MXPA97003461A - New compositions based on a synergistic mixture of at least one linked vdr and a rethink - Google Patents

Abstract

The present invention relates to a new combination of one or more ligands with selective activity of the VDR receptor and one or more selective retinoids for RAR-gamma receptors with respect to the RAR-alpha receptors, as well as to the use of these in cosmetic application and care of the skin for the treatment of disorders related to hyperproliferation of cells, in particular skin cells, such as psoriasis

Description

NEW COMPOSITIONS BASED ON A SYNERGISTIC MIXTURE OF AT LEAST ONE LIGANDO VDR AND ONE RBTTJfOIDE FIELD OF THE INVENTION The invention relates to a novel composition, in particular a pharmaceutical composition, which consists of a synergistic combination of at least one ligand which has -activity for nuclear receptors of the VDR type and at least-a specific retinoid, as well as the use of this composition in the pharmaceutical or cosmetic field.

BACKGROUND OF THE INVENTION It is known that a ligand which has activity for nuclear receptors of the VDR type (vitamin D3 receptor), such as lalfa, 25-dihydroxyvitamin D3 or analogs thereof, inhibits the proliferation of keratinocytes. Thus, this type of compound is used to treat psoriasis. In any case these compounds, such as lalfa, 25-dihydroxyvitamin D3, have side effects: hypercalcemia or hypercalciuria, due to an increase in the level of calcium in the serum. It is known that retinoic acid is a modulator (i.e., an inhibitor or, on the contrary, a stimulator, which depends on the nature of the treated cells) of the different REF: 24694 retention and / or proliferation of many types of normal or transformed cells. For example, retinoic acid inhibits the differentiation of epithelial cells, such as the epidermal que-ratinocytes, without being especially active according to the proliferation of these cells. It also inhibits the proliferation of many transformed cells, such as melanoma cells. It is known, in general, cju = the retinoic acid in all its trans positions acts in the differentiation and / or pro-liferation of cells by interaction with nuclear receptors or RAR's (retinoic acid receptors) contained in the -cell nuclei. Many analogous synthetic structures of retinoic acid in all their trans or 9-cis retinoic acid positions, commonly known as "retinoids", have been described so far in the literature. Here there are currently three identified sub-types of RAR receptors referred respectively as RAR-alpha, RAR-beta and RAR-gamma. After binding of the ligand (i.e. of retinoic acid in all its trans positions) these receptors interact with the promoter region of genes regulated by retinoic acid at the level of specific response elements (RARE). Certain analogs can bind and activate a specific subtype of RAR receptor (alpha, beta or gamma). Other analogues, -finally, do not have specific selective activity towards these various receptors. In this regard, and, for example, when retinoic acid in all its trans positions activates the -RAR's (agonizing RAR specific ligand), all the subtypes are driven together, while the 13-cis retinoic acid does not bind to the receptors alpha or range. Some of these retinoids have already been combined with -derivatives of vitamin D. Thus, in the application of the patent AU-A-37161/93, 9-cis or 13-cis retinoic acid, is combined with vitamin derivatives D. In any case, these combinations prove to be relatively unsatisfactory, particularly in the treatment of psoriasis.

The need to find specific combinations which are remarkably effective, in particular in the treatment of psoriasis, may therefore be appreciated.

BRIEF DESCRIPTION OF THE INVENTION One of the purposes of the present invention is, in this way, to be able to make a new product available which shows considerable inhibition to cell-proliferation, in particular of skin cells, and more particularly of keratinocytes, allowing this product to be used in the treatment of disorders associated with cell hyperproliferation, in particular dermatological disorders associated with cellular hyperproliferation. Another purpose of the present invention is to be able to make an available medicinal product which reduces, or even completely removed, the side effects of the ligands, which have activity for nuclear VDR type receptors.

DETAILED DESCRIPTION OF THE INVENTION It was proposed that the combination, which is new per se, and in particular as a medicinal product, of at least one ligand which has activity for nuclear receptors of the VDR type and a specific retinoid which is selective for RAR-range receptors. In relation to RAR-alpha receptors, it makes it possible to inhibit the proliferation of keratinocytes in a completely remarkable manner. This result is completely the most unexpected and surprising, since these retinoids, when used alone, do not have, or substantially do not have, intrinsic antiproliferative activity towards these same cells. This discovery forms the basis of the present invention. Given the remarkable activity that this combination, according to the present invention, presents towards the keratinocytes, it naturally finds a preferential application in the treatment of dermatological disorders associated with the hyperproliferation of skin cells, and more particularly, -te of keratinocytes. Thus, in one of the first aspects, the purpose of the present invention is a combination product consisting of the combination of at least one ligand which has activity for nuclear receptors of the VDR type and at least one retinoid which is selective for RAR-range and relative receivers for RAR-alpha receptors. Generally and qualitatively, a given substance (or ligand) is said to be specific for a particular receptor, - when said substance shows an affinity for that particular receptor, which is stronger than that presented elsewhere for the others receivers. The dissociation constants are determined by tests which are standard for those experts in the field. These tests are described in particular in the following references: (1) "Selective Synthetic Ligands for Nuclear Retinoic Acid Receptor Subtypes" in RETINOIDS, Pro- -gress in Research and Clinical Applications, Chapter 19 (pp 261-267), Marcel Dekker Inc ., published by Maria A. Livrea and Lester Packer; (2) "Synthetic Retinoids: Receptor Selec-tivity and Biological Activity" in Pharmacol. Skin, Basle, Karger, 1993, Volume 5, pp. 117-127; (3) "Selective Synthetic Ligands for Human Nuclear Retinoic Acid Receptors" in Skin Pharmacology, 1992, Volume 5, pp. 57-65; (4) "Iden-tification of Synthetic Retinoids with Selectivity for Human Nuclear Retinoic Acid Receptor-gamma" in Biochemical and Biophyse sical Research Communications, Volume 186, No. 2, July 1992, p. 977-983; (5) "Selective High Affinity RAR-alpha or RAR-beta Retinoic Acid Receptor Ligands" in Mol. Pharmacol., Volume 40, pp. 556-562. Advantageously, the retinoids which are selectable for the RAR-gamma receptors and relative for the RAR-alpha receptors, have an index of the dissociation constant RAR-alpha / RAR-gamma, greater than or equal to 8. Among the retinoids which are selective for the RAR-gamma receptors and relative for the RAR-alpha receptors, particular mention may be made of 6- (3- (l-adamantyl) -4-hydroxyphenyl) -2-acid Naphthoic (RAR-alpha / RAR-gamma = 8.5), 6- (3- (l-adamantyl) -4-methoxyphenyl) -2-naphthoic acid (RAR-alpha / RAR-gamma = 84.4) and 2-hydroxy acid 4- (3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -l-propynyl) benzoic acid (RAR-alpha / RAR-gamma) = 36.6) or derivatives thereof. In general, the weight ratio between at least one ligand which has activity for nuclear receptors of the VDR type and at least one retinoid which is selective for the RAR-gamma receptors and relative for the RAR-alpha receptors, is around 1/1000 and 1000/1. Preferably, this weight ratio is about 1/10 and 10/1. The subject of the present invention is also a novel composition, in particular a pharmaceutical composition, characterized in that it comprises, in a physiologically acceptable support, a combination product as defined above. The ligands which have activity for the VDR receptor, they are used for the treatment of osteoporosis, and - with this the use of this combination product according to the invention can be conceived for the treatment of osteoporosis. In any case, this combination product proves to be very advantageous for a treatment designed to inhibit cell proliferation, in particular the proliferation of skin cells, and more specifically of keratinocytes, in particular for the treatment of psoriasis. The reason for the invention is thus, the use of at least one retinoid which is selective for RAR-gamma receptors and relative for RAR-alpha receptors, for the preparation of a pharmaceutical composition designed to increase the inhibitory activity on proliferation. cell, in particular - on skin cells, more specifically on keratinocytes, due to at least one ligand which has activity for the VDR receptor used, for the treatment of disorders associated with cell hyperproliferation, in particular Dermatological disorders associated with hyperproliferation of skin cells. Thus, under the context of use according to the present invention, the retinoid can be administered, either simultaneously or differently, via the same or different routes for the administration of the ligand which has activity for the VDR receptor. The present invention, in this manner, is also related to a product which consists of at least one binding which has activity for nuclear receptors of the VDR type and at least one retinoid which is selective for RAR-range receptors. and relative for RAR-alpha receptors, as a combination product for simultaneous or separate use or prolonged use over time, for the treatment of disorders associated with cellular hyperproliferation, in particular, dermatological disorders associated with hyperproliferation of skin cells, more specifically of keratin cytos. In the case where the retinoid is administered simultaneously, and thus via an identical route, with the administration of the ligand having activity for the VDR receptor, the purpose of the invention is finally, the use of the aforementioned combi-nation product for the preparation of a pharmaceutical composition, more particularly a dermatological composition, designed for the treatment of disorders associated with cellular hyperproliferation, in particular dermatological disorders associated with the hyperproliferation of skin cells, and more specifically of keratinocytes. This composition is particularly designed for the treatment of psoriasis. The term "skin cells" is understood to refer to keratinocytes, melanocytes, fibroblasts, Merkel cells and Langerhans cells. It will be noted in general that the active doses will be used in order to obtain the desired effect that may be the lowest, which is an appreciable advantage when there is a behavior with problems of undesirable secondary effects, responsible for originating in the organisms to be treated or in the course of treatment, effects such as hypercalcemia or hypercalciuria. Other characteristics, aspects, objectives and advantages of the invention will become more clearly apparent by reading the description and figures that follow, as well as various specific examples projected to illustrate it, but not in a restrictive way.

DESCRIPTION OF THE FIGURES Figure 1: Effect of the combination of 1,25-dihydroxyvitamin D3 and compound 1 (= 6- (3- (1-adamantyl) -4-hydro-xyphenyl) -2-naphthoic acid) on the inhibition in the proliferation of keratinocytes. The results are expressed as a percentage relative to the control in the proliferation of keratinocytes (DMSO) as a function of the concentration expressed in -nM of 1,25-dihydroxyvitamin D3 in the absence (°) or in the oresence (* ) of compound 1 at a concentration of 100 -nM Figure 2: Effect of the combination of 1,25-dihydroxyvitamin D3 and compound 1, on the inhibition in the proliferation of keratinocytes. The results are expressed as a percentage relative to the control in keratinocyte proliferation (DMSO) as a function of the concentration expressed in nM of compound 1 in the presence of 1 nM of 1,25-dihydroxyvitamin D3 (°). In this figure, the value of compound 1 only at 100 nM (*) is also given. The 6- (3- (l-Adamantyl) -4-methoxyphenyl) -2-naphthoic acid and the 6- (3- (Adamantyl) -4-hydroxyphenyl) -2-naphthoic acid, have already been described in the Patent US 4,717,720. 2-Hydroxy-4- (3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -l-propynyl) -benzoic acid is described in the patent application EP 661, 258. Its derivatives may correspond to its esters, its amines, its salts, its alcohols or its aldehydes, among the ligands that have activity for the receptor.

VDR, mention may be made of the following compounds: - vitamin D3 (cholecalciferol), - vitamin D2 (ergocalciferol), - calcipotriol (or calcipotriene), sold in particular by the Leo company under the registered name Daivonex. - 25-hydroxyvitamin D3, - lalfa-hydroxyvitamin D3, lalfa, 25-dihydroxyvitamin D3 (calcitriol), lalfa, 25,26-trihydroxyvitamin D3, - lalfa, 23, 25-trihydroxyvitamin D3, 24, 25-dihydroxyvitamin D3, lalfa, 25-dihydroxyvitamin D2, lalfa-hydroxyvitamin D2, lalfa, 24-dihydroxyvitamin D2, lalfa, 24-dihydroxyvitamin D3 (tacalcitol), - (5Z, 7E, 23S) -26,26,26,27,27,27-hexafluoro -9,10-secocholesterol- 5, 7, 10 (19) -trieno-lalfa-3beta, 23, 25-tetraol, -26,26,26,27,27,27-hexafluoro-9,10-secocholesterol-5 , 7,10 (19) -tri- ene-lalfa, 25-diol (26,26, 26, 27,27, 27-hexafluoro-lalfa, 25-dihydro-vitamin D3), or - the vitamin derivatives D described in the application of the patent WO 96/22776. It is preferred to use lalfa, 25-dihydroxyvitamin D3.

In the following text, the term topical route is meant to refer to any technique of administration of a product by direct application thereof to a superficial (or external) part of the body, such as the skin or mucous membranes, and the term "systemic route" is understood to refer to any technique of administering a product via another route other than topical, for example, oral, interal and / or parenteral. The reason for the present invention is, in this way, inter alia, a new pharmaceutical composition projected in particular for treating the skin, characterized in that it comprises, in a physiologically acceptable form which is compatible with the of administration selected for this composition, at least one ligand which has activity for the VDR receptor and at least one retinoid which is reactive for RAR-gamma receptors and relative for -RAR-alpha receptors, as active principles. The administration of the active agents (retinoid or-ligand having activity for the VDR receptor) or of the combination according to the invention, can be conducted outside the enteral, parenteral, topical or ocular route. In any case, the compositions (or combinations) according to the invention are preferably encompassed in such a way that they are suitable for topical application. Via the enteral route, the compositions may be in the form of tablets, gelatin capsules, coated tablets, syrups, suspensions., solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymeric vesicles that allow controlled release. Via the parental route, the compositions may be in the form of solutions or suspensions for infusion or for injection. The mixtures of active agents according to the invention are generally administered in daily doses of approximately 0.01 mg / kg to 100 mg / kg of body weight, taken at a rate of 1 to 3 times / day. Via topical route, the pharmaceutical compositions, which are therefore particularly designed to treat the skin, may be in the form of ointments, creams, milks, ointments, powders, impregnated pads, solutions, gels, s- -prays, lotions or suspensions. These may also be in the form of microspheres or nanospheres or lipid vesicles or polymeric vesicles or polyeric patches and hydrogels that allow the controlled release of the active agents. These topical route compositions can also be in either of the two forms: anhydrous or in an aqueous form, depending on the clinical application. The compositions for topical use, according to the invention, contain the ligand or VDR ligands at a concentration generally of about 0.001% and 10% by weight, preferably between 0.1 and 1% by weight, relative to the total weight of the composition . Similarly, compositions for topical use according to the invention contain the retinoid or retinoids at a concentration generally of about 0.001% and 10% by weight, preferably between 0.1 and 1% by weight, relative to the total weight of the composition . Via the eye route, the compositions are mainly eye drops.

The compositions according to the invention can, of course, also contain inert or pharmacodynamically uniform active additives, or combinations of > -the additives, and -in particular: humidified agents; depigmented agents such as hydroquinone, azelaic acid, caffeic acid or cushionic acid; emollients; moisturizing agents such as glycerol, PEG 400, thiamorpholinone and derivatives thereof or u-rea; antiseborrhoeic or anti-acne agents such as S-carbo-xymethylcysteine, S-benzylcysteamine, its salts or derivatives thereof, or benzoyl peroxide; antifungal agents such as that toconazole or poly (4,5-methylene-3-isothiazolidone); antibacterial agents, and carotenoids, in particular, beta-carotene; antipsoriatic agents such as anthralin and derivatives thereof; and, finally, eicosa-5, 8, 11, 14-tetranoic acid and eicosa-5,8, 11-trinoic acid, and esters and amides thereof. The compositions according to the invention may also contain flavor enhancers, preservatives such as para-hydroxybenzoic acid esters, stabilizers, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifying agents, agents -of protection against UV-A and UV-B, and antioxidants such as alpha-tocopherol, butylhydroxyanisole or butylhydroxytoluene. The dermatological disorders associated with the hyperproliferation of skin cells are, in particular, the following: 1) Dermatological diseases linked to a keratinization disorder which has a relationship on cell proliferation, in particular common acne, comedones, leukocytes - Dolimorfonucleares, nodulocystic acne, acne conglobado, acne is nil and acne secondary such as solar, acne related to medication or acne related to the profession. 2) Other types of keratinisation disorders, in particular, ichthyosis, ichthyosiformis states, Darier's disease, palmar-plantar halterderma, leukoplakia and leukoplasiform states, and cutaneous lichen or mucous (buccal). 3) Other dermatological diseases associated with a keratinization disorder with an inflammatory and / or immune-allergic component and, in particular, all forms of psoriasis, whether it is cutaneous, mucosal or ungular psoriasis, and constant psoriatic rheumatism, or alternatively atopy cutaneous such as the - eczema or respiratory atopy, alternatively gingival hypertrophy. 4) All dermal or epidermal proliferations, whether benign or malignant, whether of virial or other origin, such as common warts, flat warts and epidermodisplasia -verruciform, oral or florid papillomatous, proliferations induced by ultraviolet radiation, in particular, in the case of basal cell and spinoceular epithelioma. 5) For the treatment of other dermatological disorders such as bulosis and collagen diseases. 6) Aging of the skin, be it aging by induced or chronological light, or by actinic keratoses and pigmentations, or any pathology associated with aging-chronological or actinic. 7) Stigmas of epidermal and / or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy. 8) Scarring disorders 9) Sebaceous functioning disorders such as acneic hyperseborrhea or simple seborrhoea. 10) Cancerous or precancerous states of the skin. 11) Any disease of virial origin on the skin. 12) Dermatological diseases with an immunological component. The compositions according to the invention prove to be particularly effective for treatments 1) to 4), and more specifically to treat all forms of psoriasis. Various projected examples will now be given, by one, to demonstrate the effects associated with the present invention, and, on the other hand, to illustrate various specific formulations according to the invention, without any implied limitations.

EXAMPLES Example 1 The purpose of this example is to demonstrate the in vitro activity of the synergistic combination, according to the invention, on the proliferation of keratinocytes. The keratinocytes are obtained from a skin sample obtained from plastic surgery. Keratinocytes are used in a second step. The experimental procedure and the methods to determine the proliferation are the following: Culture of keratinocytes The cells are cultured at 37 ° C in a humid atmosphere in the presence of 5% CO according to the method of -Rheinwald and Green, in the presence of treated 3T3 fibroblasts -with fetal calf serum (FCS) in a medium of mitomycin containing 10% (v / v), 0.4 μg / ml of hydrocortisone, 10 ng / ml _9 of EGF (epidermal growth factor) and 10 M of cyclo-leratoxin. The 3T3 cells are inoculated 24 hrs. before the 2 keratinocytes at a rate of 15,000 cells per cm. Subsequently, the keratinocytes are inoculated at a rate of 4000 cells 2 per cm.

Treatment of cells The cells are treated 2 hrs. after inoculation of keratinocytes, with compound 1 or 1,25-dihydroxyvitamin D3 diluted in DMSO. The final concentration of DMSO in the culture medium should not exceed 0.2% (v / v). After a culture for 4 days, the cells are harvested in order to determine proliferation.

Measurement of proliferation Cell proliferation is determined using a kit-with the reference name "cell proliferation kit II" (XTT assay) used in accordance with the manufacturer's instructions (Boehringer, ref 1465 05). Proliferation is expressed in absorbance units at 495 nm. The lowest value measured in the equipment indicates how much proliferation of keratinocytes has been inhibited. The results obtained are compared in Figures 1 and 2. These figures quantify the change in the level of -proliferation of keratinocytes as a function of the concentration of the active agents used. These figures clearly show that the combination of compound 1 with 1,25-dihydroxyvitamin D3 has very good inhibition on the proliferation of keratinocytes.

The same experiment was also performed outside with a combination of 9-cis, 13-cis acid and all trans retinoic positions with 1, 25-dihydroxyvitamin D3, under identical conditions. The non-synergism of inhibition on the proliferation of keratinocytes was observed.

Example 2 In this example, several specific formulations based on combinations according to the invention are illustrated.

(Compound 1 is the same as defined above in the description).

A - ORAL ROUTE (a) Composition for a soft 100 mg capsule Compound 1 1.00 mg lalfa, 25-Dihydroxyvitamin D3 1.00 mg - BHT 0.01 mg D, L-alpha-Tocopherol 0.05 mg Vegetable oil qs 100 mg (b) Drinkable suspension in 10 ml ampoules Compound 1 0.05 g lalfa, 25-Dihydroxyvitamin D3 0.05 g - Glycerol 1,000 g Sorbitol 70% 1,000 g - Sodium saccharinate 0.010 g Methyl para-hydroxybenzoate 0.080 g Taste qs - Purified water qs 10 mi B - TOPICAL ROUTE (a) Ointment Compound 1 0.1 g lalfa, 25-Dihydroxyvitamin D3 0.1 g Petrolato qs 100 (b) Ointment Compound 1 0.1 g lalfa, 25-Dihydroxyvitamin D3 0.1 g Isopropyl myristate 81.520 g - Liquid petrolatum 9.100 g Silica ("Aerosil 200" sold by Degussa) 9.180 g (c) Non-ionic water-in-oil cream Compound 1 0.100 g lalfa, 25-Dihydroxyvitamin D3 0.100 g Mixture of emulsifiers of lanolin alcohols, waxes and oils ("anhydrous eucerin" sold by BDF) 39,900 g Methyl para-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate 0.075 g Sterile demineralized water qs 100 g (d) Lotion Compound 1 0.100 g lalfa, 25-Dihydroxyvitamin D3 0.100 g Polyethylene glycol (PEG 400) 69,800 g 95% ethanol 30,000 g (e) Hydrophobic treatment Compound 1 0.300 g lalfa, 25-Dihydroxyvitamin D3 0.300 g Isopropyl myristate 36,400 g Silicone oil ("Rhodorsil 47 V 300" sold by Rhdne-Poulenc) 36,400 g Beeswax 13,600 g Silicone oil ("DC200" 350 cps sold by Dow Corning) qs 100 g (f) Non-ionic oil-in-water cream - Compound 1 0.500 g - lalfa, 25-Dihydroxyvitamin D3 0.500 g Cetil alcohol 4000 g Glyceryl monostearate 2,500 g PEG stearate 50 2,500 g - Shea Butter 9.200 g - Propylene Glycol 2,000 g - Methyl para-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate 0.075 g Sterile demineralised water qs 100 g

Claims (17)

1. Combination product characterized by the combination of at least one ligand which has activity for nuclear receptors of the VDR type, with at least one retinoid which is selective for RAR-gamma receptors in relation to RAR-alpha receptors.

2. Product according to claim 1, for use as a medicinal product.

3. Product according to claims 1 and 2, characterized in that the retinoid which is selective for RAR-gamma receptors in relation to RAR-alpha receptors, has an index of the dissociation constant RAR-alpha / RAR-ga ma that or equal to 8.

4. Product according to one of claims 1 to 3, characterized in that the retinoid is chosen from 6- (3- (l-adamantyl) -4-hydroxyphenyl) -2-naphthoic acid, from 6- (3-) acid (l-adamantyl) -4-methoxyphenyl) -2-naphthoic acid and 2-hydroxy-4- (3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl) -2-naphthyl) -1-pro-phenyl) benzoic acid or derivatives thereof.

5. Product according to one of claims 1 to 4, characterized in that the ligands which have activity for the VDR receptor, are chosen from: vitamin D3, vitamin D2, 25-hydroxyvitamin D3, lalfa-hydroxyvitamin D3, lalfa, 25-dihydroxyvitamin D3 (calcitriol), lalfa, 25,26-trihydroxyvitamin D3, lalfa, 23, 25-trihydroxyvitamin D3, 24, 25-dihydroxyvitamin D3, lalfa, 25-dihydroxyvitamin D2, lalfa-hydroxyvitamin D2, lalfa , 24-dihydroxyvitamin D2, lalfa, 24-dihydro-xivitamin D3 (tacalcitol), (5Z, 7E, 23S) -26, 26, 26, 27,27,27-hexa-fluoro-9,10-secocholesterol-5, 7, 10 (19) -trieno-lalfa-3beta, 23,25-tetraol and 26, 26, 26, 27, 27, 27-hexafluoro-9, 10-secocolesta-5, 7, 10 (19) -trieno- lalfa, 25-diol.

6. Product according to claim 5, characterized in that the ligand which has activity for the VDR receptor, is lalfa, 25-dihydroxyvitamin D3.

7. Product according to one of claims 1 to 6, characterized in that the weight ratio between at least one ligand which has activity for the nuclear VDR type receptors and at least one retinoid which is selective for RAR-range receptors err relation to RAR-alpha receivers, is around 1/1000 and 1000/1.

8. Product according to claim 7, characterized in that the weight ratio is about -1/10 and 10/1.

9. Pharmaceutical composition, characterized in that it comprises, in a pharmaceutically acceptable carrier, at least one liking which has activity for nuclear receptors of the DO VDR, and at least one retinoid which is selective for RAR-range receptors and relative for RAR receptors -alpha, as -defined in claims 1 to 9.

10. Composition according to claim 9, characterized in that it is a composition combined in such a way that it is suitable for enteral, parenteral, topical or ocular use.

11. Composition according to claims 9 and 10, characterized in that the ligand which has activity for nuclear receptors of the VDR type, is present at a concentration of about 0.001% and 10% by weight, preferably between 0.1 and 1% by weight, relative to the total weight of the composition.

12. Composition according to one of claims 9 to 11, characterized in that the retinoid is present at a concentration of about 0.001% and 10% by weight, preferably between 0.1 and 1% by weight. of the composition.

13. Use of at least one retinoid which is selective for RAR-gamma receptors in relation to RAR-alpha receptors according to claims 1 to 4, for the preparation of a pharmaceutical composition designed to increase the inhibitory activity on the cell proliferation, from at least one ligand which has activity for the VDR receptor, to the treatment of disorders associated with cell hyperproliferation.

14. Use of the combination product according to claims 1 to 8 for the preparation of a pharmaceutical composition designed to treat disorders associated with cellular hyper-proliferation.

15. Use according to claims 13 and 14, characterized in that the disorders associated with cellular hyperproliferation are dermatological disorders associated with hyperproliferation of skin cells, and more particularly of keratinocytes.

16. Use according to claim 15, characterized in that the dermatological disorders associated with the hyperproliferation of skin cells are derived from dermatological diseases associated with a keratinization disorder which has a relation on cell proliferation, particularly acne comedones. , polymorphonuclear leukocytes, acne rosacea, nodulocystic acne, acne conglobado, acne-senile, secondary acne such as sun, acne related to medication or the profession, other disorders of keratinization, in particular ichthyosis, ichthyosiform states, sick - Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplasiform states, cutaneous lichen or mucous (buccal), other dermatological diseases associated with a keratinization disorder with an inflammatory and / or immunoallergic component and, in particular, all forms of psoriasis , be it cutaneous, mucosal or ungular psoriasis, and constant psoriatic rheumatism, or alternatively cutaneous aopathy, such as atopy -eczema or respiratory or alternatively gingival hypertrophy, -all dermal or epidermal proliferations, whether benign or nalignant, and of virial or other origin, such as common warts , flat warts and epidermodisplasia verrucifor me, oral or florid papillomatous and proliferations which can be induced by ultraviolet radiation, particularly in the case of basal cell and squamous cell epithelioma.

17. Product characterized by at least one ligand which has a nuclear activity of VDR type receivers, and at least one retinoid which is selective for RAR-gamma receptors and relative for RAR-alpha receptors, as defined in claims 1 to 8, as a combination product for simultaneous or separate use or prolonged use over time, for the treatment of associated disorders - with cellular hyperproliferation, in particular dermatological disorders associated with hyperproliferation of skin cells, more particularly of keratinocytes.