KR20070022741A - Composition in spray form comprising a combination of a corticoid and a vitamin d derivative in an oily phase - Google Patents

Abstract

The present invention relates to an anhydrous composition in spray form containing a combination of oil phase and clobetasol propionate and calcitriol as pharmaceutical actives in a physiologically acceptable medium and methods for its preparation and its use in dermatology. It is about.

Description

A spray form composition containing a combination of corticoids and vitamin D derivatives in an oil phase {COMPOSITION IN SPRAY FORM COMPRISING A COMBINATION OF A CORTICOID AND A VITAMIN D DERIVATIVE IN AN OILY PHASE}

The present invention relates to an anhydrous composition in the form of a spray, which contains a combination of oil phase and clobetasol propionate and calcitriol in a physiologically acceptable medium as a pharmaceutical active, a process for its preparation and its use in dermatology. will be.

Combinations of the above active principles are typically not used to treat skin diseases. When combining two actives, a major challenge for those skilled in the art is the problems of interaction and chemical stability that can arise if these actives are present in the same formulation.

Therefore, there is almost no compounding treatment of calcitriol and corticosteroid. This is because vitamin D and its derivatives are unstable in aqueous media and sensitive to acidic pH values, while corticoids, more particularly clobetasol propionate, are sensitive to basic media. Therefore, for those skilled in the art, it is not obvious to combine and stabilize the vitamin D-type activator and corticosteroid in a single composition.

Calcitriol is a vitamin D analogue used to regulate calcium levels in the body. Its use in the treatment of skin diseases is described in particular in US Pat. No. 4,610,978 for the treatment of psoriasis. The patent discloses compositions containing calcitriol, which may contain significant amounts of anti-inflammatory agents such as corticosteroids, but specific embodiments of combining calcitriol and corticosteroids are not described or tested for their efficacy.

Applicant has described in application FR 2 848 454 how combining calcitriol with corticosteroids can achieve a synergistic effect in the treatment of certain skin diseases such as psoriasis, atopic dermatitis, contact dermatitis and seborrheic dermatitis. There is no suggestion of a stable pharmaceutical composition combining the two activators.

In addition, in the field of formulation of dermatological and pharmaceutical compositions, those skilled in the art seek to find compositions that not only have to be physically and chemically stable, but also can enhance their efficacy by releasing activators and promoting their penetration through the skin layer.

The pharmaceutical composition should also exhibit good cosmetic qualities and preferably be nonirritating.

There are currently a number of topical compositions that contain active agents and, in particular, promote the penetration of the active agent into the skin through the presence of large amounts of glycol penetration promoters. These compositions are in the form of emulsions with a large amount of fatty phase content, commonly referred to as "lipocream", in the form of anhydrous compositions called "ointments", designed for application to the scalp. It is formulated in the form of a fluid composition with a large amount of volatile solvents such as ethanol or isopropanol, also referred to as "hair lotion", or in the form of a viscous O / W emulsion, also referred to as "O / W cream".

In order to stabilize the formulation containing the percentage of glycol, in the emulsion, a stabilizer of the glyceryl stearate or PEG 100 stearate type emulsifiers and stabilizers, alternatively white wax or cetostearyl alcohol type Using a topical or consistency factor, it is necessary to form a viscous cream. Therefore, application of the product is difficult due to such viscosity. However, these compositions, on the one hand, exhibit poor cosmetic tolerance due to their viscosity, while on the other hand they present a risk of hypersensitivity caused by the presence of high proportions of glycols. In addition, such high viscosity makes it difficult to apply the formulation to various parts of the body affected by the lesion. As a result, in many existing therapies in the form of creams or gels or ointments, third-party assistance is required to apply them to areas that are difficult to reach. Thus, the third party must touch both the product containing the activator and the psoriatic plaque, which causes a situation that is not ideal both in terms of ease of use and third party safety. The skilled person is also aware that non-compliance of the treatment due to the reasons disclosed above is one of the main causes of failure; The article " Patients with psoriasis and their compliance with medication " (Richard et al., J Am Acad Dermatol, 1999, October, 581-583) shows that almost 40% of patients with chronic diseases, such as psoriasis, follow these treatments. It is pointed out. In patients, compliance based on self-treatment has been demonstrated to be directly related to the characteristics of the carrier of the applied composition. The document " Patients with psoriasis prefer solution and foam vehicle: quantitative assessment of vehicle preference " (Housman et al., CUTIS, Dec. 2002, Vol. 70, pp. 327-332) suggests that psoriasis patients are more likely to have a solution than a plaster, cream or gel. He points out that he prefers foam.

Accordingly, those skilled in the art would like to see these variables improved by the present invention.

The closest prior art to the present invention is the international application WO 00/64450, which refers to the use of pharmaceutical compositions containing vitamin D analogs and corticosteroids. Examples of all compositions of this patent application combine only calcipotriol and betamethasone dipropionate. Preferred compositions for stabilizing the two active compounds described in the application are compositions in the form of unguents. Therefore, these compositions exhibit the disadvantages as described above, given the ease and convenience of application. Thus, in any case, reviewing the prior art makes it easy for those skilled in the art to make such application, using soluble and stable activators, clobetasol propionate and calcitriol in the composition, as described herein. It does not make it possible to infer one sprayable composition.

This is because, according to a review of the prior art, existing treatments contain a high percentage of petroleum jelly to promote the penetration and occlusiveness of the activator, but have a very greasy and sticky disadvantage, or the composition does not It contains high percentages of glycol penetration accelerators to promote, but can cause sticky and irritability problems ("The critical role of the vehicle to therapeuticefficacy and patient compliance" Piacquadio & all, Journal of American Academy of dermatology, August 1998).

Therefore, the problem of proposing a solution in the present invention is to design a physically and chemically stable composition wherein two active agents, calcitriol and clobetasol propionate, which act synergistically in the treatment of psoriasis are combined in a single composition It is further desired that the composition according to the invention is easy to use and has acceptable cosmetic properties for application to all areas of the body that may be affected by the lesion.

The term "physical stability" according to the invention refers to its macroscopic appearance (phase separation, apparent color change, etc.) or its microscopic appearance (recrystallization of the activator) after storage at temperatures of 4 ° C. and 40 ° C. for 2, 4, 8 and 12 weeks. The composition which does not show a change is shown.

The term “chemical stability” according to the invention refers to a composition in which the active ingredient content therein remains stable even after 3 months at ambient temperature and 40 ° C. Stable active ingredient content means, according to the present invention, a content that shows little change with respect to the initial content, that is, a change in the active content of time at time T is 90% of the initial content at TO. It should not be less than%, more particularly less than 95%.

Applicant has surprisingly found that a composition containing the following in a pharmaceutically acceptable carrier provides a composition that solves this problem:

a) a therapeutically effective amount of solubilized form corticosteroid, more particularly clobetasol propionate;

b) a therapeutically effective amount of a solubilized form vitamin D derivative, more particularly calcitriol;

c) an oil phase consisting of one or more oils;

Wherein the composition is in the form of anhydrous spray.

The compositions of the present invention are chemically and physically stable while effectively penetrating the active radicals. In addition, due to their spray formulations, as described in the Examples of the present invention, they exhibit very good tolerance and tolerance from the patient's point of view. Therefore, the composition according to the invention turns out to be particularly suitable for the treatment of skin diseases and more particularly for the treatment of psoriasis.

Accordingly, the present invention relates to compositions that are liquid at ambient temperature; Preferably there is provided a sprayable composition comprising the following in a pharmaceutically acceptable carrier:

a) a therapeutically effective amount of solubilized form clobetasol propionate;

b) a therapeutically effective amount of solubilized form calcitriol;

c) an oil phase consisting of one or more oils.

The solubilized form means a dispersion liquid in which the molecular state is liquid, and crystallization of the active element is not observed with the naked eye or with a cross-polarized optical microscope.

Sprayable compositions are any compositions that are liquids and fluids that flow rapidly due to their weight at ambient temperature. Ambient temperature means a temperature of approximately 25 ° C.

Nebulizers obtainable by conventional formulation methods are those known to those skilled in the art, as described below.

The composition is preferably anhydrous. Anhydrous compositions in the sense of the present invention are compositions that are substantially free of water, ie have a water content of 1% by weight or less, in particular 0.5% by weight or less, preferably 0, relative to the total weight of the composition.

Advantageously the composition according to the invention contains from 0.00001 to 0.1% by weight, preferably from 0.0001 to 0.001% by weight and more preferably from 0.0002 to 0.0005% by weight relative to the total weight of the composition. The composition according to the invention contains more particularly 0.0003% by weight of calcitriol relative to the total weight of the composition.

Advantageously the composition according to the invention contains from 0.0001 to 0.1% by weight, preferably from 0.001 to 0.05% by weight, of the corticoids relative to the total weight of the composition. Preferred compositions according to the invention contain more particularly 0.01%, 0.025% or 0.05% by weight of clobetasol propionate relative to the total weight of the composition.

The oil phase according to the invention is an oil phase suitable for pharmaceutical compositions.

The oil phase according to the present invention, among other things, acts as a solubilizer for activators (this is also called a activator solvent). Oils are only solvents for activators which can be used according to the invention. Thus, in particular alcoholic and glycolic solvents are excluded from the invention.

The oil form is ideal for psoriasis lesions and is similar to cosmetic massage oils. The liquid oil form makes it possible to provide the patient with the comfort of an emollient without the disadvantages of applying a thick, very sticky and greasy ointment.

The screening of oils and the proportion of oil mixtures are determined as a function of their spreading power and their chemical quality. The oils that can be used according to the invention are selected so that their mixture is clear and stable over time.

The oil phase of the composition according to the invention may contain, for example, vegetable, mineral, animal or synthetic oils, silicone oils and mixtures thereof.

As examples of mineral oils, for example, liquid paraffins of various viscosities can be mentioned, such as Primol 352, Marcol 82 and Marcol 152 (manufactured by Esso).

As the vegetable oil, mention may be made of sweet almond oil, palm oil, soya oil, sesame oil and sunflower oil.

As animal oils, mention may be made of lanolin oils, squalene, fish oils and mink oils.

As synthetic oils, esters such as cetearyl isononanoate, for example a product sold under the name Cetiol SN by the company Cognis France, diisopropyl adipate, for example Ceraphyl 230 by ISF Products sold under the name, isopropyl palmitate, for example products sold under the name Crodamol IPP by Croda, isononyl isononanoate, such as Dub Inin from Stearineries Dubois, and capral acid / capr Acid triglycerides such as Miglyol 812 sold by Huls / Lambert Riviere may be mentioned.

As silicone oil, a dimethicone such as Dow Corning 200 fluid from Dow Corning, or a product sold under the name Q7 9120, a cyclomethicone such as Dow Corning 244 fluid sold by Dow Corning, or SACI- A product sold under the name Mirasil CM5 by CFPA may be mentioned. Also mention may be made of volatile silicone oils, such as linear siloxanes, more preferably hexamethyldisiloxane. A product sold by Dow Corning as DC fluid 0.65 cSt may be mentioned by way of example.

Preferably, the compounds constituting the oil phase of the composition according to the invention are caprylic / capric triglycerides sold under the name Miglyol 812, cetearyl isononanoate sold under the name Cetiol SN, Mirasil CM5 Cyclomethicone 5 sold under the name, Dimethicone 200 and sweet almond oil with a viscosity of 20 cst, which are used alone or in mixtures.

The basis for selecting these preferred compounds is as follows:

-Selection of caprylic / capric triglycerides

Triglycerides are one of the components of the skin and, together with ceramides, cholesterol and phospholipids, form part of the natural skin lipo. They integrate into the deep layers of the epidermis and compensate for the loss of moisture in the skin. The protective barrier of the skin is unique and durable.

"Mid length chain triglycerides", of which Miglyol 812 is one, consists of caprylic (C8) and capric (C10) fatty acids derived from coconut oil or palm kernel oil.

Its main characteristics are:

Low-viscosity emollients that increase spreading on the skin

Solvents for fat affinity activators which quickly penetrate the skin and promote the penetration of the activators;

-No oily residue left, no greasy feeling when applied.

-Selection of cetearyl isononanoate

Cetearyl isononanoate is an ester which has the characteristic characteristic which shows dry and soft feeling to skin.

-Selection of cyclomethicone 5

Cyclomethicone 5 is a volatile silicone oil that facilitates application to the skin and leaves a relatively dry feeling after application.

Selection of Dimethicone 200 with Viscosity of 20 cst

 Dimethicone 200 is a silicone oil that facilitates application to the skin and leaves a greasy touch after application.

-Selection of sweet almond oil

Sweet almond oil is a vegetable oil that is used because of its softening properties.

Proper sorting and mixing of the oil makes it possible to obtain products that are completely oil, but much less oily than plasters or ointments.

It also applies the product to the patient in the form of a spray and, if desired, allows massage of the area to be treated, in contrast to highly volatile spray products.

Advantageously the composition according to the invention contains from 50 to 99% by weight, preferably from 70 to 99% by weight, more preferably from 95 to 99% by weight, based on the total weight.

Accordingly, the present invention provides sprayable compositions containing the following in a pharmaceutically acceptable carrier:

a) 0.0001 to 0.1% of clobetasol propionate;

b) 0.00001 to 0.1% of calcitriol;

c) 50 to 99% oil phase consisting of at least one oil selected from caprylic / capric triglycerides, cetearyl isononanoate, cyclomethicone, dimethicone and sweet almond oil.

More particularly preferred sprayable compositions according to the invention contain the following in a pharmaceutically acceptable carrier:

a) 0.001-0.05% clobetasol propionate;

b) 0.0002 to 0.0005% of calcitriol;

c) 95-99% oil phase consisting of caprylic / capric triglycerides, cetearyl isononanoate and at least one oil selected from cyclomethicone, dimethicone and sweet almond oil.

According to one preferred embodiment, the composition according to the invention also contains an antioxidant compound such as DL-α-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene, superoxide dismutase, ubiquinol or certain metal chelates. Contains reagents. Antioxidants preferably used in the compositions according to the invention are DL-α-tocopherol, butylated hydroxyanisole and butylated hydroxytoluene.

The composition according to the invention may also contain a surfactant. Surfactants that can be used according to the invention are anionic surfactant types, for example carboxylates, and in particular soaps, alkylarylsulfonates, alkyl ether sulfates, alkyl sulfates and alcohol sulfates. More particularly the anions of these surfactants are coupled with metal-based cations such as sodium or potassium. Preferred surfactants according to the invention are also surfactants of the polysorbate and poloxamer types.

Preferably the surfactants used according to the invention are sodium lauryl sulfate, polysorbate 80 (Tween 80, manufactured by Uniqema) and poloxamer 124 (Synperonic PEL44, manufactured by Uniqema).

The composition according to the invention may also contain a penetration promoter. Penetration promoters which can be used according to the invention are of the alcohol type, such as 1,2-propanediol, sold by the ethanol or glycol type such as Dow Chemical and known under the name propylene glycol.

The pharmaceutical compositions according to the invention may also contain inert additives or combinations of these additives as follows:

Wetting agents;

-Flavor enhancers;

Preservatives;

Stabilizers;

Moisture control agents;

pH adjusters;

Osmotic modifiers;

Emulsifiers;

UV-A and UV-B filters;

-Penetration promoters; And

Synthetic polymers.

Of course, those skilled in the art will note that any compound or compounds for addition to these compositions may be selected so as to, as a result of the intended addition, not alter or substantially alter the beneficial properties essentially associated with the present invention. will be.

The composition according to the invention is more particularly designed for the treatment of skin and mucosal layers, which is sprayable and suitable for packaging in the form of a spray.

Nebulizers exhibit a number of advantages over conventional forms, such as allowing the formulation to be readily delivered to body parts that are very difficult to treat, easily adjusting the dosage to be delivered, or being free from contamination during use.

Therefore, the composition according to the invention is applied in the form of a sprayable composition. The composition may be obtained by conventional formulation means known to those skilled in the art. For example, the composition can be sprayed by a mechanical sprayer that pumps the composition in a container, flask or equivalent. Similarly, the composition can be propelled through a gas, which is well known to those skilled in the art. Conventional propellants, such as air or hydrocarbons, are effective when they do not damage the composition. The composition passes through a nozzle that can point directly to the location to be applied. According to techniques known to those skilled in the art, a nozzle may be selected to apply the composition in the form of spraying or vaporizing droplets. Depending on the pharmaceutical activator chosen, the spray mechanism must always be able to deliver the same amount of activator. Mechanisms for controlling the amount of composition to be delivered by spraying are known to those skilled in the art. For example, the amount of propellant can be calculated to drive the exact amount of product desired. In the compositions according to the invention, it is possible to use metering vaporizer flasks in which application surface characteristics and dosage characteristics can be adjusted and embodied. For example, the vaporizer may consist of a flask equipped with a metering valve.

The compositions of the present invention are chemically and physically stable while effectively penetrating the active radicals. In addition, as described in the Examples of the present invention, due to its spray formulation, it exhibits very good tolerance and tolerance from the position of the patient. Therefore, it has been found that the composition according to the invention is particularly suitable for the treatment of skin diseases.

The present invention therefore also provides the use of a composition according to the invention for the manufacture of a medicament for the purpose of:

-Skin diseases associated with keratinization disorders related to differentiation and proliferation, in particular, conventional acne, scleral acne, polymorphic acne, rose acne, nodular cystic acne, clot acne, senile acne, and solar, drug related or occupational acne Secondary acne, such as

-Young, ichthyosiform condition, Darrier disease, palmarplantar keratoderma, leukoplakiform condition and leukoplakiform condition and skin or mucous membrane (oral) limb,

Skin diseases with inflammatory immunoallergic factors, with or without cell proliferative disorders, in particular skin psoriasis, mucosal psoriasis or nail psoriasis, psoriasis rheumatism, skin atopy such as eczema, respiratory atopic or gingival hyperplasia,

Benign or malignant skin or epithelial proliferation of viruses or other origins, in particular common warts, squamous warts, epidermoid epidermoidosis (epidermodysplasia verruciformis), oral or flowering papilloma and T lymphoma,

Proliferation that can be caused by ultraviolet radiation, in particular basal cell epithelial and goblet cell epithelial,

Precancerous skin injuries, especially keratinocytes (keratoacanthomas),

-Immune skin diseases, in particular, lupus erythematous,

-Bullous immune disease,

Collagen diseases, especially scleroderma,

Dermatological or systemic diseases with immunological factors,

Skin disorders due to exposure to UV radiation, or photoinduced or temporal skin aging, or actin keratosis and pigmentation, or any lesion related to temporal or actinic aging, in particular, xerosis,

Sebaceous dysfunction, in particular, hyperseborrhoea acne or simple seborrheic or seborrheic dermatitis,

Scarring disorders or stretch marks in pregnancy,

Pigmentation disorders such as hyperpigmentation, blemishes, hypopigmentation or vitiligo,

-Lipid metabolic diseases such as obesity, hyperlipidemia, non-insulin dependent diabetes mellitus or X syndrome,

-Inflammatory diseases such as arthritis,

-Cancer or precancerous condition,

Hair loss of various origins, in particular hair loss by chemotherapy or radiation,

Immune system disorders, such as asthma, type 1 diabetes, multiple sclerosis or other selective dysfunction of the immune system, or

Cardiovascular diseases such as atherosclerosis or high blood pressure.

In one preferred embodiment of the composition, it will contain 0.01%, 0.025% or 0.05% clobetasol 17-propionate and 0.0003% calcitriol and will be used in the manufacture of a medicament aimed at treating psoriasis.

The following examples show, but are not limited to, formulations of the compositions according to the invention and, consequently, show chemical and physical stability.

Example 1 Stability of Calcitriol in Various Excipients

The following examples describe the stability data of calcitriol in various excipients preferred for the compositions according to the invention, containing caprylic / capric triglycerides and cetearyl isononanoate.

a) Stability of Calcitriol in Miglyol 812 (Caprylic / Capric Triglyceride)

A solution of 30 ppm of calcitriol in a sufficient amount of Miglyol 812 in 100% in the presence of 0.4% BHT.

HPLC Analysis Techniques for Reference Substances.

At start time (TO), the composition is considered to contain 100% of calcitriol.

Calcitriol concentration measured in% of TO

Stability conditions T 2 weeks T 4 weeks + 4 ℃ 98.3% 105.2% AT 95.1% 98.0% +40 ℃ 91% 93.8%

b) Stability of calcitriol in Cetiol SN (cetearyl isononanoate)

A solution of 30 ppm of calcitriol in a sufficient amount of 100% Cetiol SN (cetearyl isononanoate) in the presence of 0.4% BHT.

HPLC Analysis Techniques for Reference Substances.

At start time (TO), the composition is considered to contain 100% of calcitriol.

Calcitriol concentration measured in% of TO

Stability conditions T 2 weeks T 4 weeks + 4 ℃ 98.6% 98.1% AT 98.7% 98.4% +40 ℃ 99.0% 98.9%

Example 2-Preparation of Compositions According to the Invention

The composition according to the invention was prepared at ambient temperature under a fume hood and in non-actinic light.

Antioxidants, calcitriol and solvent oils were introduced into the flask.

Stirring was performed until calcitriol was completely dissolved.

Thereafter, clobetasol propionate was added.

Stirring was continued until clobetasol propionate was completely dissolved.

When both active elements were completely dissolved, the remaining components of the formulation were introduced continuously.

Stirring was continued until the mixture was perfectly uniform.

Example 3

ingredient % Cyclomethicone 5 Quantity 100 Medium Length Chain Triglycerides 40 Calcitriol 0.0003 Clobetasol 17-propionate 0.025 DL-alpha-tocopherol acetate One

The procedure described in Example 2 was repeated.

A very light yellow liquid solution was obtained.

Example 4

ingredient % Cyclomethicone 5 Quantity 100 Medium Length Chain Triglycerides 40 Calcitriol 0.0003 Clobetasol 17-propionate 0.025 1,2-propanediol 10 Almond oil 5 Butylated hydroxytoluene 0.04

The procedure described in Example 2 was repeated.

A very light yellow liquid solution was obtained.

Example 5

ingredient % Cetearyl Isononanoate Enough 100 Medium Length Chain Triglycerides 40 Calcitriol 0.0003 Clobetasol 17-propionate 0.025 Dimethicone 200, 20 CST 10 Almond oil 5 Butylated hydroxytoluene 0.04

The procedure described in Example 2 was repeated.

A very light yellow liquid solution was obtained.

Example 6

ingredient % Medium Length Chain Triglycerides Enough 100 Cyclomethicone 5 45 Calcitriol 0.0003 Clobetasol 17-propionate 0.025 Dimethicone 200, 20 CST 10 Almond oil 5 Butylated hydroxytoluene 0.04

The procedure described in Example 2 was repeated.

A very light yellow liquid solution was obtained.

Example 7 Physical Stability of Compositions According to Example 6

After 2, 4, 8 and 12 weeks, the formulation was observed macroscopic and microscopically at ambient temperature, 4 ° C. and 40 ° C. to determine the physical stability of the formulation.

Macroscopic observations at ambient temperature confirmed the physical integrity of the product, and microscopic observations confirmed that the dissolved activators did not recrystallize.

Microscopic observation at 4 ° C. confirmed that the dissolved activators did not recrystallize.

Macroscopic observation at 40 ° C. confirmed the integrity of the final product.

Details at TO

Macroscopic appearance : colorless or very light yellow liquid spray.

Microscopic Appearance : Absence of calcitriol and clobetasol 17-propionate crystals.

Time → Stability Condition ↓ T 1M T 2M T 3M AT Match with details Match with details Match with details +4 ℃ Match with details Match with details Match with details +40 ℃ Match with details Match with details Match with details

Example 8: Chemical Stability of Activators in Compositions According to Example 6

-Stability of calcitriol

The activators were analyzed by internal calibration on HPLC.

Time → Stability Condition ↓ T 0 T 15d T 1M T 2M T 3M AT 104.4% 100.9% 101.9% 103.2% 105.1% +40 ℃ 110.2% 101% 105.4% 104.9%

Stability of Clobetasol 17-propionate

Analysis of activators by internal calibration in HPLC

Time → Stability Condition ↓ T 0 T 15d T 1M T 2M T 3M AT 103.8% 102.0% 105.1% 104.4% 102.7% +40 ℃ 102.3% 105.3% 104.5% 102.6%

Example 9

ingredient % Medium Length Chain Triglycerides Enough 100 Cetearyl Isononanoate 45 Calcitriol 0.0003 Clobetasol 17-propionate 0.025 Almond oil 5 Butylated hydroxytoluene 0.04

The procedure described in Example 2 was repeated.

A very light yellow liquid solution was obtained.

Example 10 Physical Stability of Compositions According to Example 9

 After 2, 4, 8 and 12 weeks, the formulation was observed macroscopic and microscopically at ambient temperature, 4 ° C. and 40 ° C. to determine the physical stability of the formulation.

Macroscopic observations at ambient temperature confirmed the physical integrity of the product, and microscopic observations confirmed that the dissolved activators did not recrystallize.

Microscopic observation at 4 ° C. confirmed that the dissolved activator did not recrystallize.

Macroscopic observation at 40 ° C. confirmed the integrity of the final product.

Details at TO

Macroscopic appearance : colorless or very light yellow liquid spray.

Microscopic Appearance : Absence of calcitriol and clobetasol 17-propionate crystals.

Time → Stability Condition ↓ T 1M T 2M T 3M AT Match with details Match with details Match with details +4 ℃ Match with details Match with details Match with details +40 ℃ Match with details Match with details Match with details

Example 11 Chemical Stability of Activators in Compositions According to Example 9

-Stability of calcitriol

The activators were analyzed by internal calibration on HPLC.

Time → Stability Condition ↓ T 0 T 15d T 1M T 2M T 3M AT 100.2% 101.3% 103.2% 104.4% 106.1% +40 ℃ 103.1% 100.7% 101.9% 106%

Stability of Clobetasol 17-propionate

Analysis of activators by internal calibration in HPLC

Time → Stability Condition ↓ T 0 T 15d T 1M T 2M T 3M AT 100.6% 98.4% 102.4% 102.8% 100.6% +40 ℃ 99.6% 102.2% 102.9% 99 3%

Example 12

ingredient % Cyclomethicone 5 Quantity 100 Medium Length Chain Triglycerides 45 Calcitriol 0.0003 Clobetasol 17-propionate 0.025 Dimethicone 200, 20 CST 10 Butylated hydroxytoluene 0.04

The procedure described in Example 2 was repeated.

A very light yellow liquid solution was obtained.

Details at T0

Macroscopic appearance : colorless or very light yellow liquid spray.

Microscopic Appearance : Absence of calcitriol and clobetasol 17-propionate crystals.

Example 13

ingredient % Medium Length Chain Triglycerides Quantity 100 Cyclomethicone 5 35 Calcitriol 0.0003 Clobetasol 17-propionate 0.025 Dimethicone 200, 20 CST 10 Almond oil 5 Butylated hydroxytoluene 0.04

The procedure described in Example 2 was repeated.

A very light yellow liquid solution was obtained.

Example 14 Physical Stability of Compositions According to Example 13

 After 2, 4, 8 and 12 weeks, the formulation was observed macroscopic and microscopically at ambient temperature, 4 ° C. and 40 ° C. to determine the physical stability of the formulation.

Macroscopic observations at ambient temperature confirmed the physical integrity of the product, and microscopic observations confirmed that the dissolved activators did not recrystallize.

Microscopic observation at 4 ° C. confirmed that the dissolved activator did not recrystallize.

Macroscopic observation at 40 ° C. confirmed the integrity of the final product.

Details at TO

Macroscopic appearance : colorless or very light yellow liquid spray.

Microscopic Appearance : Absence of calcitriol and clobetasol 17-propionate crystals.

Time → Stability Condition ↓ T 1M T 2M T 3M AT Match with details Match with details Match with details +4 ℃ Match with details Match with details Match with details +40 ℃ Match with details Match with details Match with details

Example 15 Chemical Stability of Activators in Compositions According to Example 12

Calcitriol Stability

Time → Stability Condition ↓ T 0 T 15d T 1M T 2M T 3M AT 114.3% 114.1% 113.6% 115.8% 119.3% +40 ℃ 113.4% 114.8% 117.2% 119%

Stability of Clobetasol 17-propionate

Time → Stability Condition ↓ T 0 T 15d T 1M T 2M T 3M AT 98.8% 100.5% 103.2% 102.6% 100.3% +40 ℃ 100.8% 103% 102.1% 99.2%

Example 16: Study of in vitro glass / penetration on human skin of active clobetasol 17-propionate contained in three different formulations, containing one according to the invention

After 16 weeks of application on human skin in vitro, the aim is to quantify the skin penetration of formulated activators in different formulations.

Formulations Tested:

Emollient cream Temovate® containing 0.05% (w / w) clobetasol 17-propionate

Cream Temovate® containing 0.05% (w / w) clobetasol 17-propionate

A composition according to the invention of formula A:

ingredient % Medium Length Chain Triglycerides Quantity 100 Cetearyl Isononanoate 45 Calcitriol 0.0003 Clobetasol 17-propionate 0.05 Almond oil 5 Butylated hydroxytoluene 0.04

Softener cream Temovate® is sold by GlaxoSmithKline.

Experimental conditions : Percutaneous absorption was evaluated through a diffusion cell consisting of two compartments separated by human skin. The formulations were applied for a 16 hour application time without occlusion. The formulation was applied at a rate of 10 mg of formulation per cm ² (ie 10 micrograms of clobetasol 17-propionate). Throughout the course of the study, the dermis was contacted with a receiving liquid that was not updated (statically) over time. Experiments were performed with three samples from three different donors. At the end of the application period, surface excess was removed and the distribution of clobetasol 17-propionate was quantified in various compartments of the skin and in the recipient liquor. HPLC / MS / MS methods commonly known to those skilled in the art were used to quantify the concentration of clobetasol 17-propionate (LQ: 1 ng.mL- ¹ ).

The results are expressed as% of dose applied (mean +/− standard deviation), which is set forth in the table below.

Type Total amount penetrated Skin Softener Temovate Cream Average SEM 5.00 1.34 Temovate cream Average SEM 8.43 0.79 Composition A Average SEM 9.87 4.05

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

Claims (16)

A composition comprising the following in a pharmaceutically acceptable carrier, which is liquid at ambient temperature: a) therapeutically effective amount of solubilized form corticosteroid; b) a therapeutically effective amount of a solubilized form vitamin D derivative; c) an oil phase consisting of one or more oils. The composition of claim 1 wherein the composition is sprayable. The composition of claim 1 or 2, wherein the corticosteroid and vitamin D derivative are dissolved in the oil phase. 4. The composition of claim 3 wherein the corticosteroid is clobetasol propionate. The composition according to any one of claims 1 to 4, wherein the vitamin D derivative is calcitriol. The oil phase according to any one of claims 1 to 5, wherein the oil phase is selected from the group consisting of caprylic / capric triglycerides, cetearyl isononanoate, cyclomethicone, dimethicone and sweet almond oil. A composition comprising one or more oils. The composition according to any one of claims 1 to 6, which contains the following in a pharmaceutically acceptable carrier: a) 0.0001 to 0.1% of clobetasol propionate; b) 0.00001 to 0.1% of calcitriol; c) 50 to 99% oil phase consisting of at least one oil selected from caprylic / capric triglycerides, cetearyl isononanoate, cyclomethicone, dimethicone and sweet almond oil. 8. A composition according to claim 7, comprising in the pharmaceutically acceptable carrier: a) 0.001-0.05% clobetasol propionate; b) 0.0002 to 0.0005% of calcitriol; c) 95-99% oil phase consisting of at least one oil selected from caprylic / capric triglycerides, cetearyl isononanoate, cyclomethicone, dimethicone and sweet almond oil. The composition according to any one of claims 1 to 8, which further contains an antioxidant. 10. The composition of claim 9, wherein the antioxidant is selected from DL-α-tocopherol, butylated hydroxyanisole and butylated hydroxytoluene. The composition according to any one of claims 1 to 10, further comprising a surfactant. The composition of claim 11 wherein the surfactant is selected from sodium lauryl sulfate, poloxamer and polysorbate. The composition according to any one of claims 1 to 12, further comprising a penetration accelerator. 14. The composition of claim 13, wherein the penetration enhancer is 1,2-propanediol or ethanol. Use of a composition according to any one of claims 1 to 14 for the manufacture of a medicament aimed at treating the following: -Skin diseases associated with keratinization disorders related to differentiation and proliferation, in particular, conventional acne, scleral acne, polymorphic acne, rose acne, nodular cystic acne, clot acne, senile acne, and solar, drug related or occupational acne Secondary acne, such as -Young, ichthyosiform condition, Darrier disease, palmarplantar keratoderma, leukoplakiform condition and leukoplakiform condition and skin or mucous membrane (oral) limb, Skin diseases with inflammatory immunoallergic factors, with or without cell proliferative disorders, in particular skin psoriasis, mucosal psoriasis or nail psoriasis, psoriasis rheumatism, skin atopy such as eczema, respiratory atopic or gingival hyperplasia, Benign or malignant skin or epithelial proliferation of viruses or other origins, in particular common warts, squamous warts, epidermoid epidermoidosis (epidermodysplasia verruciformis), oral or flowering papilloma and T lymphoma, Proliferation that can be caused by ultraviolet radiation, in particular basal cell epithelial and goblet cell epithelial, Precancerous skin injuries, especially keratinocytes (keratoacanthomas), -Immune skin diseases, in particular, lupus erythematous, -Bullous immune disease, Collagen diseases, especially scleroderma, Dermatological or systemic diseases with immunological factors, Skin disorders due to exposure to UV radiation, or light-induced or temporal skin aging, or actin keratosis and pigmentation, or any lesions associated with temporal or actinic aging, in particular, xerosis, Sebaceous dysfunction, in particular, hyperseborrhoea acne or simple seborrheic or seborrheic dermatitis, Scarring disorders or stretch marks in pregnancy, Pigmentation disorders such as hyperpigmentation, blemishes, hypopigmentation or vitiligo, -Lipid metabolic diseases such as obesity, hyperlipidemia, non-insulin dependent diabetes mellitus or X syndrome, -Inflammatory diseases such as arthritis, -Cancer or precancerous condition, Hair loss of various origins, in particular hair loss by chemotherapy or radiation, Immune system disorders, such as asthma, type 1 diabetes, multiple sclerosis or other selective dysfunction of the immune system, or Cardiovascular diseases such as atherosclerosis or high blood pressure. Use according to claim 15 for the treatment of psoriasis.