305® par la société Seppic, la famille des polymères acryliques couplés à des chaînes hydrophobes tel que le copolymère PEG-150/decyl/SMDI vendu sous le nom de Aculyn 44® (polycondensat comprenant au moins comme éléments, un polyéthylèneglycol à 150 ou 180 moles d'oxyde d'éthylène, de l'alcool décylique et du méthylène bis(4-cyclohexylisocyanate) (SMDI), à 35% en poids dans un mélange de propylèneglycol (39%) et d'eau (26%)), la famille des amidons modifiés tels que l'amidon de pomme de terre modifié vendu sous le nom de Structure Solanace® ou bien les mélanges de deux ou plusieurs d'entre eux.These gelling agents may advantageously be chosen from the gelling agents currently used, and especially chosen from, by way of non-limiting examples, among carbomer, hydroxyethylcellulose, methylcellulose, guar gum, xanthan gum, hectorite, pectin, magnesium aluminum silicate, gelling agents of the family of polyacrylamides such as the mixture sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 sold under the name Simulgel 600 ® by the company SEPPIC, the polyacrylamide / isoparaffin C13 14 / laureth-7 as, for example, the one sold under the name Sepigel 305 ® by Seppic, the family of acrylic polymers coupled to hydrophobic chains, such as the copolymer PEG-150 / decyl / SMDI sold under the name Aculyn 44 ® (polycondensate comprising at least, as components, a polyethylene glycol containing 150 or 180 mol of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexylisocyanate) (SMDI), at 35% by weight in a mixture of propylene glycol (39%) and water (26%)), the family of modified starches such as modified potato starch sold under the name Structure Solanace ® or mixtures of two or more of them.
Les gélifiants préférés sont la gomme xanthane, le silicate de magnésium et d'aluminium (Veegum K de Vanderbilt), le silicate de magnésium et d'aluminium / aluminium / Titanium Dioxide(Veegum ULTRA de Vanderbilt) ou leurs mélanges.The preferred gelling agents are xanthan gum, magnesium aluminum silicate (Vanderbilt Veegum K), magnesium silicate and aluminum / aluminum / Titanium Dioxide (Vanderbilt Veegum ULTRA) or mixtures thereof.
Selon un mode de réalisation préféré, l'émulsion de type huile-dans-eau de la présente invention comprend : a. de 35% à 45% en poids d'une phase grasse ; b. de 5% à 15% en poids d'un système émulsionnant non ionique ; c. de 15% à 20% en poids d'au moins un agent propénétrant ; d. de 0,01% à 0,5% en poids d'au moins un agent thérapeutique ; e. de 5% à 50% en poids d'eau ; et f. des additifs, de préférence entre 0,2% à 25% en poids.According to a preferred embodiment, the oil-in-water emulsion of the present invention comprises: a. from 35% to 45% by weight of a fatty phase; b. from 5% to 15% by weight of a nonionic emulsifier system; vs. from 15% to 20% by weight of at least one propenetrating agent; d. from 0.01% to 0.5% by weight of at least one therapeutic agent; e. from 5% to 50% by weight of water; and F. additives, preferably between 0.2% to 25% by weight.
Selon un autre aspect, la présente invention concerne un procédé de préparation de l'émulsion de type huile-dans-eau telle que définie précédemment, caractérisé en ce qu'il comprend les étapes de : a. dissolution et/ou dispersion dans l'eau, sous agitation, d'au moins un agent pro-pénétrant et du ou des éventuels additifs, à une température comprise entre 600C et 95°C, jusqu'à obtention d'une phase aqueuse homogène ; b. incorporation, sous agitation, de la phase aqueuse dans la phase grasse, dans laquelle a été solubilisé le couple d'émulsionnants, préalablement chauffée à une température comprise entre 600C et 950C ; et c. incorporation, sous agitation, et à une température inférieure à 4O0C, de l'agent thérapeutique, éventuellement solubilisé au préalable dans un solvant approprié.According to another aspect, the present invention relates to a process for preparing the oil-in-water type emulsion as defined above, characterized in that it comprises the steps of: a. dissolution and / or dispersion in water, with stirring, of at least one pro-penetrating agent and the optional additive (s), at a temperature of between 60 ° C. and 95 ° C., until a phase is obtained homogeneous aqueous; b. incorporation, with stirring, of the aqueous phase in the fatty phase, in which the pair of emulsifiers, previously heated to a temperature of between 60 ° C. and 95 ° C., has been solubilized; and vs. incorporation, with stirring and at a temperature below 4O 0 C, of the therapeutic agent, may be dissolved beforehand in a suitable solvent.
Par solvant approprié, on entend tout solvant capable de solubiliser le ou les agents thérapeutique, et/ou de dissoudre le ou les agents thérapeutiques, lorsque ceux-ci sont sous forme solide, afin de permettre leur parfaite incorporation dans l'émulsion phase grasse/phase aqueuse.By appropriate solvent is meant any solvent capable of solubilizing the therapeutic agent (s), and / or of dissolving the therapeutic agent (s), when these are in solid form, in order to allow their perfect incorporation into the fatty phase emulsion. aqueous phase.
Selon encore un autre aspect, la présente invention concerne une formulation galénique physiologiquement acceptable et compatible avec l'application topique sur la peau, les phanères ou les muqueuses, comprenant au moins une émulsion de type huile-dans-eau, telle qu'elle vient d'être définie dans le présent exposé. Selon un mode de réalisation la forme galénique est une émulsion huile-dans-eau proprement dite.According to yet another aspect, the present invention relates to a physiologically acceptable galenic formulation which is compatible with topical application to the skin, superficial body growths or mucous membranes, comprising at least one oil-in-water type emulsion, as it comes from to be defined in this presentation. According to one embodiment, the dosage form is an oil-in-water emulsion itself.
L'invention concerne également l'utilisation de l'émulsion décrite supra ou de la formulation précitée pour l'application sur la peau, les phanères ou les muqueuses d'au moins un agent thérapeutique appartenant à la classe des corticostéroïdes, en particulier, en vue de leur utilisation pour la prévention et/ou le traitement des maladies dermatologiques.The invention also relates to the use of the emulsion described above or the aforementioned formulation for application to the skin, superficial body growths or mucous membranes of at least one therapeutic agent belonging to the class of corticosteroids, in particular in view of their use for the prevention and / or treatment of dermatological diseases.
Lesdits agents thérapeutiques convenant particulièrement bien dans les domaines de traitement suivants :Said therapeutic agents are particularly suitable in the following treatment areas:
1) pour traiter les affections dermatologiques liées à un désordre de la kératinisation portant sur la différenciation et sur la prolifération, notamment pour traiter les acnés vulgaires, comédoniennes, polymorphes, rosacées, les acnés nodulokystiques, conglobata, les acnés séniles, les acnés secondaires telles que l'acné solaire, médicamenteuse ou professionnelle,1) for treating dermatological disorders related to a disorder of keratinization relating to differentiation and proliferation, in particular to treat vulgar, comedonal, polymorphic, rosacea acne, nodulocystic acne, conglobata, senile acnes, secondary acnes such as that solar acne, medicated or professional,
2) pour traiter d'autres types de troubles de la kératinisation, notamment les ichtyoses, les états ichtyosiformes, la maladie de Darrier, les kératodermies palmoplantaires, les leucoplasies et les états leucoplasiformes, le lichen cutané ou muqueux (buccal),2) to treat other types of keratinization disorders, including ichthyosis, ichthyosiform states, Darrier's disease, palmoplantar keratoderma, leukoplakia and leukoplasiform states, cutaneous or mucosal lichen (buccal),
3) pour traiter d'autres affections dermatologiques avec une composante immuno-allergique inflammatoire, avec ou sans trouble de la prolifération cellulaire, et notamment toutes les formes de psoriasis, qu'il soit cutané, muqueux ou unguéal, et même le rhumatisme psoriasique, ou encore l'atopie cutanée, telle que l'eczéma ou l'atopie respiratoire ou encore l'hypertrophie gingivale,3) for treating other dermatological conditions with an inflammatory immunoallergic component, with or without cell proliferation disorder, and in particular all forms of psoriasis, whether cutaneous, mucous or ungueal, and even psoriatic arthritis, or cutaneous atopy, such as eczema or respiratory atopy or gingival hypertrophy,
4) pour traiter toutes les proliférations dermiques ou épidermiques qu'elles soient bénignes ou malignes, qu'elles soient ou non d'origine virale telles que verrues vulgaires, les verrues planes et Pépidermodysplasie verruciforme, les papillomatoses orales ou florides, le lymphome T, et les proliférations pouvant être induites par les ultra-violets notamment dans le cas des épithélioma baso et spinocellulaires, ainsi que toute lésion précancéreuse cutanées telles que les kératoacanthomes,4) to treat all dermal or epidermal proliferations whether benign or malignant, whether or not of viral origin such as common warts, flat warts and verruciform epidermodysplasia, oral or florid papillomatosis, T-cell lymphoma, and proliferations that can be induced by ultraviolet rays, in particular in the case of baso and squamous cell carcinoma, as well as any precancerous cutaneous lesions such as keratoacanthomas,
5) pour traiter d'autres désordres dermatologiques tels que les dermatoses immunes telles le lupus érythémateux, les maladies immunes huileuses et les maladies du collagène, telle la sclérodermie,5) to treat other dermatological disorders such as immune dermatoses such as lupus erythematosus, oily immune diseases and collagen diseases, such as scleroderma,
6) dans le traitement d'affections dermatologiques ou générales à composante immunologique,6) in the treatment of dermatological or general affections with an immunological component,
7) dans le traitement de désordres cutanés dus à une exposition aux rayonnements U.V. ainsi que pour réparer ou lutter contre le vieillissement de la peau, qu'il soit photo-induit ou chronologique, ou pour réduire les pigmentations et les kératoses actiniques, ou toutes pathologies associées au vieillissement chronologique ou actinique, telle la xérose,7) in the treatment of cutaneous disorders due to exposure to UV radiation as well as to repair or fight against aging of the skin, whether photo-induced or chronological, or to reduce pigmentations and actinic keratoses, or all pathologies associated with chronological or actinic aging, such as xerosis,
8) pour lutter contre les troubles de la fonction sébacée tels que l'hyperséborrhée de l'acné, la séborrhée simple, ou la dermite séborrhéique,8) for combating sebaceous function disorders such as acne hyperseborrhoea, simple seborrhoea, or seborrheic dermatitis,
9) pour prévenir ou traiter les troubles de la cicatrisation, ou pour prévenir ou pour réparer les vergetures,9) for preventing or treating healing disorders, or for preventing or repairing stretch marks,
10) dans le traitement des désordres de la pigmentation, tel l'hyperpigmentation, le mélasma, l'hypopigmentation ou le vitiligo,10) in the treatment of disorders of pigmentation, such as hyperpigmentation, melasma, hypopigmentation or vitiligo,
11) dans la prévention ou le traitement de l'alopécie de différentes origines, notamment l'alopécie due à la chimiothérapie ou aux rayonnements.11) in the prevention or treatment of alopecia of different origins, including alopecia due to chemotherapy or radiation.
Parmi les maladies dermatologiques visées, l'émulsion de type huile-dans-eau de la présente invention s'est révélée tout à fait adaptée à la prévention et au traitement de toutes les formes de psoriasis, qu'il soit cutané, muqueux ou unguéal.Among the dermatological diseases targeted, the oil-in-water emulsion of the present invention has proved to be entirely suitable for the prevention and treatment of all forms of psoriasis, whether cutaneous, mucous or ungual. .
La présente invention va maintenant être illustrée au moyen des exemples suivants qui ne conduisent à aucune limitation, mais ont pour but de présenter et d'expliquer la mise en œuvre de certains modes de réalisation préférés de l'invention. EXEMPLESThe present invention will now be illustrated by means of the following examples which do not lead to any limitation, but are intended to present and explain the implementation of certain preferred embodiments of the invention. EXAMPLES
Exemple 1 : Mode opératoire :Example 1: Procedure:
Les formulations 1, 2, 3 et 4 présentées dans les exemples 2, 3, 4 et 5 suivants, ont été obtenues selon le mode opératoire décrit ci-dessous.Formulations 1, 2, 3 and 4 presented in Examples 2, 3, 4 and 5 below, were obtained according to the procedure described below.
Préparation d'une émulsion de type huile-dans-eauPreparation of an oil-in-water emulsion
La phase grasse est pesée dans un bêcher de réception qui est ensuite placé au bain-marie à 78°C.The fat phase is weighed in a receiving beaker which is then placed in a waterbath at 78 ° C.
La phase aqueuse est pesée dans un bêcher, puis l'acide citrique est ajouté. Le citrate de sodium est ensuite dispersé sous forte agitation.The aqueous phase is weighed in a beaker and then the citric acid is added. The sodium citrate is then dispersed with vigorous stirring.
Les gélifiants sont ensuite additionnés, puis, après homogénéisation, le propylène glycol, en chauffant à 780C sous agitation Rayneri.The gelling agents are then added and, after homogenization, propylene glycol, by heating at 78 ° C. with Rayneri stirring.
La phase grasse chaude est alors placée sous agitation Rayneri.The hot fatty phase is then stirred Rayneri.
La phase aqueuse est versée dans la phase grasse sous agitation (1000 tr/mn) et en chauffant à 78°C pendant 10 mn. On laisse sous agitation (1000 tr/mn), sans chauffage.The aqueous phase is poured into the fatty phase with stirring (1000 rpm) and heating at 78 ° C for 10 min. It is left stirring (1000 rpm), without heating.
Pendant ce temps, l'agent thérapeutique est préparé en l'additionnant, sous agitation magnétique, dans un bêcher, à du propylène glycol, jusqu'à dissolution complète.Meanwhile, the therapeutic agent is prepared by adding it, under magnetic stirring, in a beaker, to propylene glycol, until complete dissolution.
Cette phase active est ensuite incorporée dans l'émulsion, en dessous de 400C.This active phase is then incorporated into the emulsion, below 40 ° C.
Exemple 2 - formulation 1Example 2 - formulation 1
Exemple 3 - formulation 2Example 3 - formulation 2
Exemple 4 - formulation 3 Example 4 - formulation 3
Stabilité physique de la formulation 3 :Physical stability of formulation 3:
À température ambiante (Ta), l'observation macroscopique permet de garantir l'intégrité physique des produits et l'observation microscopique permet de vérifier qu'il n'y a pas recristallisation de l'actif solubilisé et pas d'évolution significative de la taille des globules de Pémulsion.At room temperature (Ta), the macroscopic observation makes it possible to guarantee the physical integrity of the products and the microscopic observation makes it possible to verify that there is no recrystallization of the solubilized active ingredient and no significant evolution of the size of the blood cells of the emulsion.
À 40C, l'observation microscopique vérifie la non recristallisation de l'actif solubilisé.At 40 ° C., the microscopic observation verifies the non-recrystallization of the solubilized active agent.
À 45°C, vérification macroscopique de l'intégrité du produit fini.At 45 ° C, macroscopic verification of the integrity of the finished product.
Les résultats sont reproduits dans le tableau suivant :The results are reproduced in the following table:
Conditions de Durée de Seuil pH Apparence stockage stockage d'écoulementThreshold Duration Conditions pH Appearance Storage Flow Storage
HaakeHaake
Ta t = 0 Tau 0 = 49 Pa.s'1 5,28 Crème blanche onctueuse Ta t = 0 Tau 0 = 49 Pa.s ' 1 5,28 Creamy white cream
Données rhéologiques :Rheological data:
On utilise un rhéomètre HAAKE® de type VT500 avec un mobile de mesure SVDIN.A HAAKE ® rheometer VT500 type with a measurement mobile SVDIN is used.
Les rhéogrammes ont été réalisés à 250C en faisant varier la vitesse de cisaillement dans le temps, et en mesurant la contrainte.The rheograms were performed at 25 0 C by varying the shear rate over time, and measuring the stress.
Par seuil d'écoulement (tau 0), on entend la force nécessaire (contrainte de cisaillement minimum) pour vaincre les forces de cohésion de type Van der Waals et provoquer l'écoulement. Le seuil d'écoulement est assimilé à la valeur trouvée à 4 s"1.By flow threshold (tau 0) is meant the force required (minimum shear stress) to overcome Van der Waals cohesive forces and cause flow. The flow threshold is equivalent to the value found at 4 s -1 .
Stabilité chimique :Chemical stability:
La stabilité chimique est un dosage, par HPLC, de l'actif et des conservateurs à température ambiante (Ta) et à 45°C.Chemical stability is an assay, by HPLC, of the active and preservatives at room temperature (Ta) and at 45 ° C.
Les données sont reproduites dans les tableaux suivants :The data are reproduced in the following tables:
Propionate de clobétasolClobetasol propionate
Exemple 5 - formulation 4Example 5 - formulation 4
Stabilité physique et chimique de la formulation relative à l'exemple 5 selon les spécifications établies :Physical and chemical stability of the formulation relating to Example 5 according to the established specifications:
Exemple 6 : Formulation réalisée avec un analogue de vitamine D comme agent thérapeutique Example 6 Formulation with a Vitamin D Analog as Therapeutic Agent
Cette formulation est conforme à l'objet de la présente invention : aucune recristallisation de l'agent thérapeutique n'a été constatée après 3 mois à 4°C.This formulation is in accordance with the object of the present invention: no recrystallization of the therapeutic agent was observed after 3 months at 4 ° C.
Exemple 7 : ÉVALUATION DE L'EFFET VASOCONSTRICTEUR DES ÉMULSIONSExample 7: EVALUATION OF THE EMULSION VASOCONSTRICTOR EFFECT
Les tests d'évaluation sont effectués sur les formulations 2, 3 et 4 des exemples 3, 4 et 5, et, à titre comparatif avec les produits commerciaux Temovate Cream® et Temovate Emollient Cream®. L'étude a été réalisée sur 7 sujets sains, masculin ou féminin, âgés de 18 à 70 ans.The evaluation tests are carried out on the formulations 2, 3 and 4 of Examples 3, 4 and 5, and, for comparison with the commercial products Temovate Cream ® and Temovate Emollient Cream ® . The study was conducted on 7 healthy subjects, male or female, aged 18 to 70 years.
MÉTHODOLOGIEMETHODOLOGY
L'étude est effectuée sur 2 journées. Les trois formulations et les deux produits de référence ont été appliqués sur chaque volontaire.The study is carried out over 2 days. The three formulations and the two reference products were applied to each volunteer.
Une zone ne recevant pas de produit a servi de zone témoin.An area not receiving product served as a control area.
Sur chaque volontaire et sur chaque zone étudiée (3 zones par avant bras), les évaluations suivantes ont été réalisées :On each volunteer and on each studied area (3 zones per forearm), the following evaluations were performed:
- cotations cliniques basâtes de la vasoconstriction et mesures basâtes de la colorimétrie.- basal clinical ratings of vasoconstriction and basal measures of colorimetry.
- application du produit sur chaque zone traitée (zone de 1 ,5 cm2, 10 μL de produit/zone), puis enlèvement de l'excès, 4 heures plus tard.- application of the product to each treated area (area of 1.5 cm 2 , 10 μL of product / area), then removal of the excess, 4 hours later.
- cotations cliniques de la vasoconstriction et mesures de colorimétrie 4 heures et 20 heures après enlèvement de l'excès, soit à J0T8 et J1T24.- Clinical ratings of vasoconstriction and colorimetric measurements 4 hours and 20 hours after removal of the excess, ie on J0T8 and J1T24.
CRITÈRES D'ÉVALUATIONEVALUATION CRITERIA
Critère principal : Évaluation clinique de la vasoconstriction suivant une échelle de 0 à 4.Primary end point: Clinical assessment of vasoconstriction on a scale of 0-4.
Critère secondaire : Mesures biophysiques de la colorimétrie : a* et L*.Secondary Criterion: Biophysical measures of colorimetry: a * and L *.
ANALYSES STATISTIQUESSTATISTICAL ANALYZES
Les variables obtenues ont été soumises à une analyse de variante et chaque formulation a été comparée au site non traité et au produit de référence à chaque temps de mesure.The obtained variables were subjected to a variant analysis and each formulation was compared to the untreated site and the reference product at each measurement time.
RESULTATSRESULTS
Tous les produits testés présentent un blanchiment maximal 4 heures après enlèvement de l'excès.All the tested products show a maximum whitening 4 hours after removal of the excess.
Les deux produits de référence et les trois formulations testées ont une cinétique de blanchiment différente.Both reference products and the three formulations tested have different bleaching kinetics.
On constate que Temovate Cream® induit le blanchiment le plus important. Statistiquement, I1AUC de Temovate Cream® est significativement différente de l'AUC de la zone non traitée et de la formulation 2 de l'exemple 3 pour le paramètre a*. Pour le paramètre L*, l'AUC de Temovate Cream® est significativement différente de l'AUC de toutes les autres zones de test, excepté de celle traitée avec Temovate Emollient Cream®.It is found that Temovate Cream ® induces the most important whitening. Statistically, 1 AUC of Temovate Cream ® is significantly different from the AUC of the untreated zone and formulation 2 of Example 3 for the parameter a *. For parameter L *, the AUC of Temovate Cream ® is significantly different from the AUC all other test areas, except those treated with Temovate Emollient Cream ® .
On observe également que les 3 produits suivants : Temovate Emollient Cream®, la formulation 3 de l'exemple 4 et la formulation 2 de l'exemple 3 sont assez proches entre eux. Les AUC de ces 3 produits sont toutes significativement différentes de I1AUC de la zone non traitée pour le paramètre a*. Pour le paramètre L*, seule l'AUC de la Formulation de l'exemple 3 n'est pas différente de la zone non traitée.It is also observed that the 3 following products: Temovate Emollient Cream ® , formulation 3 of Example 4 and formulation 2 of Example 3 are quite close to each other. The AUCs of these 3 products are all significantly different from the 1 AUC of the untreated zone for parameter a *. For parameter L *, only the AUC of the Formulation of Example 3 is not different from the untreated zone.
L' AUC de la formulation 2 de l'exemple 3 apparaît comme la plus faible aussi bien pour Ie paramètre a* que pour le paramètre L*. Statistiquement, I1AUC de cette dernière apparaît comme significativement différente de la zone non traitée pour le paramètre a* mais pas pour le paramètre L*.The AUC of formulation 2 of Example 3 appears to be the weakest for both the parameter a * and the parameter L *. Statistically, I 1 AUC of the latter appears as significantly different from the untreated zone for the parameter a * but not for the parameter L *.
Au niveau statistique, c'est le test t de Student qui a été réalisé avec un seuil de significativité inférieur à 0,1.At the statistical level, Student's t-test was performed with a significance threshold of less than 0.1.
CONCLUSIONCONCLUSION
Les formulations des exemples 3, 4 et 5 présentent donc des effets vasoconstricteurs équivalents à des composition sur le marché (Temovate Cream®) de type onguent.The formulations of Examples 3, 4 and 5 thus have vasoconstrictor effects equivalent to compositions on the market (Temovate Cream®) of ointment type.
Exemple 8 ÉVALUATION DE L'EFFET IRRITANT DES ÉMULSIONSExample 8 EVALUATION OF THE IRRITATING EFFECT OF EMULSIONS
PRINCIPE DU TESTPRINCIPLE OF THE TEST
Ce test permet d'évaluer le potentiel irritant de la Formulation 2 et de la Formulation 3 dans différents tests d'irritation chez le volontaire sain.This test evaluates the irritating potential of Formulation 2 and Formulation 3 in various irritation tests in healthy volunteers.
L'étude a été réalisée sur 12 sujets sains âgés de 18 à 55 ans. Le traitement a été effectué sur diverses zones, comme suit :The study was conducted on 12 healthy subjects aged 18 to 55 years. The treatment was carried out on various zones, as follows:
• Zones "pli du coude" : 1 application quotidienne pendant 14 jours. • "Elbow fold" areas: 1 daily application for 14 days.
• Zones "stripping" : 1 application quotidienne pendant 7 jours.• Stripping zones: 1 daily application for 7 days.
• Zones "patch" : 1 application unique pendant 20 heures. • Patch areas: 1 single application for 20 hours.
MÉTHODOLOGIE L'étude s'est déroulée sur 15 jours pour chaque volontaire. Les volontaires se sont présentés tous les jours de l'étude au centre de tests, sauf à J4, J8, J16, J11 et J12 où les applications avaient lieu à domicile.METHODOLOGY The study was conducted over 15 days for each volunteer. The volunteers presented themselves every day at the test center, except at D4, D8, D16, D11 and D12 where the applications were performed at home.
Sur chaque volontaire, 3 zones de 4 x 4 cm ont été délimitées sur la face interne des avant-bras, dont une zone dans le pli du coude. Les deux Formulations ont été appliquées sur le côté gauche ou droit suivant une procédure de randomisation générée avant l'étude.On each volunteer, 3 zones of 4 x 4 cm were delimited on the inner side of the forearms, including an area in the fold of the elbow. Both Formulations were applied on the left or right side following a randomization procedure generated prior to the study.
• Z1-Z4 (zones "pli du coude") : application quotidienne des produits pendant 14jours à raison de 2 mg/cm2.• Z1-Z4 ("elbow crease" zones): daily application of the products for 14 days at a rate of 2 mg / cm 2 .
• Z2-Z5 (zones "stripping") : 20 strippings ont été réalisés à l'aide de D-squame à JO puis application quotidienne des produits pendant 7 jours à raison de 2 mg/cm2.• Z2-Z5 ("stripping" zones): 20 strippings were performed using D-squame at OJ then daily application of the products for 7 days at a rate of 2 mg / cm 2 .
• Z3-Z6 (zones "patch") : application unique des produits sous cupule en aluminium (Finn Chambers®) de 12 mm de diamètre pendant 20 h au minimum.• Z3-Z6 (Patch Zones): Unique application of 12 mm diameter Finn Chambers ® aluminum cup products for a minimum of 20 hours.
RÉSULTATSRESULTS
Les tests réalisés comme indiqués ci-dessus montrent que les Formulations des exemples 3 et 4 selon la présente invention ne présentent aucun phénomène d'irritation. The tests carried out as indicated above show that the Formulations of Examples 3 and 4 according to the present invention show no irritation phenomenon.

Claims

Revendications claims
1. Émulsion de type huile-dans-eau renfermant au moins un agent thérapeutique pour application topique et comprenant en outre : a) une phase grasse ; b) de 1 % à 15% en poids d'un système émulsionnant non ionique ; c) de 1 % à 30% en poids d'au moins un agent propénétrant ; et d) de 5% à 50% en poids d'eau, caractérisée en ce que la quantité de ladite phase grasse représente de 35% à 50% en poids.An oil-in-water type emulsion containing at least one therapeutic agent for topical application and further comprising: a) a fat phase; b) from 1% to 15% by weight of a nonionic emulsifier system; c) from 1% to 30% by weight of at least one propenetrating agent; and d) from 5% to 50% by weight of water, characterized in that the amount of said fat phase is from 35% to 50% by weight.
2. Émulsion selon la revendication 1 , dans laquelle la phase grasse consiste essentiellement en composés choisis parmi les émollients, les cires et les alcools gras.2. Emulsion according to claim 1, wherein the fatty phase consists essentially of compounds chosen from emollients, waxes and fatty alcohols.
3. Émulsion selon l'une quelconque des revendications précédentes, dans laquelle le système émulsionnant non ionique comprend au moins un tensioactif non ionique présentant une HLB supérieure à environ 10 et au moins un tensioactif non ionique présentant une HLB inférieure à environ 10.An emulsion according to any one of the preceding claims, wherein the nonionic emulsifier system comprises at least one nonionic surfactant having an HLB greater than about 10 and at least one nonionic surfactant having an HLB of less than about 10.
4. Émulsion selon l'une quelconque des revendications précédentes, dans laquelle le système émulsionnant est composé du couple de tensioactifs monostéarate de glycérol / Ceteareth 20.An emulsion according to any one of the preceding claims, wherein the emulsifier system is composed of the glycerol monostearate / Ceteareth 20 surfactant pair.
5. Émulsion selon l'une quelconque des revendications précédentes, dans laquelle l'agent propénétrant est choisi parmi le propylène glycol, le dipropylène glycol, le dipélargonate de propylène glycol, le lauroglycol, l'éthoxydiglycol, l'urée, l'acétone, l'acide oléique et les mélanges d'un ou plusieurs d'entre eux, de préférence parmi le propylène glycol, le dipropylène glycol et le dipélargonate de propylène glycol, de préférence encore l'agent propénétrant est le propylène glycol.Emulsion according to any one of the preceding claims, in which the propenetrating agent is chosen from propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol, ethoxydiglycol, urea and acetone. oleic acid and mixtures of one or more of them, preferably from propylene glycol, dipropylene glycol and propylene glycol dipelargonate, more preferably the propenetrating agent is propylene glycol.
6. Émulsion selon l'une quelconque des revendications précédentes, dans laquelle l'agent thérapeutique est un composé utile dans le traitement et/ou la prévention des maladies de la peau. Emulsion according to any one of the preceding claims, wherein the therapeutic agent is a compound useful in the treatment and / or prevention of skin diseases.
7. Émulsion selon l'une quelconque des revendications précédentes, dans laquelle l'agent thérapeutique appartient à la classe des corticostéroïdes.Emulsion according to any one of the preceding claims, wherein the therapeutic agent belongs to the class of corticosteroids.
8. Émulsion selon la revendication 7, dans laquelle l'agent thérapeutique est choisi parmi le clobétasol 17-propionate, le désonide et le valérate de bétaméthasone.An emulsion according to claim 7, wherein the therapeutic agent is selected from clobetasol 17-propionate, desonide and betamethasone valerate.
9. Émulsion selon l'une des revendications 1 à 6, dans laquelle l'agent thérapeutique appartient à la classe des rétinoides.9. Emulsion according to one of claims 1 to 6, wherein the therapeutic agent belongs to the class of retinoids.
10. Émulsion selon l'une des revendications 1 à 6, dans laquelle l'agent thérapeutique appartient à la classe des analogues de vitamines D.10. Emulsion according to one of claims 1 to 6, wherein the therapeutic agent belongs to the class of vitamin D analogs.
11. Émulsion selon l'une quelconque des revendications précédentes, dans laquelle la quantité d'eau représente de 5% à 50%, avantageusement environ 30% en poids de l'émulsion.An emulsion according to any one of the preceding claims, wherein the amount of water is from 5% to 50%, advantageously about 30% by weight of the emulsion.
12. Émulsion selon l'une quelconque des revendications précédentes, comprenant en outre un ou plusieurs additifs.An emulsion according to any one of the preceding claims, further comprising one or more additives.
13. Émulsion selon la revendication 12, dans laquelle le ou les additifs sont choisis parmi les séquestrants, les antioxydants, les filtres solaires, les conservateurs, les charges, les électrolytes, les humectants, les tampons pH, les colorants, basiques ou d'acides usuels, minéraux ou organiques, les parfums, les huiles essentielles, les actifs cosmétiques, les hydratants, les vitamines, les sphingolipides, les composés autobronzants, les gélifiants, les agents apaisants et les protecteurs de la peau.An emulsion according to claim 12, wherein the one or more additives are selected from sequestering agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, pH buffers, dyes, or basic common, mineral or organic acids, perfumes, essential oils, cosmetic active ingredients, moisturizers, vitamins, sphingolipids, self-tanning compounds, gelling agents, soothing agents and skin protectors.
14. Émulsion selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle comprend : a. de 35% à 45% en poids d'une phase grasse ; b. de 5% à 15% en poids d'un système émulsionnant non ionique ; c. de 15% à 20% en poids d'au moins un agent propénétrant ; d. des additifs ; e. de 0,01% à 0,5% en poids d'au moins un agent thérapeutique ; et f. de 5% à 50% en poids d'eau. 14. Emulsion according to any one of the preceding claims, characterized in that it comprises: a. from 35% to 45% by weight of a fatty phase; b. from 5% to 15% by weight of a nonionic emulsifier system; vs. from 15% to 20% by weight of at least one propenetrating agent; d. additives; e. from 0.01% to 0.5% by weight of at least one therapeutic agent; and F. from 5% to 50% by weight of water.
15. Procédé de préparation d'une émulsion selon l'une des revendications 1 à 14, comprenant les étapes de : a. dissolution et/ou dispersion dans l'eau, sous agitation, d'au moins un agent pro-pénétrant et du ou des éventuels additifs, à une température comprise entre 6O0C et 950C, jusqu'à obtention d'une phase aqueuse homogène ; b. incorporation, sous agitation, de la phase aqueuse dans la phase grasse, dans laquelle ont été solubilisés le couple d'émulsionnant, préalablement chauffée à une température comprise entre 600C et 95°C ; et c. incorporation, sous agitation, et à une température inférieure à 400C, de l'agent thérapeutique, éventuellement solubilisé au préalable dans un solvant approprié.15. Process for preparing an emulsion according to one of claims 1 to 14, comprising the steps of: a. dissolution and / or dispersion in water, with stirring, of at least one pro-penetrating agent and the optional additive (s), at a temperature of between 60 ° C. and 95 ° C., until a phase is obtained homogeneous aqueous; b. incorporation, with stirring, of the aqueous phase in the fatty phase, in which the emulsifier pair, solubilized beforehand, has been solubilized and previously heated to a temperature of between 60 ° C. and 95 ° C .; and c. incorporation, with stirring, and at a temperature below 40 0 C, the therapeutic agent, optionally solubilized beforehand in a suitable solvent.
16. Utilisation d'une émulsion selon l'une quelconque des revendications 1 à 14, pour la préparation d'un médicament pour la prévention et/ou le traitement des maladies dermatologiques.16. Use of an emulsion according to any one of claims 1 to 14, for the preparation of a medicament for the prevention and / or treatment of dermatological diseases.
17. Utilisation selon la revendication 16 pour la prévention et/ou le traitement du psoriasis. 17. Use according to claim 16 for the prevention and / or treatment of psoriasis.
EP06794313A 2005-08-11 2006-08-09 Oil-in-water-type emulsion for topical application in dermatology Withdrawn EP1915133A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0508524A FR2889662B1 (en) 2005-08-11 2005-08-11 OIL-IN-WATER EMULSION FOR TOPICAL APPLICATION IN DERMATOLOGY
PCT/FR2006/001930 WO2007020349A1 (en) 2005-08-11 2006-08-09 Oil-in-water-type emulsion for topical application in dermatology

Publications (1)

Publication Number Publication Date
EP1915133A1 true EP1915133A1 (en) 2008-04-30

Family

ID=36273334

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06794313A Withdrawn EP1915133A1 (en) 2005-08-11 2006-08-09 Oil-in-water-type emulsion for topical application in dermatology

Country Status (12)

Country Link
US (1) US20080207570A1 (en)
EP (1) EP1915133A1 (en)
JP (1) JP2009504619A (en)
KR (1) KR20080033389A (en)
CN (1) CN101304729A (en)
AU (1) AU2006281346B2 (en)
BR (1) BRPI0616520A2 (en)
CA (1) CA2617963A1 (en)
FR (1) FR2889662B1 (en)
MX (1) MX2008002012A (en)
RU (2) RU2008108973A (en)
WO (1) WO2007020349A1 (en)

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
EP2526930B1 (en) 2005-06-01 2013-12-25 GlaxoSmithKline Intellectual Property Development Limited Vitamin formulation
FR2892936A1 (en) * 2005-11-10 2007-05-11 Galderma Res & Dev PHARMACEUTICAL OR COSMETIC COMPOSITION, AND MIXED SOLUBILIZATION METHOD FOR PREPARING THE COMPOSITION.
PL2474545T3 (en) 2005-12-13 2017-04-28 Incyte Holdings Corporation Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors
FR2898498B1 (en) * 2006-03-15 2008-11-28 Galderma Sa NOVEL TOPIC COMPOSITIONS IN THE FORM OF O / W EMULSION COMPRISING PRO-PENETRANT GLYCOL
FR2898499B1 (en) * 2006-03-15 2008-11-28 Galderma Sa NOVEL TOPIC COMPOSITIONS IN THE FORM OF O / W EMULSION COMPRISING PRO-PENETRANT GLYCOL
US10265265B2 (en) * 2007-03-15 2019-04-23 Drug Delivery Solutions Limited Topical composition
FR2915682B1 (en) * 2007-05-04 2009-07-03 Galderma Res & Dev DERMATOLOGICAL AND COSMETIC DEPIGMENTING COMPOSITIONS, PROCESSES FOR THEIR PREPARATION, AND USES THEREOF
HUE043732T2 (en) 2007-06-13 2019-09-30 Incyte Holdings Corp Use of salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h- pyrazol-1-yl)-3- cyclopentylpropanenitrile
EP2008651A1 (en) 2007-06-26 2008-12-31 Drug Delivery Solutions Limited A bioerodible patch
US20100249060A1 (en) * 2009-02-23 2010-09-30 Smith Jan G Topical formulation of low level clobetasol propionate for treating disorders of the skin and mucous membranes
WO2010115164A1 (en) * 2009-04-03 2010-10-07 Medicis Pharmaceutical Corporation Topical compositions
AU2010249380B2 (en) 2009-05-22 2015-08-20 Incyte Holdings Corporation N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as Janus kinase inhibitors
CA2761954C (en) 2009-05-22 2018-07-31 Incyte Corporation 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octane- or heptane-nitrile as jak inhibitors
US9364485B2 (en) 2009-08-31 2016-06-14 Dr. Reddy's Laboratories Ltd. Topical formulations comprising a steroid
TW201113285A (en) 2009-09-01 2011-04-16 Incyte Corp Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
US20110212035A1 (en) * 2010-02-26 2011-09-01 Collegium Pharmaceutical, Inc. Emollient foams for treatment of dermatoses
AR081315A1 (en) 2010-03-10 2012-08-08 Incyte Corp HETEROCICLIC DERIVATIVES OF PIPERIDIN AND PIRIMIDIN -4-IL-AZETIDINA, A CRYSTALLINE FORM OF THE SALT OF ACETONITRILADIPICO ACID OF A PYRIMIDINIC DERIVATIVE, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND USE OF THE SAME THINGS WITH THE TREATMENT OF INJECTION , T
NZ603686A (en) * 2010-05-21 2014-11-28 Incyte Corp Topical formulation for a jak inhibitor
EA026201B1 (en) 2010-11-19 2017-03-31 Инсайт Холдингс Корпорейшн Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors
PL2686017T3 (en) 2011-03-14 2020-03-31 Drug Delivery Solutions Limited An ophthalmic composition
AR086983A1 (en) 2011-06-20 2014-02-05 Incyte Corp DERIVATIVES OF AZETIDINIL FENIL, PIRIDIL OR PIRAZINIL CARBOXAMIDA AS JAK INHIBITORS
TW201313721A (en) 2011-08-18 2013-04-01 Incyte Corp Cyclohexyl azetidine derivatives as JAK inhibitors
UA111854C2 (en) 2011-09-07 2016-06-24 Інсайт Холдінгс Корпорейшн METHODS AND INTERMEDIATE COMPOUNDS FOR JAK INHIBITORS
JP5909941B2 (en) * 2011-09-08 2016-04-27 大正製薬株式会社 External preparation containing steroidal anti-inflammatory drug
AR091079A1 (en) 2012-05-18 2014-12-30 Incyte Corp DERIVATIVES OF PIRROLOPIRIMIDINA AND PIRROLOPIRIDINA REPLACED WITH PIPERIDINILCICLOBUTILO AS JAK INHIBITORS
PL2919766T3 (en) 2012-11-15 2021-10-04 Incyte Holdings Corporation Sustained-release dosage forms of ruxolitinib
AU2014225938B2 (en) 2013-03-06 2018-07-19 Incyte Holdings Corporation Processes and intermediates for making a JAK inhibitor
US10292955B2 (en) * 2013-04-04 2019-05-21 Hyundai Pharm Co., Ltd. Composition for external use preparation with improved transdermal permeability
CA2912873A1 (en) * 2013-06-03 2014-12-11 Tolmar, Inc. Corticosteroid compositions
MX2016001639A (en) 2013-08-07 2016-10-07 Incyte Corp Sustained release dosage forms for a jak1 inhibitor.
US20160184431A1 (en) * 2014-03-11 2016-06-30 Promius Pharma Llc Topical compositions comprising a corticosteroid
WO2015184305A1 (en) 2014-05-30 2015-12-03 Incyte Corporation TREATMENT OF CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (aCML) BY INHIBITORS OF JAK1
DE102014010875A1 (en) * 2014-07-25 2016-01-28 Basf Se Transparent textile care products
WO2017037663A1 (en) 2015-09-02 2017-03-09 Cadila Healthcare Limited Topical compositions comprising corticosteroids
CN108348456B (en) 2015-10-30 2021-09-17 亭铂医药有限责任公司 Isotretinoin formulations and uses and methods thereof
CR20200024A (en) * 2017-06-23 2020-03-12 Salvat Lab Sa An oil-in-water nanoemulsion composition of clobetasol
US10596161B2 (en) 2017-12-08 2020-03-24 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
DK3746429T3 (en) 2018-01-30 2022-05-02 Incyte Corp PROCEDURES FOR THE PREPARATION OF (1- (3-FLUORO-2- (TRIFLUOROMETHYL) ISONICOTINYL) PIPERIDIN-4-ON)
EP3542788A1 (en) 2018-03-19 2019-09-25 MC2 Therapeutics Limited Topical composition comprising calcipotriol and betamethasone dipropionate
UA127925C2 (en) 2018-03-30 2024-02-14 Інсайт Корпорейшн Treatment of hidradenitis suppurativa using jak inhibitors
AU2019472201A1 (en) * 2019-11-01 2022-05-12 Colgate-Palmolive Company Stable low pH personal care compositions and methods for the same
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
CN113925800A (en) * 2021-11-03 2022-01-14 时垠(上海)生物科技有限公司 Method for improving emulsifying capacity of glycerin monostearate emulsifying system

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4837378A (en) * 1986-01-15 1989-06-06 Curatek Pharmaceuticals, Inc. Topical metronidazole formulations and therapeutic uses thereof
JP3454385B2 (en) * 1993-10-15 2003-10-06 啓次郎 佐藤 Method for producing O / W type skin cream
AU4991497A (en) * 1996-11-12 1998-06-03 Pharmacia & Upjohn Company Pharmaceutical compositions containing kukui nut oil
US5972993A (en) * 1998-03-20 1999-10-26 Avon Products, Inc. Composition and method for treating rosacea and sensitive skin with free radical scavengers
FR2787025B1 (en) * 1998-12-14 2002-10-11 Oreal COMPOSITION IN THE FORM OF AN O/W EMULSION WITH A HIGH WAX CONTENT AND USES THEREOF IN THE COSMETIC AND DERMATOLOGICAL FIELDS
US6403654B1 (en) * 2000-04-13 2002-06-11 Mariana De Oliveira Compositions for and method of treatment for psoriasis
US6699464B1 (en) * 2001-07-30 2004-03-02 Stiefel Laboratories, Inc. Compositions for treatment of hyperpigmentation and methods for making and using such compositions
FR2833841B1 (en) * 2001-12-21 2005-07-22 Galderma Res & Dev GEL COMPRISING AT LEAST ONE RETINOID AND BENZOYL PEROXIDE
US20030129208A1 (en) * 2002-01-07 2003-07-10 Alberts David S. Topical application of alpha-DFMO and anti-inflammatory drug for treatment of actinic keratoses
WO2003097100A1 (en) * 2002-05-15 2003-11-27 Engelbrecht, Edna Topical composition for the treatment of inflammatory conditions of the skin
ATE556711T1 (en) * 2003-03-13 2012-05-15 3M Innovative Properties Co METHOD FOR IMPROVING SKIN QUALITY
TWI397427B (en) * 2004-08-31 2013-06-01 Stiefel Res Australia Pty Ltd Micro emulsion and sub-micron emulsion process and composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007020349A1 *

Also Published As

Publication number Publication date
CA2617963A1 (en) 2007-02-22
CN101304729A (en) 2008-11-12
AU2006281346B2 (en) 2012-03-29
RU2011125550A (en) 2012-12-27
KR20080033389A (en) 2008-04-16
FR2889662A1 (en) 2007-02-16
AU2006281346A1 (en) 2007-02-22
MX2008002012A (en) 2008-03-25
WO2007020349A1 (en) 2007-02-22
RU2008108973A (en) 2009-09-20
FR2889662B1 (en) 2011-01-14
BRPI0616520A2 (en) 2011-06-21
JP2009504619A (en) 2009-02-05
US20080207570A1 (en) 2008-08-28

Similar Documents

Publication Publication Date Title
EP1915133A1 (en) Oil-in-water-type emulsion for topical application in dermatology
CA2466321C (en) Gel comprising at least a retinoid and benzoyl peroxide
EP3025763B1 (en) Cream gel comprising at least one retinoid and benzoyl peroxide
EP2125117B1 (en) Emulsion comprising at least one retinoid and benzoyl peroxide
CA2631123C (en) Composition in the form of a spray containing a corticoid and an oil phase
CA2670601A1 (en) Ointment compositions comprising a vitamin d derivative
EP1758588A1 (en) Pharmaceutical composition comprising an ointment and two solubilized active principles
CA2745457A1 (en) Topical pharmaceutical composition containing a water-sensitive active principle
EP2240152B1 (en) Composition containing a retinoid and dispersed benzoyle peroxide
EP2872116B1 (en) Dermatological composition including oleosomes and retinoids, method for preparing same and use thereof
EP2029133B1 (en) Compositions comprising at least one naphthoic acid derivative and at least one film-forming agent, methods for preparing same, and uses thereof
FR2894474A1 (en) Depigmenting composition in the form of hydroalcoholic gel, useful e.g. to prevent/treat dermatological disorders related to pigmentation disorders, comprises a phenolic derivative, a retinoid and a corticoid
EP2173326A2 (en) Dermatological composition containing calcitriol lipidic vesicles, method for preparing same and use thereof

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080311

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

17Q First examination report despatched

Effective date: 20090512

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20121217