Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1997-07-11
2004-07-06
Pak, Michael (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S569000, C514S828000
Reexamination Certificate
active
06759396
ABSTRACT:
The invention relates to a novel composition, in particular a pharmaceutical composition, comprising a synergistic combination of at least one ligand having activity for nuclear receptors of VDR type and at least one specific retinoid, as well as to the use of this composition in the pharmaceutical or cosmetic field.
It is known that a ligand having activity for nuclear receptors of VDR (vitamin D3 receptor) type, such as 1&agr;,25-dihydroxyvitamin D3 or analogues thereof, inhibits the proliferation of keratinocytes. Thus, this type of compound is used to treat psoriasis. However, these compounds, such as 1&agr;,25-dihydroxyvitamin D3, have side-effects: hypercalcaemia 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, depending on the nature of the cells treated) of the differentiation and/or proliferation of many normal or transformed cell types. For example, it inhibits the differentiation of epithelial cells, such as epidermal keratinocytes, without being especially active on the proliferation of these cells. It also inhibits the proliferation of many transformed cells, such as melanoma cells.
It is known, in general, that all-trans retinoic acid acts on the differentiation and/or proliferation of cells by interacting with nuclear receptors or RARs (retinoic acid receptors) contained in the cell nucleus. Many synthetic structural analogues of all-trans retinoic acid or of 9-cis-retinoic acid, commonly known as “retinoids”, have been described to date in the literature. There exists, at the present time, three identified subtypes of RAR receptors referred to respectively as RAR-&agr;, RAR-&bgr; and RAR-&ggr;. After binding of the ligand (i.e. of the all-trans retinoic acid), these receptors interact with the promoter region of genes regulated by retinoic acid at the level of specific response elements (RARE).
Certain analogues may bind and activate a specific subtype of RAR (&agr;, &bgr; or &ggr;) receptor. Other analogues, lastly, have no specific selective activity towards these various receptors. In this respect, and, for example, all-trans retinoic acid activates RARs (specific RAR agonist ligand), all subtypes being taken together, whereas 13-cis retinoic acid does not bind to the &agr; or &ggr; receptors.
Some of these retinoids have already been combined with vitamin D derivatives. Thus, in patent application AU-A-37161/93, 9-cis- or 13-cis-retinoic acid is combined with vitamin D derivatives. However; these combinations prove to be relatively unsatisfactory, in particular in the treatment of psoriasis. The need to find specific combinations which are of noteworthy efficacy, in particular in the treatment of psoriasis, may thus be appreciated.
One of the aims of the present invention is thus to be able to make available a novel product which exhibits appreciable inhibition of 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 cell hyperproliferation.
Another aim of the present invention is to be able to make available a medicinal product which reduces, or even does away altogether with, the side-effects of ligands having activity for nuclear receptors of VDR type.
The Applicant has just discovered that the combination, which is novel per se, and in particular as a medicinal product, of at least one ligand having activity for nuclear receptors of VDR type and a specific retinoid which is selective for RAR&ggr; receptors relative to RAR&agr; receptors, makes it possible to inhibit the proliferation of keratinocytes in an entirely noteworthy manner. This result is all the more unexpected and surprising since these retinoids, when they are used alone, have no, or substantially no, intrinsic antiproliferative activity towards these same cells.
This discovery forms the basis of the present invention.
Given the noteworthy activities which this combination in accordance with the invention exhibits towards keratinocytes, it naturally finds a preferred application in the treatment of dermatological disorders associated with hyperproliferation of skin cells, and more particularly of keratinocytes.
Thus, in one of its first aspects, the subject of the present invention is a combination product consisting of the combination of at least one ligand having activity for nuclear receptors of VDR type and at least one retinoid which is selective for RAR&ggr; receptors relative to RAR&agr; receptors.
In a general and qualitative manner, a given substance (or ligand) is said to be specific for a particular receptor when the said substance exhibits an affinity for the said particular receptor which is stronger than that which it exhibits elsewhere for the other receptors.
The dissociation constants are determined by means of tests which are standard to those skilled in the art. These tests are described in particular in the following references: (1) “Selective Synthetic Ligands for Nuclear Retinoic Acid Receptor Subtypes” in RETINOIDS, Progress 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 Selectivity 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, Vol. 5, pp. 57-65; (4) “Identification of Synthetic Retinoids with Selectivity for Human Nuclear Retinoic Acid Receptor-&ggr;” in Biochemical and Biophysical Research Communications, Vol. 186, No. 2, July 1992, pp. 977-983; (5) “Selective High Affinity RAR-&agr; or RAR-&bgr; Retinoic Acid Receptor Ligands” in Mol. Pharmacol., Vol. 40, pp. 556-562.
In an advantageous manner, the retinoids which are selective for the RAR&ggr; receptors relative to the RAR&agr; receptors have an RAR&agr;/RAR&ggr; dissociation constant ratio greater than or equal to 8.
Among the retinoids which are selective for the RAR&ggr; receptors relative to the RAR&agr; receptors, mention may be made in particular of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid (RAR&agr;/RAR&ggr;=8.5), 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (RAR&agr;/RAR&ggr;=84.4) and 2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid (RAR&agr;/RAR&ggr;=36.6) or derivatives thereof.
In general, the weight ratio between at least one ligand having activity for nuclear receptors of VDR type and at least one retinoid which is selective for RAR&ggr; receptors relative to RAR&agr; receptors is between 1/1000 and 1000/1. Preferably, this weight ratio is between 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 having activity for the VDR receptor are used for the treatment of osteoporosis, and it may thus be envisaged to use this combination product according to the invention for the treatment of osteoporosis.
However, this combination product proves to be very advantageous for a treatment intended to inhibit cell proliferation, in particular the proliferation of skin cells, and more particularly of keratinocytes, in particular for the treatment of psoriasis.
The subject of the invention is thus the use of at least one retinoid which is selective for RAR&ggr; receptors relative to RAR&agr; receptors, for the manufacture of a pharmaceutical composition intended to increase the inhibitory activity on cell proliferation, in particular on skin cells, more particularly on keratinocytes, due to at least one ligand having activity for the VDR receptor used, for the treatment of disorders associated with cell hyperproliferat
Dionisius-Pouget Veronique
Michel Serge
Burns Doane Swecker & Mathis L.L.P.
Centre International de Recherches Dermatalogiques Galderma (C.I
Pak Michael
LandOfFree
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