KR20070022754A - Pharmaceutical composition comprising an ointment and two solubilized active principles - Google Patents

Abstract

The present invention relates to an anhydrous pharmaceutical composition for the treatment of psoriasis, which comprises oily ointment and calcitriol and clobetasol 17-propionate as active ingredients, wherein the active ingredient is in solubilized form in the composition. Each exists.

Description

Pharmaceutical composition comprising ointment and two solubilizing active ingredients {PHARMACEUTICAL COMPOSITION COMPRISING AN OINTMENT AND TWO SOLUBILIZED ACTIVE PRINCIPLES}

The present invention relates to the field of formulation of active ingredients for the purpose of topical pharmaceutical application.

The present invention more specifically relates to oily ointments and stable anhydrous pharmaceutical compositions comprising calcitriol and clobetasol 17-propionate as active ingredients, methods for their preparation, and their use for topical treatment of psoriasis and other skin disorders. It is about.

Calcitriol is an analog of vitamin D and is particularly used to regulate calcium levels in the body. Vitamin D and its derivatives generally have a proven advantage for the treatment of the disease, which is characterized by the limitation of excessive production of skin cells on the surface where psoriasis has been affected and especially characterized by the presence of thick, scaly dry damage. Used in the treatment of psoriasis in dermatology.

Clobetasol 17-propionate is a corticosteroid. The mechanism of action of corticosteroids is due to its inflammatory process inhibition (Lange K et al., Skin Pharmacol Appl Skin Physiol 13 (2): 93-103 (2000)).

Document US 4,610,978 describes a composition comprising calcitriol for topical application, for example in the treatment of dermatological diseases such as psoriasis. The composition may additionally contain corticosteroids such as, for example, hydrocortisone or dexamethasone. Documents WO 00/64450 and WO 02/34235 describe pharmaceutical compositions for use on the skin containing vitamin D or vitamin D analogs and corticosteroids. A given example relates more specifically to a composition comprising calcitriol (vitamin D analog) and betamethasone (corticosteroid). A comparison of efficacy in psoriasis patients on a composition containing calcipotriol alone, betamethasone alone, or a combination of two actives indicates that the effect obtained by the combination corresponds to an additional effect. Thus, while reading the document, one skilled in the art could never think that a combination of corticosteroids and vitamin D analogs would have a synergistic effect. Moreover, the combination of calcitriol and clobetasol propionate is not explicitly described in this document.

In document FR 2 848 454, Applicants have found that the combination of clobetasol propionate and calcitriol makes it possible to obtain a synergistic effect in the treatment of certain dermatological diseases such as psoriasis, atopic dermatitis, contact dermatitis and seborrheic dermatitis. .

However, the combination in a single pharmaceutical composition of clobetasol propionate and calcitriol necessarily poses certain problems. This is because calcitriol is unstable in aqueous media and more particularly at acidic pH values, while clobetasol 17-propionate is unstable in basic environments.

Therefore, it is suitable to formulate the active ingredient in anhydrous compositions. Anhydrous compositions currently available, which allow for the formulation of such ingredients while providing effective chemical stability to the active ingredients which are water-sensitive, are generally ointment compositions. The ointment composition consists mainly of petroleum jelly, mineral oil and / or vegetable oil. However, currently commercially available treatments contain a high proportion of petrolatum to promote occlusion and penetration of the active, or contain a high proportion of glycol permeation accelerator to promote the penetration of the active, but will cause sticky and irritable problems. can (article [ "The critical role of the vehicle to therapeutic efficacy and patient compliance " , Piacquadio et al, J. Am. Acad. Dermatol, August 1998].

Ointment compositions currently commercialized are not always suitable for formulation of the active ingredient in solubilized form.

One of the aims of the present invention is for topical application and to reflow anhydrous pharmaceutical compositions which eliminate the above drawbacks.

Another object of the present invention is to provide anhydrous pharmaceutical compositions for topical application and whose active ingredient is in solubilized form and exhibits extended stability.

It is a further object of the present invention to provide anhydrous pharmaceutical compositions for topical application and which exhibit very good tolerability.

The present invention therefore provides an anhydrous ointment comprising at least one butter, and an anhydrous pharmaceutical composition for the treatment of psoriasis, characterized in that it comprises calcitriol and clobetasol 17-propionate as active ingredients, said active agent Are each present in solubilized form in the composition.

Since the solubilized form means a dispersion in the liquid state in the liquid, there is no crystallization of the active substance which can be seen with an optical microscope with naked eyes or cross polarization.

Advantageously, the amount of calcitriol in solubilized form in the composition of the present invention is from 0.00001 to 5% by weight, preferably from 0.0001 to 3% by weight and more particularly from 0.0003 to 1% by weight relative to the total weight of the composition.

The amount of clobetasol 17-propionate in solubilized form is 0.0001 to 3% by weight, preferably 0.00005 to 1% by weight, more particularly 0.001 to 0.1% by weight relative to the total weight of the composition.

The composition of the invention is more particularly for topical application.

The active ingredient forming portions of the compositions of the present invention, namely calcitriol and clobetasol 17-propionate, are in a solubilized state, with a more favorable kinetics for the compositions of the present invention, with good skin penetration / release for each of these active ingredients. Give it a characteristic. The term "effective release / penetration capability" refers to the effective distribution of the composition of the invention, and therefore the active ingredient it contains, across the stratum corneum of the skin and across the subcutaneous layers such as epidermis and dermis.

The expression "anhydrous composition" means, for the purposes of the present invention, a composition that is substantially free of moisture, in other words having a moisture content of at most 5% by weight, in particular at most 3% by weight, more particularly at zero relative to the total weight of the composition. Point to.

For the purposes of the present invention and in accordance with US Pharmacopoeia (USP), the term "ointment" refers to a semisolid formulation for external application to the skin or mucous membranes. Ointments or plasters are used topically for many applications, such as, for example, barrier creams, sterile creams, softening creams and the like. Ointment is used for its softening effect; It is easy to apply and easily penetrates the skin.

There are usually five types of ointments that are distinguished based on their physical composition. The most common type of ointment (the invention relates to this) is an ointment based on an oily base, referred to as an "oily ointment"; The ointment is anhydrous, hydrophobic and mainly contains petrolatum and / or liquid paraffin. Other components of the ointment can be:

Oils of mineral, animal, vegetable or synthetic origin;

Thickeners, such as waxes of mineral, vegetable and animal origin;

Butter: Cocoa Butter, Karite Butter, Copra Butter;

Lanolin and its derivatives.

Vaseline is a mixture of long chain aliphatic hydrocarbons and is an excellent moisturizer. This is because its occlusion properties block the fine percutaneous moisture loss by the formation of inert occlusion membranes and trap moisture under the skin surface ( " Effects of petrolatum on stratum corneum structure and function " Ghadially & all ; Journal of the american academy of dermatology 1992; 26: 387-96 ). Vaseline accelerates the recovery of normal skin barrier properties, for example in the case of damaged skin such as atopic dermatitis or psoriasis. Vaseline alone is a good moisturizer due to its softening properties and can fade psoriasis spots. In addition, petrolatum is inert and therefore has no non-compatibility at all, regardless of the active ingredient or components.

Vaseline based ointments are recognized to be one of the best systems for release of actives in terms of efficacy. This is because occluded skin becomes more permeable and the active ingredient can penetrate better. It is also known that the efficacy of topical steroids can be enhanced by the application of obstructive membranes produced by ointments ("Hospital practice: current treatment options in psoriasis" Khachemoune et al, 2000, pp. 1-13).

Examples of mineral oils may refer to various viscous liquid paraffins such as Primol 352, Marcol 82 and Marcol 152 sold by Esso.

Vegetable oils may include sweet almond oil, palm oil, soybean oil, sesame oil and sunflower oil.

Animal oils may be mentioned lanolin, squalene, fish oil and mink oil.

Synthetic oils include esters such as cetearyl isononanoate, such as the product sold under the name Cetiol SN by Cognis France, diisopropyl adipate, such as the product sold under the name Ceraphyl 230 by the ISF, under the name Crodamol IPP from Croda. Mention may be made of isopropyl palmitate, such as the product sold, and caprylic / capric triglyceride, such as Miglyol 812, sold by Hul / Lambert Riviere.

The term "wax" is generally a solid (with a reversible solid / liquid state change) at ambient temperature (25 ° C) and has a lipophilic point with a melting point that can be at least 30 ° C and in the range of up to 200 ° C, in particular up to 120 ° C Point to a compound.

Waxes useful in the compositions according to the invention are selected from the group consisting of waxes of animal, vegetable, mineral or synthetic origin, and mixtures thereof.

According to one particular embodiment, the hydrocarbon wax may be selected from saturated and unsaturated acids, in particular glyceryl esters of polyunsaturated acids having 10 to 24 carbon atoms, unsaturated fatty acids, in particular polyunsaturated fatty acids.

Hydrocarbon waxes of the type which are esters of glycerides and polyunsaturated fatty acids and which can be used in the compositions according to the invention, in particular the atomized glyceryl dipalmitostearate (C ₁₆ -C ₁₈ ) sold under the name Precirol ATO 5 ^® by Gattefosse Mention may be made of, for example, atomized glyceryl behenate (C ₂₂ ) sold under the name Compritol ^® in Gattefosse, and mixtures thereof.

Hydrocarbon waxes such as beeswax, lanolin wax and China insect wax; Rice wax, carnauba wax, candelilla wax, aurikuri wax, Alfa wax, cork fiber wax, sugar cane wax, wax and chemac wax; Montan wax, microcrystalline wax, paraffin and waxes; It is also possible to use polyethylene waxes, waxes and beeswax copolymers obtained by Fischer-Tropsch synthesis, and also esters thereof.

Mention may also be made of waxes obtained by catalytic hydrogenation of animal or vegetable oils with C ₈ -C ₃₂ linear or branched fatty chains.

Among these waxes, in particular hydrogenated jojoba oil, isomerized jojoba oil, such as trans-isomerized, partially hydrogenated jojoba oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated copra oil manufactured or sold by Desert Whale under the commercial reference ISO-JOJOBA-50 ^®. Oils and hydrogenated lanolin oils, di (1,1,1-trimethylolpropane) tetrastearate sold under the name Hest 2T-4S at Heterene, and di (1,1,1 sold under the name Hest 2T-4B at Heterene Trimethylolpropane) tetrabehenate may be mentioned.

Silicone waxes and fluoro waxes may also be mentioned.

Waxes obtained by hydrogenation of esterified olive oil with stearyl alcohol, sold under the name Phytowax Olive 18L57, or else obtained by hydrogenation of esterified castor oil with cetyl alcohol (the wax is the name Phytowax ricin 16L64 from Sophim and Sold under 22L73). Such waxes are described in application FR-A-2792190.

Thickeners may be selected from butter and lanolin.

According to one preferred embodiment of the invention, the thickener is beeswax, hydrogenated castor oil, carnauba oil, alkylmethylsiloxane wax (ST wax 30) or candelilla wax.

The additional thickener content, where appropriate, depends on the viscosity of the desired composition. This can of course be determined by one skilled in the art through simple and routine work.

Generally speaking, the amount of additional thickeners, in particular pasty or solid hydrocarbon compounds, is from 2 to 20% by weight, in particular from 5 to 10% by weight, relative to the total weight of the composition.

Carite butter (shea butter) is a basic product of African pharmacology, a vegetable fat substance traditionally used in the African continent. For example, in Africa, newborns are rubbed with carite butter from birth to protect them from extreme weather conditions. Carite butter has been used by cosmetic chemists for over 20 years. It is a natural fat (Butyrospermum parkii) obtained from Carite trees. From chemical analysis of carite butter, it was found that it consists of fatty acids and their glycerides. The fatty acids present in carite butter are saturated or unsaturated. Carite butter is particularly known for:

-Its calm and soft advantage in dry and sensitive skin,

-Its decongestive effect,

-Efficacy in reducing its signs of aging,

Its scar-forming and regenerative action,

-Its moisturizing effect, and

-Its anti-erythetic UV protection (in animals).

Moreover, carite butter has excellent tolerability.

As indicated above, the amount of butter is 2 to 20% by weight, in particular 5 to 10% by weight, relative to the total weight of the composition.

According to an advantageous embodiment of the invention, the components of the oily ointment are more particularly selected from the group consisting of petrolatum and / or liquid paraffin, carite butter and additionally softeners.

The action of the softener product is to make the skin supple and smooth and to promote the health of the skin. The softening action is taken in the form of a reward for moisturizing or insufficient sebum secretion of the stratum corneum.

The stratum corneum can be moisturized in a number of ways: the use of substances (fats: waxes, oils, fatty alcohols, silicone oils) to slow dehydration by the occlusion effect or the use of humectants (polyols, glycerol, urea).

Insufficient sebum secretion is compensated by the use of a lipid product such as oil, as far as it is concerned.

According to another advantageous embodiment of the invention, the active ingredient is solubilized in a single solvent or in two or more solvents.

The solvents of the present invention are selected from pharmaceutically acceptable compounds, in other words those whose use is particularly suitable for application to the skin, mucous membranes and / or keratinous fibers. It is generally a fluid, especially a liquid, under ambient temperature and atmospheric pressure.

As solvents according to the invention, mention may in particular be made:

Propylene glycol,

Oils such as caprylic and capric triglycerides (Miglyol 812), cetearyl isononanoate (Cetiol SN) and vegetable oils (sweet almond oil, sesame oil, sunflower oil, etc.) and mixtures thereof, and

Mixtures thereof.

The solvent is generally present in the composition of the present invention in an amount sufficient to provide the solubility necessary for the active ingredient to be formulated on the one hand, and to maintain the extended chemical stability of the same active ingredient on the other hand. do. In other words, the solvent should be chemically inert with respect to the active ingredient.

Advantageously, the amount of solvent for each active in the compositions of the invention is 10 to 30% by weight, preferably 5 to 20% by weight relative to the total weight of the composition.

The solvent further provides a beneficial effect on the rate of skin penetration of the active ingredient.

The composition according to the present invention may further comprise other various elements. The selection of said supplementary elements, and their respective amounts, is carried out so as not to impair the expected properties of the composition. In other words, the compound should not adversely affect the chemical stability of the active ingredient or its solubility.

The composition of the present invention may further comprise a lipophilic anti-irritant. By way of example, mention may be made of DL-alpha-tocopherol acetate, oil of Melaleuca alternifolia, green tea extract, marigold extract and carite butter.

According to another advantageous embodiment, the composition of the present invention comprises an antioxidant selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), DL-alpha-tocopherol and propyl gallate. It may further comprise.

According to one preferred embodiment, the composition of the present invention is an anhydrous pharmaceutical composition comprising petrolatum and calcitriol and clobetasol 17-propionate in solubilized form as active.

Compositions of this kind are physically and chemically stable, synergistically effective against psoriasis, while allowing for optimized release of the two actives while at the same time allowing very good tolerance.

In addition to the actives and petrolatum, one preferred embodiment of the present invention further comprises carite butter and emollients such as caprylic / capric triglyceride or cetearyl isononanoate or vegetable oils and propylene glycol.

The combination of petrolatum, carite butter, and emollients allows recovery of the skin barrier that has been altered by the condition of psoriasis while ensuring very good tolerance of the compositions of the present invention.

The compositions of the present invention have been found to be particularly effective in preserving the satisfactory chemical stability of active ingredients which are generally sensitive to oxidation, moisture and aqueous media. The term "satisfactory chemical stability" refers to a composition as follows at ambient temperature and 40 ° C., respectively, for a period of at least 3 months:

-Does not exhibit substantial deformation in its visual appearance,

Having an active ingredient content of at least 80%, in particular at least 90%, more particularly at least 95% of the initial weight content.

The present invention further provides the use of an oily ointment for the preparation of anhydrous pharmaceutical compositions for the treatment of psoriasis, said composition comprising calcitriol and clobetasol 17-propionate as active ingredients, each said active ingredient being It is present in the composition in solubilized form.

The present invention provides a use as defined above, wherein the composition is as defined above.

The following examples illustrate it without limiting the invention in any way.

Example  1: Topical of the composition of the present invention Yong-Sung  Research

Tolerability studies were performed in comparison to vehicle (Daivonex ^® ), which is known for its excellent tolerability on the vehicle formulations of the present invention (no actives).

Treatment: 20 μl of the composition was applied to the right ear of the mouse once daily from 1 to 6 days.

Evaluation method: mouse ear thickness measurement and clinical observation from 2 to 12 days. Animal Weighing from 1 to 12 days.

conclusion:

After 12 days, the vehicle of the present invention was found to be non-irritating and nearly equivalent to the Daivonex ^® vehicle and untreated group.

Example  2: Solubility and Stability of Compositions of the Invention

The stability of calcitriol was evaluated in two oil solvents: Miglyol 812 and Cetiol SN.

a) Miglyol  812 (caprylic acid and capric acid Triglycerides ) Of Calcitriol  stability

A solution of 30 ppm of calcitriol in qs 100% Miglyol 812 in the presence of 0.4% BHT (antioxidant) was prepared and maintained under nitrogen.

The results of HPLC analysis techniques against the standards are shown in Table 1 below.

Initial time T0 was taken to be 100%.

Stability conditions T2 weeks T4 weeks +4 ℃ 98.2% 105.2% Ambient temperature 95.8% 98.0% +40 ℃ 93.1% 95.0%

Calcitriol was stable for 1 month in solution in caprylic / capric triglycerides.

b) Cetiol SN  ( Cetearyl Isononanoate ) Of Calcitriol  stability

A solution of 30 ppm of calcitriol in qs 100% Cetiol SN in the presence of 0.4% BHT was prepared and maintained under nitrogen.

The results of HPLC analysis techniques against the standards are shown in Table 2 below.

Initial time T0 was taken to be 100%.

Stability conditions T2 weeks T4 weeks +4 ℃ 103.7% 97.9% AT 99.6% 98.7% +40 ℃ 99.4% 98.1%

Calcitriol was stable for 1 month in solution in cetearyl isononanoate.

Example  3: Preparation of the composition of the present invention

The present invention relates to anhydrous formulations which allow for effective mixing of the components by allowing all components to be incorporated at high temperatures where the petroleum jelly is a liquid. This also makes it possible to obtain effective stability at 30 ° C. without any exudates.

The process is carried out in a water bath, which allows to maintain a homogeneous temperature throughout the production; It is also important to cover the formulation beakers to prevent any crusting. The process is carried out by a butterfly blade, which allows for effective circulation in the pasty product, thus ensuring effective homogenization.

a) first step: preparation of a fatty phase comprising an oily ointment

Vaseline (oily ointment), thickeners and lipophilic anti-stimulants were weighed and distributed to beakers.

The beaker was heated at 75 ° C. with gentle Rayneri (butterfly blade) stirring in a water bath.

b) second step: preparation of a phase comprising the active ingredient

A stock solution of calcitriol was prepared in a suitable solvent, antioxidant was added and the mixture was stirred until the active was solubilized.

Clobetasol 17-propionate and its solvent were weighed and distributed and the mixture was stirred until the actives were solubilized.

The two active phases were incorporated into the fat phase prepared as above at 75 ° C. with Rayneri stirring.

The mixture was homogenized and the composition was cooled to 30 ° C. with Rayneri stirring in a water bath.

The composition was packaged at 30 ° C., at which temperature the composition was not yet completely solidified.

Example  4: example of a composition according to the invention

Composition 1 Raw material Weight percent by weight White petrolatum qs 100 Carnauba wax 9 Caprylic / Capric Triglycerides 10 Shea butter 2 dl-alpha-tocopherol acetate One Calcitriol 0.0009 Clobetasol Propionate 0.01 Propylene glycol 10

Composition 2 Raw material Weight percent by weight White petrolatum qs 100 beeswax 5 Caprylic / Capric Triglycerides 15 Shea butter 5 Butylated hydroxytoluene 0.04 Calcitriol 0.0003 Clobetasol Propionate 0.025 Propylene glycol 10

Physical stability of compositions 1 and 2 was measured by visual and microscopic observation of the composition at ambient temperature, 4 ° C. and 30 ° C. after 15 days, 1 month, 2 months and 3 months.

At ambient temperature, visual observation assured the physical integrity of the product, and microscopic observation made it possible to prove that there was no recrystallization of the solubilizing active.

Microscopy at 4 ° C. demonstrated non-recrystallization of the solubilizing active.

Visual observation at 30 ° C. demonstrated the integrity of each final composition.

Characterization of each final composition was completed by pour point measurement. Haake VT550 flowmeter was used with the SVDIN measuring spindle. A rheogram was performed at 25 ° C. and shear rate 4 s ⁻¹ (γ) to measure the shear stress. Pour point (? 0, expressed in Pascals) means the force (minimum shear stress) needed to overcome van der Waals bonding forces and generate flow. Pour point is a shear rate of 4 s ^- is taken as the value found in the ^first.

The measurements were taken at T0 after 1 month, 2 months and 3 months.

Composition 2

At T0  details Tau  0 219 Visual appearance Polish Pale Yellow Ointment Centrifugation 3000 rpm RAS Microscopic appearance Numerous yellow, purple, and blue refraction features of petroleum jelly 10000 rpm Exudate

Physical stability

T15d AT Visually fitness microscope fitness Tau  0 230 Centrifugation 3000 fitness 10000 fitness 4 ℃ Visually fitness microscope fitness 30 ℃ Visually fitness microscope fitness Tau  0 NR

Chemical stability

Chemical stability T0 AT Calcitriol: 97.6% Clobetasol Propionate: 97.3% 40 ℃ Calcitriol: / Clobetasol Propionate: / T15d AT Calcitriol: 95.1 Clobetasol Propionate: 95.2 40 ° C. calcitriol: 86.8 clobetasol propionate: 92.3

Example  5: activity contained in three different formulations, including according to the invention Clobetasol  17- Propionate  In Vitro Glass / Infiltration Studies on Human Skin

The aim is to quantify in vitro skin penetration on human skin 16 hours after application of the actives formulated in different formulations.

Formulations Tested:

Softening cream Temovate ^{® with} 0.05% (w / w) clobetasol 17-propionate

Cream Temovate ^{® with} 0.05% (w / w) clobetasol 17-propionate

A composition according to the invention of formula A:

Starting material Weight / wt% amount White petrolatum Qs 100 beeswax 5 Caprylic / Capric Triglycerides 15 Shea butter 5 Butylhydroxytoluene 0.04 Calcitriol 0.0003 Clobetasol Propionate 0.05 Propylene glycol 10

Softening cream Temovate ^® is sold by GlaxoSmithKline.

Experimental Conditions: Transdermal uptake was assessed with diffuse cells consisting of two compartments separated by human skin. The formulation was applied without occlusion for a 16 hour application time. The formulation was applied at a rate of 10 mg of the formulation per cm ² (ie 10 μg clobetasol 17-propionate). The dermis was contacted with a receiving liquid that did not resume as a function of time (static mode) throughout the study. Experiments were performed with three skin samples from three different donors. At the end of the application period, the supernatant was removed and the distribution of clobetasol 17-propionate was quantified in various compartments of the skin and in the receiving liquid. The concentration of clobetasol 17-propionate was quantified using HPLC / MS / MS methods commonly known to those skilled in the art. (LQ: 1 ngml ^-1 ).

The results are expressed in% of mean dose applied (mean +/− standard deviation) and are described in the table below.

Formulation Total penetration Softening Temovate Cream Average SEM 5.00 1.34 Temovate cream Average SEM 8.43 0.79 Composition A Average SEM 9.33 0.97

The results show that the amount of clobetasol penetrated with the composition according to the invention is equivalent to the amount of Temovate softening cream.

Claims (17)

An anhydrous ointment comprising at least one butter, and an active pharmaceutical composition for the treatment of psoriasis, characterized in that it comprises calcitriol and clobetasol 17-propionate as active ingredients, each of which is solubilized in the composition. Compositions present in form. The composition of claim 1 for topical application. 3. The composition according to claim 1, wherein the composition has a water content of 5% by weight or less, in particular 3% by weight or less and more particularly 0 to the total weight of the composition. The composition according to any one of claims 1 to 3, wherein the oily ointment is selected from the group consisting of petrolatum and / or liquid paraffin. The composition of claim 1, wherein the ointment further comprises a softener. 6. The composition of any one of claims 1 to 5, wherein the butter is a karite butter. 7. A composition according to any one of claims 1 to 6, wherein the active ingredient is solubilized in a single solvent or in two or more solvents. 8. A composition according to claim 7, wherein the solvent is selected from the group consisting of: Propylene glycol, Oils such as caprylic and capric triglycerides, cetearyl isononanoate, vegetable oils (sweet almond oil, sesame oil, sunflower oil) and mixtures thereof; And Mixtures thereof. 8. The amount of calcitriol in solubilized form according to claim 1, wherein the amount of calcitriol in solubilized form is from 0.00001 to 5% by weight, preferably from 0.0001 to 3% by weight, more particularly from 0.0003 to 1% by weight. The composition characterized in that the. The amount of clobetasol 17-propionate in solubilized form is from 0.0001 to 3% by weight, preferably from 0.00005 to 1% by weight, based on the total weight of the composition. In particular, the composition, characterized in that 0.001 to 0.1% by weight. The composition according to any one of claims 7 to 10, wherein the amount of solvent is 10 to 30% by weight, preferably 5 to 20% by weight, relative to the total weight of the composition. The method of claim 1, further comprising a thickener selected from solid or pasty hydrocarbon compounds such as hydrocarbon waxes, butters, lanolin and mixtures thereof of animal, vegetable, mineral or synthetic origin. Characterized in that the composition. 13. The composition of any one of the preceding claims, further comprising a lipophilic anti-irritant. 14. The composition of any one of claims 1 to 13, further comprising an antioxidant. The composition of claim 1 comprising one or more pharmaceutical excipients suitable for topical application. Use of an oily ointment to prepare an anhydrous composition comprising solubilized calcitriol and solubilized clobetasol 17-propionate. Use according to claim 16, wherein the composition is as defined in any of claims 1-15.