WO2011113826A1 - Novel topical corticosteroid formulation - Google Patents

Novel topical corticosteroid formulation Download PDF

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Publication number
WO2011113826A1
WO2011113826A1 PCT/EP2011/053882 EP2011053882W WO2011113826A1 WO 2011113826 A1 WO2011113826 A1 WO 2011113826A1 EP 2011053882 W EP2011053882 W EP 2011053882W WO 2011113826 A1 WO2011113826 A1 WO 2011113826A1
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WO
WIPO (PCT)
Prior art keywords
composition
weight
corticosteroid
glycerol
vaseline
Prior art date
Application number
PCT/EP2011/053882
Other languages
French (fr)
Inventor
Jean-François CORDOLIANI
Valérie MUGUET
Virginie Blanchard
Original Assignee
Pierre Fabre Dermo-Cosmetique
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Publication of WO2011113826A1 publication Critical patent/WO2011113826A1/en

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    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/04—Antipruritics
    • 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

  • the invention relates to a novel topical corticosteroid formulation.
  • TCS topical corticosteroids
  • TCS cross the cytoplasmic membrane by simple diffusion and bind to a specific receptor.
  • the TCS- receptor complex crosses the nuclear membrane and, by interaction with a nuclear chromatin receptor site, acts on DNA, modifies gene expression and induces modification of transcription. They act on genes involved in proliferation, which explains their antiproliferative action, and on genes involved in synthesis of cytokines (IL-1, TNF- , etc.), which explains their immunosuppressive action.
  • TCS are thus anti-inflammatories , immunosuppressors and antimitotics.
  • TCS anti-inflammatory activity
  • the new TCS classification adopted in France is the international classification. TCS are classified in four activity levels: very potent, potent, moderately potent, and mildly potent.
  • - psoriasis especially used for the scalp and face, inverse psoriasis and localised plaques. They can be associated with salicylic acid in very hyperkeratotic lesions;
  • TCS eliminates pruritus and decreases infiltration. It is preferable to use level 4 TCS.
  • Celestoderm ® (moderately potent TCS) contains betamethasone valerate (0.05%) and as excipients chlorocresol , macrogol 1000 monocetyl ether, cetostearyl alcohol, Vaseline, liquid paraffin, sodium dihydrogen phosphate monohydrate, concentrated phosphoric acid and water.
  • Betneval ® in cream form contains betamethasone valerate (0.1%) and as excipients chlorocresol, cetomacrogol 1000, cetostearyl alcohol, Vaseline, liquid paraffin, sodium phosphate dihydrate, concentrated phosphoric acid and water.
  • Diprosone ® (potent TCS) in cream form contains betamethasone dipropionate (0.05%) and as excipients Vaseline, liquid paraffin, macrogol 1000 monocetyl ether, sodium dihydrogen phosphate monohydrate, chlorocresol, concentrated phosphoric acid and water.
  • Dermoval ® (very potent TCS) in gel form contains clobetasol propionate (0.05%) and as excipients carbomer, isopropyl alcohol, 4% sodium hydroxide solution and water. Applications are limited to two per day. Suggesting dosage is one application per day.
  • Eumovate ® (moderately potent TCS) in cream form contains 0.05% clobetasone butyrate and as excipients glycerol, glycerol monostearate, cetostearyl alcohol, beeswax substitute 6621, Arlacel ® 165 (glyceryl stearate and stearate PEG-100 emulsifier) , dimethicone, chlorocresol, sodium citrate, citric acid monohydrate and purified water.
  • Tridesonit ® (moderately potent TCS) in cream form contains :
  • Lanette SX ® cetostearyl alcohol, sodium lauryl sulphate, sodium cetostearyl sulphate
  • synthetic spermaceti Cutina CP-A
  • synthetic beeswax B-Wax
  • Vaseline light liquid paraffin
  • glycerol 5%)
  • sodium lauryl sulphate 1%
  • calcium acetate calcium acetate
  • aluminium sulphate white dextrin (0.019%)
  • purified water and
  • Application WO2007/070423 discloses a topical composition comprising fluticasone propionate, at least 40% propylene glycol by weight and benzyl alcohol in a quantity sufficient to dissolve fluticasone propionate.
  • United States patent 5,635,497 discloses an oil- in-water, fatty cream for topical administration comprising 60% to 80% by weight of fatty components, 1.5% to 5% by weight of at least one non-ionic, hydrophilic surfactant, about 6% fatty alcohols and esters, an active ingredient and water.
  • the active ingredient is hydrocortisone.
  • the inventors sought to provide a novel dermatological corticosteroid composition wherein the corticosteroid preserves its stability and wherein the composition preserves the properties of its emollient base in terms of hydration of the skin and improvement of the barrier function of the skin (WO/EP2009/056021) .
  • the inventors also sought to classify the potency of this novel topical corticosteroid formulation compared to known formulations Diprosone ® , Dermoval ® and Eumovate ® .
  • this novel topical corticosteroid formulation shows a delayed vasoconstrictor effect of the corticosteroid.
  • This delay effect has as an advantageous consequence to make it possible to space applications further apart than the proprietary drugs described above and thus to decrease the side effects of corticosteroids applied locally to the dermis.
  • the invention relates to a dermatological composition
  • a dermatological composition comprising a corticosteroid in combination with an emollient base consisting of an oil-in-water or water-in-oil emulsion of glycerol, Vaseline and liquid paraffin.
  • the invention further relates to a method for preparing a composition according to the invention, wherein the corticosteroid is introduced into the lipophilic phase of the final emulsion, comprising the following steps:
  • the invention further relates to a transdermal device comprising a composition according to the invention on the surface in contact with the skin.
  • the invention further relates to a composition according to the invention as a drug.
  • the invention further relates to a composition according to the invention for the use thereof in the treatment of eczema, atopic dermatitis, stasis dermatitis, psoriasis, seborrhoeic dermatitis, lichenification, non-parasitic prurigo, granuloma annulare, discoid lupus erythematosus, genital lichen sclerosus, dyshidrosis, and pruritus due to mycosis fungoides or insect bites.
  • the invention further relates to the use of a composition according to the invention for preparing a drug for treating eczema, atopic dermatitis, stasis dermatitis, psoriasis, seborrhoeic dermatitis, lichenification, non-parasitic prurigo, granuloma annulare, discoid lupus erythematosus, genital lichen sclerosus, dyshidrosis, and pruritus due to mycosis fungoides or insect bites.
  • the present invention further relates to a method for treating eczema, atopic dermatitis, stasis dermatitis, psoriasis, seborrhoeic dermatitis, lichenification, non-parasitic prurigo, granuloma annulare, discoid lupus erythematosus, genital lichen sclerosus, dyshidrosis, and pruritus due to mycosis fungoides or insect bites, comprising the topical administration of an effective quantity of a composition according to the invention to a patient who has need of it.
  • the invention further relates to a composition according to the invention as a drug applied to the skin with a dosing schedule such that two successive applications are spaced at least 24 h apart, preferably at least 48 h apart.
  • the invention further relates to the use in a topical corticosteroid formulation of an emollient base in oil-in-water or water-in-oil emulsion form consisting of glycerol, Vaseline and liquid paraffin, to delay the effect of the corticosteroid.
  • the invention further relates to the use in a topical corticosteroid formulation of the combination of an emollient base in oil-in-water or water-in-oil emulsion form consisting of glycerol, Vaseline and liquid paraffin and of at least one hydrophobic silicone, preferably two, to delay the effect of the corticosteroid.
  • the invention further relates to the use of a composition according to the invention for preparing a drug applied to the skin with a dosing schedule such that two successive applications are spaced at least 24 h apart.
  • the invention further relates to a composition according to the invention as a drug to delay the effect of the corticosteroid.
  • the invention further relates to the use of a composition according to the invention for preparing a drug to delay the effect of the corticosteroid.
  • the invention further relates to a method of treatment comprising local application, at least every 24 h, preferably at least every 48 h, of a dermatological composition according to the invention.
  • the dermatological composition according to the invention comprises a corticosteroid in combination with an emollient base consisting of an oil-in-water or water-in-oil emulsion of glycerol, Vaseline and liquid paraffin .
  • the dermatological composition according to the invention further comprises squalane.
  • Suitable corticosteroids in the composition according to the invention can be selected from the group comprising alclometasone dipropionate, amcinonide, beclomethasone dipropionate, bethamethasone benzoate, betamethasone valerate, bethamethasone dipropionate, bethamethasone valerate, budesonide, clobetasol propionate, preferentially clobetasol-17- propionate, clobetasol butyrate, desonide, desoximetasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, flurandrenolone, fluprednidene acetate, fluocortolone, fluocortin butyl, fluocinonide, fluocinolone acetonide, fluclorolone acetonide, flumethasone pyvalate, furdiline hydrochloride, flumetholone,
  • the corticosteroid is advantageously betamethasone dipropionate .
  • the dermatological composition according to the invention comprises another dermatological active ingredient, preferably one or more other corticosteroids.
  • the corticosteroid concentration in the composition according to the invention can vary from 0.001% to 2% by weight, preferably from 0.005% to 0.1% by weight compared to the total weight of the composition, more preferably from 0.01% to 0.05% by weight compared to the total weight of the composition.
  • the corticosteroid of the composition according to the invention is betamethasone dipropionate and its concentration can vary from 0.005% to 0.5% by weight compared to the total weight of the composition.
  • the corticosteroid of the composition according to the invention is betamethasone dipropionate and its concentration is 0.05%.
  • emollient base means the combination of glycerol, Vaseline and liquid paraffin in the form of an oil-in- water or water-in-oil emulsion.
  • the emollient base of the composition according to the invention is formulated with a pH between about 4.0 and about 6.0, preferably between about 4.0 and about 5.5, most preferably between about 4.3 and about 5.3.
  • the emollient base is present in a proportion between 10% and 50% and preferentially between 20% and 30% by weight compared to the total weight of the composition.
  • the glycerol concentration is between 5% and 30%, preferentially between 10% and 20% and most preferentially about 15% by weight compared to the total weight of the composition.
  • the Vaseline concentration is between 3% and 20%, preferentially between 5% and 10% and most preferentially about 8% by weight compared to the total weight of the composition.
  • the liquid paraffin concentration is between 0.5% and 5%, preferentially between 1% and 3% and most preferentially about 2% by weight compared to the total weight of the composition.
  • composition according to the invention contains between 0% and 10% squalane, preferentially between 0.5% and 9.5%, and most preferentially about 9.5% by weight compared to the total weight of the composition .
  • water is between 30% and 80% by weight compared to the total weight of the composition .
  • the composition according to the invention comprises about 15% glycerol, about 8% Vaseline and about 2% liquid paraffin by weight compared to the total weight of the composition.
  • the dermatological composition according to the invention further comprises typical dermatologically compatible excipients.
  • the dermatologically compatible excipients can be any excipient among those known to persons skilled in the art in order to obtain a composition for topical application in the form of a cream, lotion, gel, pomade, emulsion, microemulsion, spray, etc.
  • composition according to the invention can in particular contain additives and formulation aids such as emulsifiers, thickeners, gelling agents, water fixatives, spreading agents, stabilisers, dyes, pH adjusters, fragrances and preservatives.
  • additives and formulation aids such as emulsifiers, thickeners, gelling agents, water fixatives, spreading agents, stabilisers, dyes, pH adjusters, fragrances and preservatives.
  • Suitable emulsifiers include stearic acid, trolamine or soda, macrogol stearate, macrogol cetostearyl ether, macrogol stearyl ether or the mixture cetostearyl alcohol/ceteareth-20 , macrogol 15 hydroxystearate, macrogol 20 glycerol monostearate , sorbitan stearate and polysorbate 60, sucrose stearate, propylene glycol mono palmitostearate, stearoyl macrogolglycerides , sodium stearate and cetostearyl ether .
  • the composition according to the invention comprises at least one emulsifier on a stearic base, most preferentially macrogol stearate.
  • emulsifier on a stearic base means any amphiphilic molecule comprising one or more stearic chains (ether or ester) .
  • the composition according to the invention contains about 0.5% to 10% emulsifier by weight compared to the total weight of the composition.
  • the composition according to the invention contains between 1% and 5% stearic acid, preferably about 3% by weight compared to the total weight of the composition.
  • the composition according to the invention contains between 0% and 2% trolamine or soda, preferably about 0.5% by weight compared to the total weight of the composition.
  • the composition according to the invention contains between 0% and 2% macrogol stearate, preferably about 0.5% by weight compared to the total weight of the composition.
  • the composition according to the invention contains between 0% and 2% macrogol cetostearyl ether, preferably about 2% by weight compared to the total weight of the composition.
  • the emulsifiers of the composition according to the invention consist of stearic acid and a stearic emulsifier, preferably macrogol stearate.
  • Suitable thickeners include glycerol monostearate, glycerol dibehenate, glycerol distearate, solid paraffins, waxes of plant, mineral or animal origin, fatty acid esters such as cetyl palmitate and fatty alcohols such as cetyl alcohol.
  • the composition according to the invention contains about 5% thickener by weight compared to the total weight of the composition.
  • the composition according to the invention contains between 0.5% and 10% glycerol monostearate, preferably about 5% by weight compared to the total weight of the composition.
  • the thickeners of the composition according to the invention consist of glycerol monostearate.
  • Suitable antimicrobial preservatives include methyl, propyl and butyl parahydroxybenzoates, chlorocresol , benzoic acid and phenoxyethanol.
  • the composition according to the invention contains between 0% and 0.5% antimicrobial preservative by weight compared to the total weight of the composition, as a function of the antimicrobial protection desired.
  • the composition according to the invention contains between 0.05% and 0.5% chlorocresol , preferably about 0.075% by weight compared to the total weight of the composition.
  • the preservatives of the composition according to the invention consist of an antimicrobial preservative, preferably chlorocresol.
  • Suitable spreading agents include silicone oils such as dimethicone, polydimethylcyclosiloxane, isopropyl myristate, isopropyl palmitate, squalane, octyldodecanol , dipropylene glycol dipelargonate , propylene glycol dicaprylate dicaprate and cetostearyl isononanoate .
  • the composition according to the invention contains about 2% spreading agents by weight compared to the total weight of the composition.
  • the composition according to the invention contains between 0.2% and 2% dimethicone, preferably about 0.5% by weight compared to the total weight of the composition.
  • the composition according to the invention contains between 1% and 3% polydimethylcyclosiloxane, preferably about 2.5% by weight compared to the total weight of the composition.
  • the spreading agents of the composition according to the invention consist of dimethicone and polydimethylcyclosiloxane.
  • composition according to the invention as a drug comprises at least one hydrophobic silicone, preferably two.
  • the composition according to the invention as a drug further comprises at least one linear silicone and one cyclic silicone, most preferentially dimethicone and polydimethylcyclosiloxane .
  • Suitable water fixatives include polyethylene glycol, preferably polyethylene glycol 600.
  • the composition according to the invention contains about 8% water fixatives by weight compared to the total weight of the composition.
  • the composition according to the invention contains between 2% and 10% polyethylene glycol, preferably about 5% by weight compared to the total weight of the composition.
  • Suitable pH adjusters include citric acid and/or salts thereof, phosphoric acid and/or salts thereof, alone or in combination.
  • the composition according to the invention contains between 0% and 1% pH adjusters compared to the total weight of the composition.
  • the water used for the aqueous phase of the emulsion can be purified or thermal spring water having dermato-cosmetic properties.
  • composition according to the invention comprises:
  • composition according to the invention comprises:
  • composition according to the invention comprises:
  • composition according to the invention comprises:
  • composition according to the invention comprises:
  • the present invention further relates to a method for preparing a composition according to the invention, wherein the corticosteroid is introduced into the lipophilic phase of the final emulsion, with the method comprising the following steps:
  • Steps (i) and (ii) are preferably carried out simultaneously .
  • the corticoid is introduced into the lipophilic phase of the final emulsion by its introduction in the emulsion after the step (iii) .
  • the lipophilic phase of step I comprises emulsifiers, thickeners and/or spreading agents .
  • the aqueous phase of step (ii) comprises purified water, glycerol and a water fixative (PEG 600, for example) .
  • PEG 600 a water fixative
  • composition according to the invention as a drug is applied for at least two weeks, preferably at least one month.
  • composition according to the invention as a drug is applied every 24 h, preferably every 48 h, for at least two weeks, preferably at least one month.
  • composition according to the invention as a drug and the treatment method according to the invention are for treating eczema, atopic dermatitis, stasis dermatitis, psoriasis, seborrhoeic dermatitis, lichenification, non-parasitic prurigo, granuloma annulare, discoid lupus erythematosus, genital lichen sclerosus, dyshidrosis, and pruritus due to mycosis fungoides or insect bites.
  • the treatment method according to the invention is undertaken for at least two weeks, preferably at least one month.
  • the treatment method according to the invention is undertaken for at least one month with an application every 24 h, preferably every 48 h.
  • Figure 1 Comparison of mean values of the area under the curve (from 0 to 24 h) for measurements of corneometry (normalised compared to the baseline value before application) , after application of the various products to be tested.
  • Figure 2 Comparison of mean values of the area under the curve at Day 19 for measurements of corneometry (normalised compared to the baseline value before application) , after application of the various products to be tested.
  • Figure 3 Comparison of mean values of the area under the curve at Day 22 for measurements of corneometry (normalised compared to the baseline value before application) , after application of the various products to be tested.
  • Figure 4 Evolution over time of mean values of the Aa* parameter (normalised compared to the baseline value before application) , after application of the various products to be tested.
  • Figure 5 Evolution over time of mean values of the visual score (VS) parameter, after application of the various products to be tested.
  • Example 1 Formulations Formulation 1 (composition in g/100 g)
  • Betamethasone valerate 0.0243 g
  • Liquid paraffin 2 g
  • Glycerol monostearate 5 g
  • Macrogol glycerol hydroxystearate 0.5 g
  • Formulation 2 composition in g/100 g
  • Betamethasone dipropionate 0.064 g (equivalent to
  • Liquid paraffin 2 g
  • Betamethasone dipropionate 0.128 g (equivalent to
  • Liquid paraffin 4 g
  • Macrogol cetostearyl ether 2 g
  • Formulation 4 composition in g/100 g
  • Betamethasone dipropionate 0.064 g (equivalent to 0.05 g in base)
  • Liquid paraffin 2 g
  • Glycerol monostearate 5 g
  • Macrogol 600 5 g
  • Formulation 5 composition in g/100 g
  • Betamethasone dipropionate 0.064 g (equivalent to 0.05 g in base)
  • Glycerol monostearate 5 g
  • Macrogol 600 5 g
  • formulations 4 and 5 The stability of formulations 4 and 5 was evaluated compared to Diprosone ® cream.
  • Betamethasone dipropionate 0.064 g (equivalent to
  • Macrogol 1000 monocetyl ether 2.25 g
  • Formulation 4 without buffering agent is galenically more desirable than formulation 5.
  • the presence of buffer notoriously fluidifies the preparation .
  • the drop in active ingredient observed in formulations 4, 5 and Diprosone ® after 3 months at 25°C and 40°C is comparable.
  • Formulation 4 is stable after two months of storage at 25°C and 40°C.
  • Example 2 Double-blind test of tolerance and emollient properties (by corneometry) vs . Diprosone ® 0.05% cream in healthy volunteers
  • the emollient properties of the formulations according to the invention were evaluated on 36 healthy volunteers after repeated applications, compared to the carrier and the reference product Diprosone ® cream.
  • the products are applied daily in an amount of 10 ⁇ per product tested, on the ventral surface of the forearms, in non-occlusive conditions, for 5 days per week from Monday to Friday, for a 3-week period. Hydration of the skin, and more precisely of the stratum corneum, is measured by means of a corneometer according to standardised procedures, on the application zones of the products tested.
  • the volunteers included in the study all exhibited dry skin (either a value ⁇ 50 CM, arbitrary unit related to the measurement of electrical conductance) before inclusion in the study.
  • the hydration of the stratum corneum obtained after application of the formulations according to the invention proves significantly better than after application of Diprosone ® cream.
  • the hydrating effect is shown as of 4 hours after a single application ( Figure 1) , is maintained after repeated applications ( Figure 2) , and persists after the applications are stopped, i.e., remanence of the hydrating effect evaluated by measurement of corneometry 3 days after the last application ( Figure 3) .
  • Formulations according to the invention tested (composition in g/100 g)
  • Betamethasone dipropionate 0.05%, 0.025% and 0.010%
  • White Vaseline 8 g
  • Liquid paraffin 2 g
  • Glycerol monostearate 5 g
  • Macrogol 600 5 g
  • Diprosone ® cream, Dermoval ® cream and Eumovate ® cream after application on healthy skin of healthy subjects, for their response to vasoconstriction.
  • vasoconstrictive properties of the products were evaluated by measurements of skin colour measured by means of a chromameter (Aa*, principal criterion;
  • AL* secondary criterion
  • VS visual score, secondary criterion graded on a 5-point scale
  • Carrier means the formulation according to the invention lacking corticosteroid.
  • vasoconstrictive properties of the formulations according to the invention were evaluated in 40 healthy volunteers after a single application of the products, compared to the carrier and to the reference products Diprosone * cream, Dermoval * cream and Eumovate ® cream.
  • the products are applied in an amount of 10 ⁇ per product tested, on the forearms, in non-occlusive conditions, for 6 hours.
  • Measurements and evaluations take place 30 minutes before the application (baseline value) , at 6 hours (T 6h ), 8 hours (T 8h ), 10 hours (T 10h ) , 12 hours (T 12h ) , 14 hours (Ti4h) , 24 hours (T 2 4h) and 30 hours (T 30 h) after application of the products to be tested at T 0 .
  • the visual lightening response of the skin is graded on a 5-point scale.
  • the formulations according to the invention show stable or strongly decreasing (Dermoval ® ) vasoconstriction between 14 h and 30 h after the single application
  • the formulations according to the invention in particular the 0.05% formulation, show vasoconstriction that strongly increases between 14 h and 30 h after the single application, revealing a delay effect of the corticosteroid in the formulations according to the invention ( Figure 4 by chromametric measurement and Figure 5 by visual measurement) .

Abstract

The invention relates to a dermatological composition comprising a corticosteroid in combination with an emollient base consisting of an oil-in-water or water- in-oil emulsion of glycerol, Vaseline and liquid paraffin.

Description

NOVEL TOPICAL CORTICOSTEROID FORMULATION
DESCRIPTION The invention relates to a novel topical corticosteroid formulation.
Local steroidal anti-inflammatories or topical corticosteroids (TCS) are widely used in dermatological therapeutics .
TCS cross the cytoplasmic membrane by simple diffusion and bind to a specific receptor. The TCS- receptor complex crosses the nuclear membrane and, by interaction with a nuclear chromatin receptor site, acts on DNA, modifies gene expression and induces modification of transcription. They act on genes involved in proliferation, which explains their antiproliferative action, and on genes involved in synthesis of cytokines (IL-1, TNF- , etc.), which explains their immunosuppressive action.
They also inhibit release of arachidonic acid, a precursor of many molecules involved in inflammation ( leukotrienes ) .
TCS are thus anti-inflammatories , immunosuppressors and antimitotics.
Their potency depends on their cutaneous bioavailability and the affinity of TCS for the receptor .
Their cutaneous bioavailability corresponds to the penetration and diffusion of TCS in the epidermis. It varies as a function of TCS lipid solubility and the nature of the excipient.
Their anti-inflammatory activity is due to binding (affinity) with cell receptors. This is the most sought therapeutic effect of TCS. There are multiple targets of this effect: leukocytes, macrophages and endogenous chemical mediators. They decrease erythema and oedema whatever the cause of the inflammation. The new TCS classification adopted in France is the international classification. TCS are classified in four activity levels: very potent, potent, moderately potent, and mildly potent.
The indications for TCS for their anti¬ inflammatory effect are as follows:
contact eczema associated with expulsion of the allergen;
atopic dermatitis;
other eczemas: varicose, nummular, dyshidrotic eczema;
- photosensitizations ;
localised lichen planus;
- insect bites.
The indications for TCS for their anti¬ proliferative effect are:
- psoriasis: especially used for the scalp and face, inverse psoriasis and localised plaques. They can be associated with salicylic acid in very hyperkeratotic lesions;
- hypertrophic and keloids scars: very potent TCS;
lichenification : TCS eliminates pruritus and decreases infiltration. It is preferable to use level 4 TCS.
The indications for TCS for their immunosuppressive effect are:
- bullous pemphigoid: use of very potent TCS.
Several commercial dermatological corticosteroid formulations are known.
Celestoderm® (moderately potent TCS) contains betamethasone valerate (0.05%) and as excipients chlorocresol , macrogol 1000 monocetyl ether, cetostearyl alcohol, Vaseline, liquid paraffin, sodium dihydrogen phosphate monohydrate, concentrated phosphoric acid and water.
Betneval® (potent TCS) in cream form contains betamethasone valerate (0.1%) and as excipients chlorocresol, cetomacrogol 1000, cetostearyl alcohol, Vaseline, liquid paraffin, sodium phosphate dihydrate, concentrated phosphoric acid and water.
Diprosone® (potent TCS) in cream form contains betamethasone dipropionate (0.05%) and as excipients Vaseline, liquid paraffin, macrogol 1000 monocetyl ether, sodium dihydrogen phosphate monohydrate, chlorocresol, concentrated phosphoric acid and water.
Dermoval® (very potent TCS) in gel form contains clobetasol propionate (0.05%) and as excipients carbomer, isopropyl alcohol, 4% sodium hydroxide solution and water. Applications are limited to two per day. Suggesting dosage is one application per day.
Eumovate® (moderately potent TCS) in cream form contains 0.05% clobetasone butyrate and as excipients glycerol, glycerol monostearate, cetostearyl alcohol, beeswax substitute 6621, Arlacel® 165 (glyceryl stearate and stearate PEG-100 emulsifier) , dimethicone, chlorocresol, sodium citrate, citric acid monohydrate and purified water.
Tridesonit® (moderately potent TCS) in cream form contains :
- desonide as corticosteroid (0.05%) and
- as excipients:
Lanette SX® (cetostearyl alcohol, sodium lauryl sulphate, sodium cetostearyl sulphate) , synthetic spermaceti (Cutina CP-A) , synthetic beeswax (B-Wax) , Vaseline, light liquid paraffin, glycerol (5%) , sodium lauryl sulphate (1%), calcium acetate, aluminium sulphate, white dextrin (0.019%), purified water, and
- methyl parahydroxybenzoate (0.15% ) as preservative .
Application WO2007/070423 discloses a topical composition comprising fluticasone propionate, at least 40% propylene glycol by weight and benzyl alcohol in a quantity sufficient to dissolve fluticasone propionate.
United States patent 5,635,497 discloses an oil- in-water, fatty cream for topical administration comprising 60% to 80% by weight of fatty components, 1.5% to 5% by weight of at least one non-ionic, hydrophilic surfactant, about 6% fatty alcohols and esters, an active ingredient and water. In the examples, the active ingredient is hydrocortisone.
The inventors sought to provide a novel dermatological corticosteroid composition wherein the corticosteroid preserves its stability and wherein the composition preserves the properties of its emollient base in terms of hydration of the skin and improvement of the barrier function of the skin (WO/EP2009/056021) .
The inventors also sought to classify the potency of this novel topical corticosteroid formulation compared to known formulations Diprosone®, Dermoval® and Eumovate®.
They then observed, in a surprising manner, that, contrary to all the other proprietary drugs, this novel topical corticosteroid formulation shows a delayed vasoconstrictor effect of the corticosteroid.
This delay effect has as an advantageous consequence to make it possible to space applications further apart than the proprietary drugs described above and thus to decrease the side effects of corticosteroids applied locally to the dermis.
Summary of the invention This is why the invention relates to a dermatological composition comprising a corticosteroid in combination with an emollient base consisting of an oil-in-water or water-in-oil emulsion of glycerol, Vaseline and liquid paraffin.
The invention further relates to a method for preparing a composition according to the invention, wherein the corticosteroid is introduced into the lipophilic phase of the final emulsion, comprising the following steps:
(i) heating the lipophilic phase at a temperature between about 70°C and about 85°C under stirring,
(ii) heating the aqueous phase at a temperature between about 70°C and about 85°C under stirring,
(iii)emulsification by introduction of the aqueous phase (ii) into the lipophilic phase (i) under stirring at a temperature between about 70°C and about 85°C,
(iv)cooling under stirring to a temperature between about 28°C and about 32°C.
The invention further relates to a transdermal device comprising a composition according to the invention on the surface in contact with the skin.
The invention further relates to a composition according to the invention as a drug.
The invention further relates to a composition according to the invention for the use thereof in the treatment of eczema, atopic dermatitis, stasis dermatitis, psoriasis, seborrhoeic dermatitis, lichenification, non-parasitic prurigo, granuloma annulare, discoid lupus erythematosus, genital lichen sclerosus, dyshidrosis, and pruritus due to mycosis fungoides or insect bites. The invention further relates to the use of a composition according to the invention for preparing a drug for treating eczema, atopic dermatitis, stasis dermatitis, psoriasis, seborrhoeic dermatitis, lichenification, non-parasitic prurigo, granuloma annulare, discoid lupus erythematosus, genital lichen sclerosus, dyshidrosis, and pruritus due to mycosis fungoides or insect bites.
The present invention further relates to a method for treating eczema, atopic dermatitis, stasis dermatitis, psoriasis, seborrhoeic dermatitis, lichenification, non-parasitic prurigo, granuloma annulare, discoid lupus erythematosus, genital lichen sclerosus, dyshidrosis, and pruritus due to mycosis fungoides or insect bites, comprising the topical administration of an effective quantity of a composition according to the invention to a patient who has need of it.
The invention further relates to a composition according to the invention as a drug applied to the skin with a dosing schedule such that two successive applications are spaced at least 24 h apart, preferably at least 48 h apart.
The invention further relates to the use in a topical corticosteroid formulation of an emollient base in oil-in-water or water-in-oil emulsion form consisting of glycerol, Vaseline and liquid paraffin, to delay the effect of the corticosteroid.
The invention further relates to the use in a topical corticosteroid formulation of the combination of an emollient base in oil-in-water or water-in-oil emulsion form consisting of glycerol, Vaseline and liquid paraffin and of at least one hydrophobic silicone, preferably two, to delay the effect of the corticosteroid. The invention further relates to the use of a composition according to the invention for preparing a drug applied to the skin with a dosing schedule such that two successive applications are spaced at least 24 h apart.
The invention further relates to a composition according to the invention as a drug to delay the effect of the corticosteroid.
The invention further relates to the use of a composition according to the invention for preparing a drug to delay the effect of the corticosteroid.
The invention further relates to a method of treatment comprising local application, at least every 24 h, preferably at least every 48 h, of a dermatological composition according to the invention.
Detailed description
The dermatological composition according to the invention comprises a corticosteroid in combination with an emollient base consisting of an oil-in-water or water-in-oil emulsion of glycerol, Vaseline and liquid paraffin .
According to one embodiment of the invention, the dermatological composition according to the invention further comprises squalane.
Suitable corticosteroids in the composition according to the invention can be selected from the group comprising alclometasone dipropionate, amcinonide, beclomethasone dipropionate, bethamethasone benzoate, betamethasone valerate, bethamethasone dipropionate, bethamethasone valerate, budesonide, clobetasol propionate, preferentially clobetasol-17- propionate, clobetasol butyrate, desonide, desoximetasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, flurandrenolone, fluprednidene acetate, fluocortolone, fluocortin butyl, fluocinonide, fluocinolone acetonide, fluclorolone acetonide, flumethasone pyvalate, feudiline hydrochloride, flumetholone, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, methylprednisolone acetate, mometasone furoate, methylprednisolone, prednisolone and triamcinolone acetonide or pharmaceutically acceptable mixtures thereof.
The corticosteroid is advantageously betamethasone dipropionate .
Advantageously, the dermatological composition according to the invention comprises another dermatological active ingredient, preferably one or more other corticosteroids.
The corticosteroid concentration in the composition according to the invention can vary from 0.001% to 2% by weight, preferably from 0.005% to 0.1% by weight compared to the total weight of the composition, more preferably from 0.01% to 0.05% by weight compared to the total weight of the composition.
Advantageously, the corticosteroid of the composition according to the invention is betamethasone dipropionate and its concentration can vary from 0.005% to 0.5% by weight compared to the total weight of the composition. In a particularly preferred manner, the corticosteroid of the composition according to the invention is betamethasone dipropionate and its concentration is 0.05%.
In the context of the present invention, "emollient base" means the combination of glycerol, Vaseline and liquid paraffin in the form of an oil-in- water or water-in-oil emulsion.
Advantageously, the emollient base of the composition according to the invention is formulated with a pH between about 4.0 and about 6.0, preferably between about 4.0 and about 5.5, most preferably between about 4.3 and about 5.3.
In the composition according to the invention, the emollient base is present in a proportion between 10% and 50% and preferentially between 20% and 30% by weight compared to the total weight of the composition.
In the composition according to the invention, the glycerol concentration is between 5% and 30%, preferentially between 10% and 20% and most preferentially about 15% by weight compared to the total weight of the composition.
In the composition according to the invention, the Vaseline concentration is between 3% and 20%, preferentially between 5% and 10% and most preferentially about 8% by weight compared to the total weight of the composition.
In the composition according to the invention, the liquid paraffin concentration is between 0.5% and 5%, preferentially between 1% and 3% and most preferentially about 2% by weight compared to the total weight of the composition.
The composition according to the invention contains between 0% and 10% squalane, preferentially between 0.5% and 9.5%, and most preferentially about 9.5% by weight compared to the total weight of the composition .
In the aqueous phase, water is between 30% and 80% by weight compared to the total weight of the composition .
Advantageously, the composition according to the invention comprises about 15% glycerol, about 8% Vaseline and about 2% liquid paraffin by weight compared to the total weight of the composition. The dermatological composition according to the invention further comprises typical dermatologically compatible excipients.
The dermatologically compatible excipients can be any excipient among those known to persons skilled in the art in order to obtain a composition for topical application in the form of a cream, lotion, gel, pomade, emulsion, microemulsion, spray, etc.
The composition according to the invention can in particular contain additives and formulation aids such as emulsifiers, thickeners, gelling agents, water fixatives, spreading agents, stabilisers, dyes, pH adjusters, fragrances and preservatives.
Suitable emulsifiers include stearic acid, trolamine or soda, macrogol stearate, macrogol cetostearyl ether, macrogol stearyl ether or the mixture cetostearyl alcohol/ceteareth-20 , macrogol 15 hydroxystearate, macrogol 20 glycerol monostearate , sorbitan stearate and polysorbate 60, sucrose stearate, propylene glycol mono palmitostearate, stearoyl macrogolglycerides , sodium stearate and cetostearyl ether .
Preferentially, the composition according to the invention comprises at least one emulsifier on a stearic base, most preferentially macrogol stearate.
The term "emulsifier on a stearic base" means any amphiphilic molecule comprising one or more stearic chains (ether or ester) .
Preferably, the composition according to the invention contains about 0.5% to 10% emulsifier by weight compared to the total weight of the composition.
Advantageously, the composition according to the invention contains between 1% and 5% stearic acid, preferably about 3% by weight compared to the total weight of the composition. Advantageously, the composition according to the invention contains between 0% and 2% trolamine or soda, preferably about 0.5% by weight compared to the total weight of the composition.
Advantageously, the composition according to the invention contains between 0% and 2% macrogol stearate, preferably about 0.5% by weight compared to the total weight of the composition.
Advantageously, the composition according to the invention contains between 0% and 2% macrogol cetostearyl ether, preferably about 2% by weight compared to the total weight of the composition.
Advantageously, the emulsifiers of the composition according to the invention consist of stearic acid and a stearic emulsifier, preferably macrogol stearate.
Suitable thickeners include glycerol monostearate, glycerol dibehenate, glycerol distearate, solid paraffins, waxes of plant, mineral or animal origin, fatty acid esters such as cetyl palmitate and fatty alcohols such as cetyl alcohol.
Preferably, the composition according to the invention contains about 5% thickener by weight compared to the total weight of the composition.
Advantageously, the composition according to the invention contains between 0.5% and 10% glycerol monostearate, preferably about 5% by weight compared to the total weight of the composition.
Advantageously, the thickeners of the composition according to the invention consist of glycerol monostearate.
Suitable antimicrobial preservatives include methyl, propyl and butyl parahydroxybenzoates, chlorocresol , benzoic acid and phenoxyethanol.
Preferably, the composition according to the invention contains between 0% and 0.5% antimicrobial preservative by weight compared to the total weight of the composition, as a function of the antimicrobial protection desired.
Advantageously, the composition according to the invention contains between 0.05% and 0.5% chlorocresol , preferably about 0.075% by weight compared to the total weight of the composition.
Advantageously, the preservatives of the composition according to the invention consist of an antimicrobial preservative, preferably chlorocresol.
Suitable spreading agents include silicone oils such as dimethicone, polydimethylcyclosiloxane, isopropyl myristate, isopropyl palmitate, squalane, octyldodecanol , dipropylene glycol dipelargonate , propylene glycol dicaprylate dicaprate and cetostearyl isononanoate .
Preferably, the composition according to the invention contains about 2% spreading agents by weight compared to the total weight of the composition.
Advantageously, the composition according to the invention contains between 0.2% and 2% dimethicone, preferably about 0.5% by weight compared to the total weight of the composition.
Advantageously, the composition according to the invention contains between 1% and 3% polydimethylcyclosiloxane, preferably about 2.5% by weight compared to the total weight of the composition.
Advantageously, the spreading agents of the composition according to the invention consist of dimethicone and polydimethylcyclosiloxane.
Advantageously, the composition according to the invention as a drug comprises at least one hydrophobic silicone, preferably two.
Preferentially, the composition according to the invention as a drug further comprises at least one linear silicone and one cyclic silicone, most preferentially dimethicone and polydimethylcyclosiloxane .
Suitable water fixatives include polyethylene glycol, preferably polyethylene glycol 600.
Preferably, the composition according to the invention contains about 8% water fixatives by weight compared to the total weight of the composition.
Advantageously, the composition according to the invention contains between 2% and 10% polyethylene glycol, preferably about 5% by weight compared to the total weight of the composition.
Suitable pH adjusters include citric acid and/or salts thereof, phosphoric acid and/or salts thereof, alone or in combination.
Preferably, the composition according to the invention contains between 0% and 1% pH adjusters compared to the total weight of the composition.
The water used for the aqueous phase of the emulsion can be purified or thermal spring water having dermato-cosmetic properties.
Advantageously, the composition according to the invention comprises:
- about 0.001% to 2% corticosteroid by weight, preferably 0.005% to 0.1% by weight,
- about 10% to 20% glycerol by weight,
about 3% to 20% Vaseline by weight,
about 0.5% to 5% liquid paraffin by weight,
- about 0% to 10% squalane,
- stearic acid and an emulsifier on a stearate base .
Advantageously, the composition according to the invention comprises:
- about 0.001% to 2% corticosteroid by weight, preferably 0.005% to 0.1% by weight - about 10% to 20% glycerol by weight,
about 5% to 10% Vaseline by weight,
about 1% to 3% liquid paraffin by weight, stearic acid and an emulsifier on a stearate base.
Advantageously, the composition according to the invention comprises:
- about 0.005% to 0.1% corticosteroid by weight,
- about 15% glycerol by weight,
- about 8% Vaseline by weight,
about 2% liquid paraffin by weight,
stearic acid and an emulsifier on a stearate base .
Advantageously, the composition according to the invention comprises:
- about 0.005% to 0.1% corticosteroid by weight,
- about 15% glycerol by weight,
about 8% Vaseline by weight,
about 2% liquid paraffin by weight, and as excipients:
- stearic acid, glycerol monostearate, polyethylene glycol 600, chlorocresol , silicone oils, macrogol stearate and water.
Advantageously, the composition according to the invention comprises:
- about 0.005% to 0.1% corticosteroid,
- about 15% glycerol,
- about 8% Vaseline,
about 2% liquid paraffin, and as excipients: - about 1% to 5% stearic acid,
- about 0.5% to 10% glycerol monostearate,
about 1% to 3% polydimethylcyclosiloxane, about 0.2% to 2% dimethicone,
- about 2% to 10% polyethylene glycol 600,
- about 0% to 2% macrogol stearate, - about 0.05% to 1% chlorocresol
complete to 100% with water.
The present invention further relates to a method for preparing a composition according to the invention, wherein the corticosteroid is introduced into the lipophilic phase of the final emulsion, with the method comprising the following steps:
(i) heating the lipophilic phase at a temperature between about 70°C and about 85°C under stirring,
(ii) heating the aqueous phase at a temperature between about 70°C and about 85°C under stirring,
(iii)emulsification by introduction of the aqueous phase (ii) into the lipophilic phase (i) under stirring at a temperature between about 70 °C and about 85°C,
(iv)cooling under stirring to a temperature between about 28°C and about 32°C.
Steps (i) and (ii) are preferably carried out simultaneously .
Preferably, the corticoid is introduced into the lipophilic phase of the final emulsion by its introduction in the emulsion after the step (iii) .
Preferably, the lipophilic phase of step I comprises emulsifiers, thickeners and/or spreading agents .
Preferably, the aqueous phase of step (ii) comprises purified water, glycerol and a water fixative (PEG 600, for example) .
Advantageously, the composition according to the invention as a drug is applied for at least two weeks, preferably at least one month.
Most preferably, the composition according to the invention as a drug is applied every 24 h, preferably every 48 h, for at least two weeks, preferably at least one month.
Advantageously, the composition according to the invention as a drug and the treatment method according to the invention are for treating eczema, atopic dermatitis, stasis dermatitis, psoriasis, seborrhoeic dermatitis, lichenification, non-parasitic prurigo, granuloma annulare, discoid lupus erythematosus, genital lichen sclerosus, dyshidrosis, and pruritus due to mycosis fungoides or insect bites.
Advantageously, the treatment method according to the invention is undertaken for at least two weeks, preferably at least one month.
Most preferably, the treatment method according to the invention is undertaken for at least one month with an application every 24 h, preferably every 48 h.
The present invention is illustrated by the following figures and examples.
Figure 1 : Comparison of mean values of the area under the curve (from 0 to 24 h) for measurements of corneometry (normalised compared to the baseline value before application) , after application of the various products to be tested.
Figure 2 : Comparison of mean values of the area under the curve at Day 19 for measurements of corneometry (normalised compared to the baseline value before application) , after application of the various products to be tested.
Figure 3 : Comparison of mean values of the area under the curve at Day 22 for measurements of corneometry (normalised compared to the baseline value before application) , after application of the various products to be tested.
Figure 4 : Evolution over time of mean values of the Aa* parameter (normalised compared to the baseline value before application) , after application of the various products to be tested.
Figure 5 : Evolution over time of mean values of the visual score (VS) parameter, after application of the various products to be tested.
EXAMPLES
Example 1 : Formulations Formulation 1 (composition in g/100 g)
Betamethasone valerate: 0.0243 g
White Vaseline: 8 g
Liquid paraffin: 2 g
Silicone oil: 2 g
Stearic acid: 2.5 g
Glycerol monostearate : 5 g
Macrogol glycerol hydroxystearate: 0.5 g
Glycerol: 10 g
Chlorocresol : 0.075 g
Water qsp : 100 g
Formulation 2 (composition in g/100 g)
Betamethasone dipropionate : 0.064 g (equivalent to
0.05 g in base)
White Vaseline: 5 g
Liquid paraffin: 2 g
Silicone oil: 1 g
Stearic acid: 2.5 g
Glycerol dibehenate : 2 g
Macrogol stearate (40): 0.25 g
Triethanolamine : 0.01 g
Glycerol: 17 g
Phenoxyethanol : 0.5 g
Water qsp: 100 g Formulation 3 (composition in g/100 g)
Betamethasone dipropionate : 0.128 g (equivalent to
0.1 g in base)
Liquid paraffin: 4 g
White Vaseline: 3 g
Squalane: 4 g
Solid paraffin: 1 g
Stearic acid: 1 g
Cetostearyl alcohol: 7 g
Macrogol cetostearyl ether: 2 g
Glycerol: 10 g
Methylparaben : 0.10 g
Propylparaben: 0.05 g
Phosphate buffer qsp pH 5.5
Water qsp: 100 g
Formulation 4 (composition in g/100 g)
Betamethasone dipropionate: 0.064 g (equivalent to 0.05 g in base)
White Vaseline: 8 g
Liquid paraffin: 2 g
Decamethylcyclopentasiloxane : 2.5 g
Dimethicone: 0.5 g
Stearic acid: 3 g
Glycerol monostearate : 5 g
Macrogol stearate (40): 0.5 g
Glycerol: 15 g
Macrogol 600: 5 g
pH: about 5
Water: qsp 100 g
Formulation 5 (composition in g/100 g)
Betamethasone dipropionate: 0.064 g (equivalent to 0.05 g in base)
White Vaseline: 8 g Liquid paraffin: 2 g
Decamethylcyclopentasiloxane : 2.5 g
Dimethicone: 0.5 g
Stearic acid: 3 g
Glycerol monostearate: 5 g
Macrogol stearate (40): 0.5 g
Glycerol: 15 g
Macrogol 600: 5 g
H3P04: 0.002 g
NaH2P04, 2H20: 0.3 g
pH: about 5
Water: qsp 100 g
The stability of formulations 4 and 5 was evaluated compared to Diprosone® cream.
Formula of Diprosone®
Betamethasone dipropionate : 0.064 g (equivalent to
0.05 g in base)
Vaseline: 15 g
Liquid paraffin: 6 g
Cetostearyl acid: 7.2 g
Macrogol 1000 monocetyl ether: 2.25 g
H3PO4: 0.002 g
NaH2P04, 1H20: 0.3 g
Chlorocresol : 0.1 g
Purified water: qsp 100 g
pH: about 5 The results are as follows:
Formulation 4 without buffering agent is galenically more desirable than formulation 5. The presence of buffer notoriously fluidifies the preparation . The drop in active ingredient observed in formulations 4, 5 and Diprosone® after 3 months at 25°C and 40°C is comparable.
Formulation 4 is stable after two months of storage at 25°C and 40°C.
Example 2: Double-blind test of tolerance and emollient properties (by corneometry) vs . Diprosone® 0.05% cream in healthy volunteers
The formulations according to the invention
(formulation 4 + 0.075% chlorocresol ) are compared with the carrier and the reference product Diprosone® 0.05% cream after repeated applications on healthy skin of healthy subjects, for their local tolerance (principal criterion) and their emollient properties (secondary criterion) . "Carrier" means the emollient formulation lacking corticosteroid.
Local tolerance of the formulations according to the invention was evaluated on 36 healthy volunteers after repeated applications, compared to the carrier and to the reference product Diprosone® cream. The products are applied daily in an amount of 50 μΐ per product tested, on the back, in occlusive conditions (small aluminium cup) , for 5 days per week from Monday to Friday, for a 3-week period. The cutaneous reaction (erythema and/or oedema) is graded on a 5-point scale. The cumulative irritation indices (sum of cutaneous reaction scores measured from Day 2 to Day 22, for each subject and each product) and mean cumulative irritation index (related to the number of effective visits) make it possible to compare the local tolerance of the formulations tested. Under the test conditions, the formulations according to the invention, whatever the concentration of betamethasone dipropionate (0.010%, 0.025% and 0.050%), are non-irritating and are tolerated as well as the reference product Diprosone" cream.
The emollient properties of the formulations according to the invention were evaluated on 36 healthy volunteers after repeated applications, compared to the carrier and the reference product Diprosone® cream. The products are applied daily in an amount of 10 μΐ per product tested, on the ventral surface of the forearms, in non-occlusive conditions, for 5 days per week from Monday to Friday, for a 3-week period. Hydration of the skin, and more precisely of the stratum corneum, is measured by means of a corneometer according to standardised procedures, on the application zones of the products tested. The volunteers included in the study all exhibited dry skin (either a value < 50 CM, arbitrary unit related to the measurement of electrical conductance) before inclusion in the study.
The hydration of the stratum corneum obtained after application of the formulations according to the invention proves significantly better than after application of Diprosone® cream. The hydrating effect is shown as of 4 hours after a single application (Figure 1) , is maintained after repeated applications (Figure 2) , and persists after the applications are stopped, i.e., remanence of the hydrating effect evaluated by measurement of corneometry 3 days after the last application (Figure 3) .
Two undesirable events in total, occurring in two patients among the 36 included, were reported during the study. None of these events was related to the products tested.
No unexpected adverse effect was observed during the study. Diprosone®, Dermoval® and Eumovate® in healthy volunteers
Formulations according to the invention tested: (composition in g/100 g)
Betamethasone dipropionate: 0.05%, 0.025% and 0.010% White Vaseline: 8 g
Liquid paraffin: 2 g
Decamethylcyclopentasiloxane : 2.5 g
Dimethicone: 0.5 g
Stearic acid: 3 g
Glycerol monostearate : 5 g
Macrogol stearate (40): 0.5 g
Glycerol: 15 g
Macrogol 600: 5 g
pH: around 5
Water: qsp 100 g
The formulations according to the invention are compared with the carrier and the reference products
Diprosone® cream, Dermoval® cream and Eumovate® cream after application on healthy skin of healthy subjects, for their response to vasoconstriction.
The vasoconstrictive properties of the products were evaluated by measurements of skin colour measured by means of a chromameter (Aa*, principal criterion;
AL*, secondary criterion) and by visual evaluation of the level of lightening (VS : visual score, secondary criterion graded on a 5-point scale) .
"Carrier" means the formulation according to the invention lacking corticosteroid.
The vasoconstrictive properties of the formulations according to the invention were evaluated in 40 healthy volunteers after a single application of the products, compared to the carrier and to the reference products Diprosone* cream, Dermoval* cream and Eumovate® cream. The products are applied in an amount of 10 μΐ per product tested, on the forearms, in non-occlusive conditions, for 6 hours.
Measurements and evaluations take place 30 minutes before the application (baseline value) , at 6 hours (T6h), 8 hours (T8h), 10 hours (T10h) , 12 hours (T12h) , 14 hours (Ti4h) , 24 hours (T24h) and 30 hours (T30h) after application of the products to be tested at T0.
The visual lightening response of the skin is graded on a 5-point scale.
Whereas the three proprietary drugs show stable or strongly decreasing (Dermoval®) vasoconstriction between 14 h and 30 h after the single application, the formulations according to the invention, in particular the 0.05% formulation, show vasoconstriction that strongly increases between 14 h and 30 h after the single application, revealing a delay effect of the corticosteroid in the formulations according to the invention (Figure 4 by chromametric measurement and Figure 5 by visual measurement) .

Claims

1. A dermatological composition comprising a corticosteroid in combination with an emollient base consisting of an oil-in-water or water-in-oil emulsion of glycerol, Vaseline and liquid paraffin.
2. The composition of claim 1, further comprising squalane.
3. The composition of any of the preceding claims, wherein the corticosteroid concentration is 0.001% to 2% by weight compared to the total weight of the composition.
4. The composition of any of the preceding claims, wherein the emollient base is formulated with a pH between about 4.3 and about 5.3.
5. The composition of any of the preceding claims, wherein the corticosteroid is betamethasone dipropionate .
6. The composition of claim 5, wherein the betamethasone dipropionate concentration is 0.005% to
0.5% by weight compared to the total weight of the composition .
7. The composition of any of the preceding claims, wherein the emollient base is present in a proportion between 10% and 50% by weight compared to the total weight of the composition.
8. The composition of any of the preceding claims, wherein the glycerol concentration is between 5% and 30%, preferentially between 10% and 20%, and most preferentially about 15% by weight compared to the total weight of the composition.
9. The composition of any of the preceding claims, wherein the Vaseline concentration is between 3% and 20% by weight compared to the total weight of the composition.
10. The composition of any of the preceding claims, wherein the liquid paraffin concentration is between 0.5% and 5% by weight compared to the total weight of the composition.
11. The composition of any of claims 2 to 10, wherein the squalane concentration is between 0% and 10% by weight compared to the total weight of the composition .
12. The composition of any of the preceding claims, comprising about 15% glycerol, about 8% Vaseline and about 2% liquid paraffin by weight compared to the total weight of the composition.
13. The composition of any of the preceding claims, comprising at least one hydrophobic silicone, preferably two.
14. The composition of claim 13, comprising at least one linear silicone and one cyclic silicone, preferably dimethicone and polydimethylcyclosiloxane.
15. The composition of any of the preceding claims, comprising: - about 0.001% to 2% corticosteroid by weight, preferably from 0.005% to 0.1%,
- about 10% to 20% glycerol by weight,
about 3% to 20% Vaseline by weight,
- about 0.5% to 5% liquid paraffin by weight,
- about 0% to 10% squalane,
stearic acid and an emulsifier on a stearate base .
16. The composition of any of the preceding claims, comprising:
- about 0.005% to 0.1% corticosteroid by weight,
- about 15% glycerol by weight,
about 8% Vaseline by weight,
- about 2% liquid paraffin by weight,
stearic acid and a stearic emulsifier.
17. The composition of any of the preceding claims, comprising:
- about 0.005% to 0.1% corticosteroid by weight,
- about 15% glycerol by weight,
about 8% Vaseline by weight,
about 2% liquid paraffin by weight, and as excipients :
- stearic acid, glycerol monostearate, decamethylcyclopentasiloxane, polyethylene glycol 600, chlorocresol , dimethicone, macrogol stearate and water.
18. A method for preparing a composition of any of the preceding claims, wherein the corticosteroid is introduced into the lipophilic phase of the final emulsion, comprising the following steps: (i) heating the lipophilic phase at a temperature between about 70°C and about 85°C under stirring,
(ii) heating the aqueous phase at a temperature between about 70°C and about 85°C under stirring,
(iii)emulsification by introduction of the aqueous phase (ii) into the lipophilic phase (i) under stirring at a temperature between about 70 °C and about 85°C,
(iv)cooling under stirring to a temperature between about 28°C and about 32°C.
19. A transdermal device comprising the composition of any of claims 1 to 17 on the surface in contact with the skin.
20. The composition of any of claims 1 to 17 as a drug .
21. The composition of any of claims 1 to 17 for the use thereof in the treatment of eczema, atopic dermatitis, stasis dermatitis, psoriasis, seborrhoeic dermatitis, lichenification, non-parasitic prurigo, granuloma annulare, discoid lupus erythematosus, genital lichen sclerosus, dyshidrosis, and pruritus due to mycosis fungoides or insect bites.
22. The composition of any of claims 1 to 17, as a drug applied to the skin with a dosing schedule such that two successive applications are spaced at least 24 h apart, preferably at least 48 h apart.
23. The composition of claim 20 or 22, wherein the aforesaid drug is applied for at least two weeks, preferably at least one month.
24. The composition of claim 23, wherein the aforesaid drug is applied every 48 h for at least one month .
25. The composition of claim 22, wherein the aforesaid drug is for treating eczema, atopic dermatitis, stasis dermatitis, psoriasis, seborrhoeic dermatitis, lichenification, non-parasitic prurigo, granuloma annulare, discoid lupus erythematosus, genital lichen sclerosus, dyshidrosis, and pruritus due to mycosis fungoides or insect bites.
26. Use in a topical corticosteroid formulation of an emollient base in oil-in-water or water-in-oil emulsion form comprised of glycerol, Vaseline and liquid paraffin, to delay the effect of the corticosteroid.
27. Use in a topical corticosteroid formulation of the combination of an emollient base in oil-in-water or water-in-oil emulsion form comprised of glycerol, Vaseline and liquid paraffin and of at least one hydrophobic silicone, preferably two, to delay the effect of the corticosteroid.
PCT/EP2011/053882 2010-03-15 2011-03-15 Novel topical corticosteroid formulation WO2011113826A1 (en)

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FR2957260A1 (en) 2011-09-16

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