FR2924943A1 - Composition, useful for preparing medicament to treat dermatological disorders, preferably psoriasis, comprises vitamin D derivative comprising e.g. calcitriol and calcipotriol, and nanocapsules dispersed in continuous hydrophilic phase - Google Patents

Abstract

Composition comprises: at least a vitamin D derivative comprising calcitriol, calcipotriol and (4-[6-ethyl-4'-(1-ethyl-1-hydroxy-propyl)-2'-propyl-biphenyl-3-yloxymethyl]-2-hydroxymethyl-phenyl)-methanol; and nanocapsules dispersed in a continuous hydrophilic phase, where the nanocapsules comprise a continuous polymer envelope insoluble in water and oily internal phase in which the vitamin D derivative is solubilized. An independent claim is included for a preparation of the composition comprising preparing an organic phase by mixing the vitamin D derivative with a biodegradable or non-biodegradable polymer, oily solvent, a coating agent and an organic solvent, preparing a hydrophilic phase by mixing water with a hydrosoluble surfactant, and mixing organic and hydrophilic phases. ACTIVITY : Dermatological; Antipsoriatic. MECHANISM OF ACTION : None given.

Description

The present invention relates to a pharmaceutical composition, especially dermatological, based on a compound of the family of vitamin D derivatives, and more particularly calcitriol, in the form of nanocapsules dispersed in a hydrophilic phase. It also relates to its preparation process and its use in the preparation of a medicament for the treatment of dermatological conditions, in particular psoriasis.

Vitamin D derivatives, especially calcitriol, are used to regulate calcium levels in the body. The use of calcitriol in the treatment of dermatological diseases has in particular been described in US Pat. No. 4,610,978 for the treatment of psoriasis.

On reading the prior art, existing treatments often contain a high percentage of petrolatum to promote occlusivity and penetration of the active ingredient but therefore have the disadvantage of being very greasy and sticky, thus not favoring the comfort and ease of application.

Other types of compositions commonly have a high percentage of propenetrating glycol to promote the penetration of the active ingredient but are sticky and may cause intolerance problems. (Piacquadio & ail, Journal of the American Academy of Dermatology) encountered in the prior art contain a, August 1998).

The problem which the present invention proposes to solve here is therefore to design a physically and chemically stable composition containing calcitriol for the treatment of psoriasis, the composition according to the invention making it possible: to protect the active ingredient from - screw degradation in contact with water through a polymeric envelope; - to vectorize the asset; 30 - and improve its skin penetration thanks to the small particle size. Such a composition would also provide more comfort to the patient and ensure better compliance treatment.

However, vitamin D derivatives, and especially calcitrol, are unstable in aqueous media, and sensitive to acidic pH.

The object of the present invention is therefore to provide an aqueous composition which achieves the aforementioned objectives. To this end, it seems interesting to work on the structure of the interface between the solubilization medium of calcitriol and the aqueous phase.

The subject of the present invention is therefore a composition, in particular a pharmaceutical composition, comprising at least one derivative of vitamin D, preferably calcitriol, said composition comprising nanocapsules dispersed in a continuous hydrophilic phase, said nanocapsules comprising a continuous polymeric envelope insoluble in water, an oily internal phase in which the vitamin D derivative is solubilized and preferably an external lamellar coating.

As shown in the examples, the encapsulation of the vitamin D derivative, in particular calcitriol, makes it possible to stabilize the active agent in aqueous solution at 4 ° C. and at room temperature. This type of encapsulation therefore makes it possible to formulate a vitamin D derivative, and especially calcitriol, in hydrophilic formulations. Furthermore, the nanocapsules according to the invention have a structure that mimics that of the intercellular cement of the stratum corneum. By this biomimicry, in particular provided by the nature of the outer lamellar coating, the nanocapsules have good compatibility with the skin.

The composition according to the invention comprises from 0.00001 to 0.1% of at least one vitamin D derivative by weight relative to the total weight of the composition, preferably from 0.0001 to 0.05%. Preferably, the composition according to the invention contains from 0.0001% to 0.05% of calcitriol, preferably from 0.003% to 0.015%.

Nanocapsule means a system having a core-shell structure, that is to say a structure consisting of an internal oily phase (or lipidic core) which is liquid at ambient temperature and contains the vitamin D derivative in the form solubilized, said oily internal phase being encapsulated in a continuous protective envelope insoluble in the medium. Such nanocapsules are capable of passing through the upper layers of the living epidermis to release the vitamin D derivative therein.

By ambient temperature is meant a temperature of between 15 and 25 ° C. The term "vitamin D derivatives" means the compounds chosen from calcitriol, calcipotriol and {4- [6-ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propyl-biphenyl-3 -yloxymethyl] -2-hydroxymethylphenyl} -methanol. Preferably, calcitriol will be used.

According to the present invention, the composition comprises nanocapsules and not nanospheres. Indeed, the nanospheres consist of a polymer matrix in which the active ingredient is absorbed and / or adsorbed and / or mixed, so the entire mass is solid. When the nanospheres contain a pharmaceutically acceptable active ingredient, it is finely dispersed in the solid matrix. The nanocapsules according to the present invention have a mean size of between 130 nm and 600 nm, preferably between 150 nm and 300 nm, preferably around 250 nm. The nanocapsules are present in the composition according to the invention in an amount of between 0.1 and 50% by weight relative to the total weight of the composition, preferably between 0.5 and 25%.

The nanocapsules each consist of an internal oily phase (lipid core) that is liquid at room temperature and encapsulated in a protective envelope, said envelope being coated with an outer lamellar phase. The protective envelope is polymeric in nature; the polymer may be biodegradable or not. The nanocapsules in biodegradable polymers penetrate the skin and degrade in the epidermis under the action of the enzymes that are present. On the other hand, nanocapsules made of non-biodegradable polymers are not degraded by the skin enzymes, only penetrate the superficial layers of the stratum corneum and are naturally removed during the renewal of the skin. 1) As biodegradable polymers, it is possible to use any polymer that may be degraded by the skin enzymes, and in particular those mentioned in document EP-A-447318. In particular, poly-L- and DL-lactides and polycaprolactones, polyglycolides and their copolymers, and polymers derived from the polymerization of alkyl cyanoacrylate (the alkyl chain containing from 2 to 6 carbon atoms) may be mentioned as biodegradable polymers. carbon).

2) According to one variant of the invention, the biodegradable polymer constituting the shell of the nanocapsules may be a polyester of the poly (alkylene adipate) type, that is to say either a homopolymer of adipic acid and an alkane diol, a poly (ester ether) type copolymer, linear or branched, obtained from adipic acid and one or more alkanediols and / or ether-diols and / or triols. The alkanediols used for the preparation of said poly (alkylene adipate) are straight or branched chain C 2 -C 6 alkanediols chosen from ethylene glycol, propylene glycol, 1,3-propanediol and 1,4-butanediol. 1,5-pentanediol, 1,6-hexanediol and neopentyl glycol. The ether diols are di-, tri- or tetra- (C2-4 alkylene) glycols such as diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, tripropylene glycol, tetrapropylene glycol or dibutylene glycol, tributylene glycol or tetrabutylene. The triols used are generally chosen from glycerol, trimethylolethane and trimethylolpropane.

The fraction of the branching units derived from the above triols does not generally exceed 50 mol% relative to all the units derived from diols and triols. According to a preferred embodiment of the present invention, the envelope of the nanocapsules is formed by a poly (ethylene adipate) or a poly (butylene adipate).

The poly (alkylene adipates) used in the present invention have a weight average molecular weight (measured by gel permeation chromatography) which is preferably between 2000 and 50,000, more preferably between 5,000 and 15,000.

A whole range of products of different chemical compositions and of different molar masses is marketed under the name FOMREZ by WITCO. SCIENTIFIC POLYMER PRODUCTS sells under the name POLY (ETHYLENE) ADIPATE a poly (ethylene adipate) with a weight average molecular weight (determined by GC) of about 10,000.

3) The non-biodegradable polymers that may be used according to the invention may be chosen from any polymer which is not degraded by the skin enzymes, and in particular the copolymers of methacrylic acid and methyl methacrylic acid ester, polyvinyl aceto-phthalate, cellulose acetate phthalate, cross-linked polyvinylpyrrolidone-vinyl acetate copolymers, polyethylenesvinylacetates, polyacrylonitriles, polyacrylamides, polyethylene glycols, polyamides, polyethylenes, polypropylenes and organopolysiloxanes, without this list being limiting. Preferably, as biodegradable polymers, polycaprolactones, such as those sold by Solvay Laboratories under the name CAPA 6506, will be used.

Among the non-biodegradable polymers, the copolymers of methacrylic acid and methacrylic acid methyl ester will preferably be used. Preferably, the 30/70 mixture of methacrylic acid / methyl methacrylate sold under the name Eudragit S100 by Degussa-Rohm Pharma will be used.

The vitamin D derivative, in particular calcitriol, is thus solubilized in the core of the nanocapsules (oily internal phase), said core being liquid at ambient temperature.

The composition of the oily internal phase is therefore essential for the stability of the active ingredient. Moreover, the oily internal phase must of course be compatible with the asset to be solubilized. This oily internal phase comprises at least one oily solvent, chosen from tocopherol esters, and triglycerides and oils containing them. Of the triglycerides and oils containing them, octanoic acid triglycerides or sunflower, corn, soya, squash, grape seed, sesame, hazelnut, apricot or macadamia oils are preferred. of arara, castor, avocado, triglycerides of caprylic / capric acids such as those sold by Stearineries Dubois or those sold under the names Miglyol 810, 812 and 818 by Dynamit Nobel, jojoba oil , and shea butter oil. Preferably, the oily solvent is selected from vitamin E acetate and caprylic / capric acid triglycerides, such as Mygliol 812N. In addition to this oily solvent (s), the internal phase may also comprise one or more non-solubilizing liquid or semi-liquid fatty substances at ambient temperature of the active substance, such as: 2-alkyl alkanols, such as: butyloctanol, hexyldecanol, octyldecanol, isostearyl alcohol, octyldodecanol, decyltetradecanol, undecylpentadecanol, dodecylhexadecanol, tetradecyloctadecanol, hexyldecyloctadecanol, tetradecylicosanol, cetylarachidol and iso alcohol mixtures -cetyl, iso-stearyl and iso-arachidyl. All these compounds are commercially available from CONDEA VISTA under the Isofol trade name, from Exxon Chemical under the name Exxal or from JarcheM under the name Jarcol. It is also possible to use the compound available from HENKEL under the trade name EUTANOL G. As esters of said alcohols, mention may be made of: Octyldodecyl octanoate; hexyldecyl caprylate; hexyldecyl laurate; hexyldecyl palmitate; hexyldecyl stearate; and octyl dodecyl meadowfoamate, which is an ester of octyldodecanol and fatty acids derived from meadowfoam seed oil Alba; esters of fatty acids or of fatty alcohols, such as isopropyl palmitate, isostearyl neopentanoate and octyl palmitate; N-acylated amino acid and fatty alcohol esters, such as isopropyl N-lauroyl sarcosinate, and liquid fatty alcohol and polypropylene glycol ethers, such as polypropylene glycol stearyl ether containing Propylene glycol units.

The oily solvent (s) is (are) present in an amount of between 90 and 99.99% by weight relative to the total weight of the internal phase; and in an amount of from 1 to 10% by weight relative to the total weight of the composition, preferably from 2 to 8%.

In a preferred embodiment according to the invention, the nanocapsules consist of an internal oily phase (lipid core) which is liquid at ambient temperature, this phase being encapsulated in a protective envelope, said envelope being coated with an outer lamellar phase. By "outer lamellar phase" is meant a structure organized into one or more lipid sheet (s) each consisting of a bilayer of amphiphilic molecules similar to that of biological membranes. These molecules are called coating agents. This coating, in addition to its function of adjusting the size of the nanocapsules, improves the sealing of the nanocapsules vis-à-vis a leakage of the active ingredient to other lipid phases of the composition. The coating agents are hydrophobic surfactants soluble in the organic phase used in the present process and which are capable, in the presence of water, of forming the lipid bilayers described above. In the method of encapsulation of active ingredients used by the applicant, this coating agent is dissolved in the organic phase (acetonic / alcoholic) containing the polymer and the lipid phase.

Examples of such coating agents include phospholipids such as lecithin according to the application EP-A-447 318, certain polycondensates of ethylene oxide and propylene oxide, such as products sold under the PLURONIC name (registered trademark) by BASF such as PLURONIC L121 or under the name SYNPERONIC (Registered trademark) by ICI, or certain silicone surfactants, such as those described in US-A-5 364 633 and US -A-5,411,744 and used in the patent application FR-A-2,742,677, for example those sold by the company Dow Corning under the names DC 5329, DC 7439-146, DC 2-5695 and Q4-3667.

The continuous hydrophilic phase comprises water. This water may be demineralized water, floral water such as blueberry water, or natural thermal or mineral water, for example chosen from Vittel water, Vichy basin water Uriage, the water of the Roche Posay, the water of the Bourboule, the water of Enghien-les-Bains, the water of Saint Gervais-les-Bains, the water of Néris-les-Bains, the water of Allevard-les-Bains, the water of Digne, the water of Maizières, the water of Neyrac-les-Bains, the water of Lons-le-Saunier, the Good Waters, the water Rochefort, the water of Saint Christau, the water of the Fumades and the water of Tercis-les-bains, the water of Avène or the water of Aix les Bains. The water may be present at a content of between 70 and 90% by weight relative to the total weight of the composition, preferably between 80 and 90% by weight.

The hydrophilic phase may also comprise a water-soluble surfactant or other hydrophilic compounds such as preservatives or humectants. By water-soluble surfactant is meant a surfactant soluble at least 1% in water, the resulting solution must be perfectly clear. Water-soluble surfactants that may be mentioned include poloxamers, such as Synperonic PE / F68 or poloxamer 188.

Among the preservatives that may be used, mention may be made especially of parabens or phenoxyethanol. Among the humectants that can be used, there may be mentioned glycerine.

The hydrophilic phase may also comprise a gelling agent. This gelling agent is preferably a cellulose derivative chosen from semi-synthetic cellulosic gelling agents, such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxymethylcellulose, and hydroxypropylcellulose, taken alone or in mixture. Hydroxypropylmethylcellulose or hydroxyethylcellulose is preferably used. These compounds are especially marketed by Dow Chemical under the name Methocel (for example: Methocel E4M) or by Hercules under the name Natrosol (for example: Natrosol 250 HHX). The gelling agent may also be chosen from natural gums such as tragacanth gum, guar gum, acacia gum, gum arabic, starch and its derivatives, copolymers of polyacrylic acid and methylmethacrylate, carboxyvinyl polymers, polyvinyl pyrrolidones and their derivatives, polyvinyl alcohols, sodium alginate, pectin, dextrin, chitosan, alone or as a mixture. The gelling agent is used in particular at a concentration of between 0.1 and 10% by weight, preferably between 0.1 and 2% by weight.

The pharmaceutical composition that can be used according to the invention is intended for the treatment of the skin and can be administered topically, parenterally or orally. Preferably, the composition is administered topically.

Orally, the pharmaceutical composition may be in liquid or pasty form, and more particularly in the form of capsules, dragees, or syrups.

Parenterally, the composition may be in the form of suspensions for infusion or for injection. Topically, the composition may be in liquid or pasty form, and more particularly in the form of creams, milks, ointments, soaked swabs, syndets, wipes, gels, sprays, foams, lotions, sticks, shampoos, or washing bases. The composition comprising the nanocapsules thus preferably comprises, in water, by weight relative to the total weight of the composition: a) 0.1 to 5% of biodegradable or non-biodegradable polymer; b) 1 to 20% oily solvent at room temperature, preferably vitamin E acetate or caprylic / capric acid triglycerides; c) between 0.00001 and 0.1% of at least one derivative of vitamin D, and preferably preferably from 0.0001 to 0.05% of calcitriol; d) 0 to 2% gelling agent, preferably a cellulose derivative.

In a preferred embodiment, the composition according to the invention also comprises a coating agent, such as the previously described phospholipids.

The pharmaceutical composition according to the invention may also contain inert additives or combinations of these additives, such as - preservatives; - propenetrating agents; stabilizing agents; humidity regulating agents; pH regulating agents; osmotic pressure modifying agents; UV-A and UV-B filters; - and antioxidants.

Among the propenetrants that can be used according to the invention, there may be mentioned propylene glycol, N-methyl-2-pyrrolidone or even dimethylsulfoxide.

Of course, one skilled in the art will take care to choose the optional compound (s) to be added to these compositions in such a way that the advantageous properties intrinsically attached to the present invention are not or not substantially impaired by the envisaged addition.

These additives may be present in the composition of 0.001 to 20% by weight relative to the total weight of the composition.

The invention also relates to a method for preparing nanocapsules comprising at least one derivative of vitamin D, preferably calcitriol, and compositions comprising them. This process involves the precipitation of the preformed polymers.

The method implemented in the present invention thus comprises the following steps:

(I) Preparation of an organic phase by mixing at least one vitamin D derivative, the biodegradable or non-biodegradable polymer, the oily solvent, a coating agent and an organic solvent. (ii) Preparation of a hydrophilic phase by mixing the water with a water-soluble surfactant.

(iii) Mixing of the phases (i) and (ii), in order to obtain the composition as defined above comprising nanocapsules dispersed in a continuous hydrophilic phase.

The organic solvent used in step (i) must be miscible with water, and the polymer must be soluble therein. Preferably, the organic solvent is acetone, lower alcohols, for example ethanol or isopropanol, or methylal and ethyl acetate, or mixtures of these solvents. The coating agent must spontaneously form a lamellar phase by contact with water. Preferably, the solvent: water ratio is between 0.05 and 0.5.

The nanocapsules are thus formed by the following mechanism: 1) a saturated solution of solvent, especially acetone, is formed at the interface of the organic (i) and hydrophilic (ii) phases; 2) the solvent diffuses into the water; 3) droplets of oily solvent are formed; 4) the polymer precipitates on the oily solvent droplets.

The invention also relates to the use of the nanocapsules according to the invention, and compositions comprising them, for the preparation of a medicament for treating human dermatological conditions. The invention also relates to the nanocapsules according to the invention as defined above for their use in the treatment of human dermatological conditions.

The use of nanocapsules, and compositions comprising them, according to the invention is more particularly intended for the treatment of psoriasis.

As an illustration and without limitation, various formulations of compositions comprising calcitriol will now be given.

Example 1 Preformulation Study of Calcitriol Preliminary preformulation studies were conducted to guide the choice of the lipid core (oily internal phase) on the one hand and the choice of the solvent phase (organic solvent) on the other hand. a) Study of solubility and stability of calcitriol in oily solvents: 1) Calcitriol in Mygliol Calcitriol 800ppm in Miglyol 812 4 ° C TA + 40 ° C Time of Nb Content Rec. Content Rec. Content Rec. stability days (pg / g)% / t = 0 (pg / g)% / t = 0 (pg / g)% / t = 0 t = 0 0 1011.5 100% 1011.5 100% 1011.5 100% t + 2 weeks 14 1020.2 100.9% 1029.6 101.8% 1028.7 101.7% t + 4 weeks 28 1009.4 99.8% 1013.6 100.2% 1013.1 100.2% 2) Calcitriol in Tocopherol Acetate Calcitriol 800ppm in Tocopherol acetate 4 ° C TA + 40 ° C Time of Nb Content Recipe . Content Rec. Content Rec. stability days (μg / g)% / t = 0 (μg / g)% / t = 0 (μg / g)% / t = 0 t = 0 0 805.1 100% 805.1 100% 805.1 100% t + 2 weeks 14 856.6 106.4% 826.9 102.7% 840.0 104.3% t + 4 weeks 28 792.5 98.4% 817.0 101.5% 834.6 103.7% These preliminary studies are aimed at finding the oil that will be the best candidate for solubilizing Calcitriol and in which it is stable.

Results: Calcitriol is stable for one month at 800ppm at three temperatures in Miglyol and tocopherol acetate. At the end of this study, Miglyol and tocopherol acetate were chosen for producing the oily heart of the nanocapsules.

b) Study the solubility of calcitriol in water / acetone mixtures in order to define the best solvent phase / dispersant phase ratio: 1520 The aim is to find the best ratio of water / organic solvent mixture in which Calcitriol is not soluble so that it does not escape from its oily core and does not come into contact with the water, in which it is unstable during the manufacturing process. The solvent retained is acetone; it makes it possible to solubilize the polymer during the manufacturing process. Calcitriol 800ppm in water / acetone mixture (v / v) Mel 1 Mel 2 Mel 3 Grade Rec. Content Rec. Content Rec. (pg / g)% / t = 0% / t = 0 (pg / g)% / t = 0 (pg / g) 7.3 0.8% 64.2 7.2% 493.3 55.2% Results: The solubility of calcitriol is inversely proportional to the water content of the binary mixture. Parameter selection: - Oily phase: Miglyol; - Ratio aqueous phase / organic phase 4: 1. EXAMPLE 2 Examples of Formulations Description of the constituents of the formulation: Based on poly-E-caprolactone: Ingredients Chemical name Function Purified water Purified water Synperonic PE / F68 vehicle Poloxamer 188 Surfactant Nipagin M Methyl Parahydroxybenzoate Antibacterial preservative Epikuron 145V Lecithin agent coating CAPA 6506 Poly-e-caprolactone Synthetic biodegradable polymer Calcitriol 0.3% Miglyol Caprylic / Caprique triglyceride Parent solution of active solution Phenoxetol Phenoxyethanol Antibacterial preservative 25 10 Formulas 0 to 3: FORMULA 0 1 2 3 Phase Ingredients 1 Water Purified 92.50 91.50 90. 80 89.30 1 Nipagin M - - 0.20 0.20 1 Synperonic PE / F68 0.50 0.50 1.00 1.50 2 Epikuron 145V 1.00 1.00 1.00 1.00 2 CAPA 6506 - 1.00 2.00 3.00 2 Calcitriol 0.3% Miglyol 5.00 5.00 5.00 5.00 Solution 3 Phenoxyethanol 1 1.00 - - Formula 0 corresponds to formulation 1 without polymeric shell, ie a nanoemulsion 5 without a wall polymeric. Based on Eudragit S100: Ingredients Chemical Name Function Purified Water Purified Water Span Vehicle 60 Sorbitan Tensio-active Stearate Nipagin M Methyl Parahydroxybenzoate Antibacterial Preservative Tween 80 Polysorbate 80 Coating Agent Eudragit S100 Methacrylic Synthetic Polymer Synthetic Polymer Methyl Methacrylate Calcitriol 0.3% Miglyol Triglyceride Stock solution of active ingredient Caprylic / Caprique solution Phenoxetol Phenoxyethanol Antibacterial preservative Formula 4 to 6: FORMULA 4 5 6 Phase Ingredients 1 Purified water 91.50 91.3 89. 3 1 Nipagin M - 0.2 0.2 1 Synperonic PE / F68 0.50 - - 1 Span 60 0.5 1 2 Tween 80 1 1.5 2 Epikuron 145V 1.00 - - 2 Eudragit S100 1.00 1 3 2 Calcitriol 0.3% Miglyol Solution 5.00 5 5 3 Phenoxyethanol 1.00 1 - 135 Formula 7 to 8: Gelled polymeric nanocapsules No. of FORMULA 7 8 Concept Triple Eudra Triple Capa Ingredients Purified Water 97.57 97.57 Nipagin M 0.23 0.23 Synperonic PE / F68 - 0.20 Span 60 0.13 - Natrosol HHX 0.80 0.80 Tween 80 0.20 - Epikuron 145V - 0.13 Eudragit S100 0.40 - Calcitriol 0.3% Miglyol 0.67 0.67 Solution CAPA 6506 - 0.40 Example 3: Procedure of the formulations 1st stage: Preparation of the aqueous phase: 10 1 / Tarant 1 beaker Form 1000ml 2 / Weigh successively: water (400m1), surfactant (Synperonic PE / F68 or Span 60) and antimicrobial preservative (Nipagin M). 3 / Once the aqueous phase is weighed, place it with slow Rayneri stirring and then heat to 85 ° C to ensure solubilization of Nipagin M. 4 / Finally allow the temperature to drop to 45 ° C.

2nd step: Preparation of the organic phase:

20 1 / Tarant 1 beaker of 250 ml 2 / Weigh successively: - The oily solution of calcitriol - CAPA 6506 / Eudragit S100 - Epikuron 145V / or Tween 80 25 - Acetone (100m1 equivalent to 79g for to be at the ratio water / acetone equivalent to 4/1) 3 / Once the organic phase weighed, place it under magnetic stirring, then heat to 50 ° C.

Step 3: Emulsification Pour the organic phase into the aqueous phase with Rayneri stirring under strong shear for about 10 minutes.

4th step: Evaporation: 10 1 / Tarant a ground 1000ml flask, 2 / Transfer the emulsion obtained in the ground 1000ml flask. 3 / Place the flask on the rotary evaporator and switch on the Marie bath at 40 ° C 4 / Evaporate the solvent under vacuum with a rotation speed of 10 rpm. This step should make it possible to evaporate all the acetone as well as 3/4 of the quantity of water in order to obtain 50 g of final product, ie a content of 5% in the oily phase.

5 / Introduce Phenoxyethanol at the end of the production and homogenize with magnetic stirring. For examples 7 and 8, the gelled forms of the polymeric nanocapsules, a gelled base is used with a cellulose derivative, base in which the concentrated solution of polymeric nanocapsules is incorporated.

EXAMPLE 4 PHYSICAL STABILITY STUDIES of the Formulations of Example 2 The physical stability of the compositions is measured by particle size. The particle size measures the average particle diameter in the composition, a measurement made using a Malvern Zetasizer type laser granulometer. The simple envelope formula corresponds to 1% of poly-ε-caprolactone or Eudragit S100. (Formulas 1, 4 and 5) The double envelope formula corresponds to 2% poly-ε-caprolactone. (Formula 2) The triple shell formula is 3% poly-E-caprolactone or Eudragit S100. (Formulas 3)

The formulations were followed for 3 to 6 months at 4 ° C, room temperature and 40 ° C. 1 2 3 5 Concept poly-E-poly-E-poly-E-Eudragit caprolactone caprolactone caprolactone Single double triple-single envelope type Size (nm) TO 196 222 212 198 pH TO ND 5.32 4.72 4.61 T1 TA 196 211 211 215 Months + 4 ° C 199 220 ND 203 + 40 ° C 149 216 215 284 T2 TA 192 213 209 241 Months + 4 ° C 196 218 ND 208 + 40 ° C 196 225 218 333 T3 TA 197 217 213 Months + 4 ° C 192 212 210 + 40 ° C 202 230 227 T6 TA 195 216 213 Months + 4 ° C 195 220 210 + 40 ° C 209 231 227 NA: Not determined

The particle size is stable over time, 3 to 6 months according to the formulas, and whatever the temperature conditions. So we managed to get a physically stable system.

Example 5: Chemical stability of the formulas Formula 3 TO 151 pg / g 140 pg / g 4 ° C 4 ° C TA T1 month (% p / r TO) 95% 99% 91% T2month (% p / r TO) 95% 103% 96% T3months (% w / w TO) 91% 82% - The nanocapsules based on poly-E-caprolactone increase the stability of Calcitriol in water at 4 ° C and this stability is even better than the the amount of polymer is greater: 1 to 3%. Calcitriol in aqueous solution degrades all the more rapidly as the temperature increases. The nanocapsules based on Eudragit S100 make it possible to stabilize Calcitriol in aqueous phase at 4 ° C. and at room temperature.

Results of the chemical stability of calcitriol in gelled formulations of polymeric nanocapsules: Formula 7 8 Concept CAPA triple EUDRAGIT TO 18.5 pg / g 18.0 pg / g 4 ° C Tamb 4 ° C Tamb Tl month 106% 102% 110% 98% T3month 107% 95% 107% 87% T5 months 107.4 107 T7.5 months 104 103 T8 months 112 101 T 9 months 113 102 For formula 8, formula for which poly-ε-caprolactone is used to form the nanocapsules, the gelling of the hydrophilic phase makes it possible to improve the chemical stability of calcitriol in comparison with the chemical results obtained with the formula 3

Example 6: In-vivo release test of the gelified nanocapsule formulations An evaluation of the release of calcitriol from the nanocapsules was performed by in-vivo tests. Both polymers were tested in the gelled forms (Example 7 and 8) with different calcitriol assays of 5, 10 and 20 ppm. The release of calcitriol in the nanocapsules was compared with that of a 10 ppm ethanol solution of calcitriol.

Application of the different formulations to be evaluated for 6 consecutive days and blood sampling after 48 hours without application. Plasma calcium and weight loss are used to evaluate the release and toxicity of our different formulations.

Claims (16)

A composition comprising at least one vitamin D derivative selected from calcitriol, calcipotriol and {4- [6-ethyl-4 '- (1-ethyl-1-hydroxy-propyl) -2'-propylbiphenyl) -3-yloxymethyl] -2-hydroxymethyl-phenyl} -methanol, characterized in that it comprises nanocapsules dispersed in a continuous hydrophilic phase, said nanocapsules comprising a continuous polymeric envelope insoluble in water and an oily internal phase in which the vitamin D derivative is solubilized. 2. Composition according to claim 1, characterized in that the vitamin D derivative is calcitriol. 3. Composition according to one of claims 1 or 2, characterized in that the oily internal phase of the nanocapsules comprises at least one oily solvent selected from the esters of tocopherols and triglycerides of caprylic / capric acids. 4. Composition according to one of claims 1 to 3, characterized in that the polymeric shell comprises at least one polymer selected from polycaprolactones and copolymers of methacrylic acid and methacrylic acid methyl ester. 5. Composition according to one of claims 1 to 4, characterized in that the nanocapsules are present in an amount of between 0.1 and 50% by weight relative to the total weight of the composition. 25 6. Composition according to one of claims 3 to 5, characterized in that the oily solvent is present in an amount of between 90 and 99.99% by weight relative to the total weight of the nanocapsules. 7. Composition according to one of claims 1 to 6, characterized in that the continuous hydrophilic phase comprises a water-soluble surfactant. 8. Composition according to one of claims 1 to 7, characterized in that the continuous hydrophilic phase comprises a gelling agent. 5 9. Composition according to claim 8, characterized in that the gelling agent is a cellulose derivative selected from methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxymethylcellulose, and hydroxypropylcellulose, taken alone or in mixture. 10. Composition according to one of claims 1 to 9, characterized in that the nanocapsules are surrounded by a lamellar coating agent. 11. Composition according to one of claims 3 to 10, characterized in that it comprises in water, by weight relative to the total weight of the composition: a) 0.1 to 5% of the polymer chosen from polycaprolactones and copolymers of methacrylic acid and methacrylic acid methyl ester; b) 1 to 20% oily solvent; c) 0.0001% to 0.05% of at least one vitamin D derivative; D) 0 to 2% gelling agent. 12. Composition according to one of claims 1 to 11, characterized in that it is in a form suitable for topical administration. 20 13. Composition according to one of claims 1 to 12, as a medicament. 14. Use of a composition according to one of claims 1 to 12 for the preparation of a medicament for the treatment of dermatological conditions. 25 15. Use according to claim 14, characterized in that the dermatological condition is psoriasis. 16. Process for the preparation of a composition according to one of claims 1 to 12, characterized in that it comprises the following steps: (i) Preparation of an organic phase by mixing at least one vitamin derivative D with a biodegradable or non-biodegradable polymer, an oily solvent, a coating agent and an organic solvent; (ii) Preparation of a hydrophilic phase by mixing water with a water-soluble surfactant; (iii) Mixture of organic and hydrophilic phases.