FR2865652A1 - USE OF PLANT EXTRACTS AND PURIFIED MOLECULES FOR LIPOLYTICALLY SLIMMING, COSMETIC, NUTRACEUTICAL OR PHARMACEUTICAL COMPOSITIONS. - Google Patents

Abstract

The invention relates in particular to new stereospecific derivatives of the 2,3-benzodiazepine type as phosphodiesterase inhibitors, in particular 2 and 4 and their applications in the therapeutic field, in particular for the prevention and treatment of pathologies involving a central and / or peripheral disorder. . The compounds of the invention more particularly correspond to the general formulas (I) and (II):

Description

R1 R1 R7 R8 R7 R8 R1 R1 R7 R8 R7 R8

  (I) a and b (II) a and b USES OF PURIFIED PLANT AND MOLECULE EXTRACTS FOR LIPOLYTICALLY SLIMMING, COSMETIC, NUTRACEUTICAL OR PHARMACEUTICAL COMPOSITIONS.

  The present invention relates to the field of cosmetics, in particular the use of plant extracts in dermocosmetics, and relates to the use of certain selected plants for the preparation of nutraceutical or pharmaceutical cosmetic products.

  The present invention consists in the discovery of extracts of certain plants having biological and biochemical activities related to lipolytic, anti-cellulite and slimming properties.

  The main object of the present invention is therefore the use as an active agent, in particular having lipolytic and thus slimming and weight loss activities, for the preparation of cosmetic or dermopharmaceutical products, of at least one plant extract whose genus The botanical group belongs to the genera Aspidosperma, Catharanthus, Eschscholzia, Bocconia, Vismia, Orbignya, Terminalia, Entada, Hypericum, Papaver, Ginkgo, Viburnum and Butea. However, according to the preferred embodiment of the invention, resulting in extracts whose activities are optimized qualitatively and quantitatively with regard to the properties claimed, the active agent is constituted by at least one extract of a plant chosen from the group formed by Aspidosperma quebracho-blanco, Eschscholzia californica, Bocconia frutescens, Vismia Latifolia, Catharanthus lanceus, Orbignya speciosa, Terminalia macroptera, Entada Africana, Hypericum perforatum, Papaver rhoeas, Ginkgo biloba, Viburnum prunifolium and Butea frondesa.

  STATE OF THE ART: Various factors of our society (unbalanced diet, passive state ....) promote the development of fat mass. The location of this fat mass can be either deep when it is attached to the organs, or subcutaneously at the level of the hypodermis. In its plastic dimension, adipose tissue ensures the contour of the forms with a very specific anatomical location related to sex. In humans, adipose tissue is localized preferentially in the abdominal position. In women, it is predominant below the waist, at the hips, thighs and buttocks. One of the major concerns of our society is to fight against this excessive fat intake, both for aesthetic reasons and for health reasons (obesity, diabetes ...).

  The current understanding of the biochemical mechanisms involved in the metabolism of fats makes it possible to identify a certain number of biological targets that are particularly interesting for combating this weight gain and overaccumulation of subcutaneous adipose mass. This metabolism occurs at the level of the adipocytes.

  The adipocyte is a metabolically very active cell that occupies a central position in controlling the energy balance of the body. To ensure this fat metabolism, the adipocyte has a set of receptors and enzymes necessary for the storage and elimination of triacylglycerols.

  The synthesis of triaglycerols is positively regulated by insulin and is either by direct capture of fatty acids resulting from the hydrolysis of chylomicrons and VLDL by lipoprotein lipase, or by neosynthesis in the cell from glucose.

  The mobilization of triacylglycerols corresponds to the process of lipolysis. This is dependent on a limiting enzyme step represented by the hormone-sensitive lipase. This enzyme is potently activated by cAMP generated by adenylate cyclase and degraded by phosphodiesterases.

  Various membrane targets have also been identified, such as G protein-coupled receptors (GPCRs). These intervene indirectly on the level of intracellular cAMP. Other biological targets identified are the kinases and phosphatases involved in the activation and inhibition of certain targets, such as phosphodiesterases, hormone-sensitive lipase, etc. These targets are all described in the scientific literature for their involvement. in lipolysis (B. FEVE and J. PAIRAULT, Cosmetology, 1999, 21, 30-33).

  Since we seek to activate lipolysis to promote fat elimination, an obvious control pathway would be to increase the level of intracellular cAMP. Given the known and explored metabolic pathways, we are therefore looking for activators of adenylate cyclase, phosphodiesterase inhibitors, in particular subtypes 3 and 4, neuropeptide Y type 1 receptor antagonists, alpha-2 receptor antagonists. adrenergic and adenosine 1 and protein phosphatase 2A inhibitors (B. FEVE and J. PAIRAULT, Cosmetology, 1999, 21, 30-33).

  The invention therefore describes the combination of certain plant extracts selected for their biological action on one or more of these biological targets.

  In addition, the action of the extract or of the purified molecule derived from this extract can occur on different subtypes of biological targets and therefore have a dual biological interest for cosmetic, nutraceutical or dermopharmaceutical purpose. For example, the combined action on various subtypes of phosphodiesterases (I to VI) may actually present the slimming action but also have an anti-inflammatory action or fight against couperose. In this case, there is an extract of poppy total or enriched in alkaloids, in particular papaverine and rhoeadine which can advantageously modulate the level of cAMP or cGMP. It is the same for all the extracts cited and having action on phosphodiesterases. Other complementary properties, such as the action on increasing skin pigmentation, can also be claimed for these extracts and molecules increasing the level of cAMP and intracellular cGMP.

DESCRIPTION OF THE INVENTION

  The present invention relates to the field of cosmetics, in particular the use of plant extracts in dermocosmetics, and relates to the use of certain selected plants for the preparation of cosmetic, nutraceutical or dermopharmaceutical products.

  The main object of the present invention is therefore the use as an active agent, in particular having lipolytic and thus slimming and weight loss activities for the preparation of cosmetic or dermopharmaceutical products, of at least one extract of a plant whose Botanical genus belongs to the group formed by the genera Aspidosperma, Catharanthus, Eschscholzia, Bocconia, Vismia, Orbignya, Terminalia, Entada, Hypericum, Papaver, Ginkgo, Viburnum and Butea.

  In the abovementioned genera, the following particular species may advantageously be selected: Aspidosperma quebracho-blanco, Catharanthus lanceus, Eschscholzia californica, Bocconia frutescens, arborea, Vismia Latifolia, Vismia guianensis, Orbignya speciosa, Orbignya phalerata, Terminalia macroptera, Terminalia catappa, Terminalia chebula , Entada Africana, Entada phaseoloides, Hypericum perforatum, Hypericum sampsonii, Papaver rhoeas, Papaver somniferum, Ginkgo biloba, Viburnum prunifolium, Butea frondesa, Butea monosperma.

  However, according to the preferred embodiment of the invention, resulting in extracts whose activities are optimized qualitatively and quantitatively with regard to the slimming activity, the active agent is constituted by at least one extract of a plant. selected from the group consisting of Aspidosperma quebracho-blanco, Eschscholzia californica, Bocconia frutescens, Catharanthus lanceus, Vismia Latifolia, Orbignya speciosa, Terminalia macroptera, Entada Africana, Hypericum perforatum, Papaver rhoeas, Ginkgo biloba, Viburnum prunifolium and Butea frondesa.

  The parts of the plants used for the preparation and obtaining of the abovementioned extracts are chosen from roots, bark (roots, stems and / or trunk of plants), leaves and leafy stems, fruits, seeds and / or flowers.

  After collection, the plant parts concerned are, directly or after drying, subjected to an extraction process, the solvent used can advantageously be chosen from the group formed by water, alcohols, ketones, esters, ethers, chlorinated solvents, polyols or mixtures of at least two aforementioned miscible solvents. According to each plant or plant organ, a particular extract may be made to optimize the extraction yield of molecules or families of desired molecules.

  Subsequently, the term extracted must be understood as an extract of plant cells belonging to the aforementioned group and more specifically as an extract of cells of at least one plant of the aforementioned group. Said material can be obtained by in vitro culture or in vivo. By in vitro culture is meant all of the techniques known to those skilled in the art that artificially allow the production of a plant or part of a plant. In vivo culture means all the cultivation techniques that make it possible to obtain a plant or a part of a plant. Thus, the extract may be an organ extract (root, stem, leaf, bark), or even organ cells, of at least one plant of the abovementioned group, or an undifferentiated cell extract of at least one such a plant.

  By way of nonlimiting illustration, various processes that can be used for carrying out the plant extracts mentioned hereinafter will be described below.

  We will only present below the liquid extraction approach. For example, extractions with supercritical CO2 can be carried out alone or in combination with a co-solvent or by using an extraction method based on wave radiation, such as microwaves or ultrasounds.

  The parts of plants used in the examples below are given for information only, the extracts object of the present invention can be made from all accessible parts of the plants indicated above.

  EXAMPLE 1 Total Extract Any extraction or purification method known to those skilled in the art can be used according to the invention. In a first step, the fresh, frozen or dry plant material is crushed in a cold aqueous solution, in a second step, the aqueous solution is filtered and finally sterilized. This aqueous solution corresponds to the extract. This extract can then be dried (evaporation, lyophilization). In a variant of this process, a methanolic, ethanolic or aqueous-alcoholic solution is used in the first step. The extract thus obtained can be evaporated to dryness, the residue being used as it is or after purification. Each extract can then be fractionated so as to enrich the desired active ingredient.

  Example 2: Application to the aforementioned plants This example presents some experimental results of extraction on various selected plants. The method applied is as follows: 100 g of dried organ of each plant were finely ground, then placed in a reactor equipped with a stirrer with 1 liter of solvent (water, ethanol or ethanol / water 50/50 v / v) - maceration, extraction for one hour at 50 ° C filtration - evaporation of the solvent - weighing and calculation of yield. The average yield is of the order of 15% aqueous Aspidosperma quebrachoecorces South America ethanol 50% 22 ethanol 20 aqueous ethanol 12 Eschscholzia leaves North America ethanol 50% 17 californica ethanol 17 aqueous 9 Vismia Latifolia leaves South America ethanol 50% 11 ethanol 10 aqueous 11 Orbignya fruit speciosa South America ethanol 50% 16 ethanol 13 aqueous 14 Terminalia macroptera barks Africa ethanol 50% 16 ethanol 14 aqueous 13 Entada Africana barks Africa ethanol 50% 15 ethanol 15 watery 19 Hypericum perforatum plants Europe ethanol 50% 22 ethanol 20 aqueous 10 Papaver rhoeas stems / leaves Europe ethanol 50% 14 ethanol 14 aqueous 17 Papaver rhoeas seed / shells Europe ethanol 50% 20 ethanol 24 aqueous 15 Butea frondesa seeds Asia ethanol 50% 18 ethanol 16 The invention therefore relates to the use of at least one plant extract of the abovementioned group as a lipolytic, anti-cellulite and slimming agent in dermoc compositions osmetic and pharmaceutical. The purpose of this agent is to reduce the body fat mass by acting on one or more of the aforementioned biological targets.

  The following examples illustrate the invention without, however, limiting its scope. These examples present the results of biological activities on the selected biological targets, extracts cited above in Examples 1 and 2.

  Example 3 Phosphodiesterase (PDE) and Adenylate Cyclase (AC) Activity The biological tests on these enzymes were carried out according to the bibliography, by HPLC monitoring of appearance or disappearance of the amount of cAMP. The extracts tested are total ethanolic extracts. The PDE3 activity is measured in terms of IC50, concentration of extract necessary to block 50% of the enzyme activity. PDE4 activity is measured in terms of percent inhibition for a given concentration of extract. Finally, the AC activity is measured as a percentage of activation relative to the normal activity of the enzyme.

  Plant Name Family Organ PDE3 (IC50 PDE4 (% inhibition AC (% activation in g / ml) at 50 gg / ml) 500 g / ml) Vismia Latifolia Clusiaceae Leaves 29 75 + 74% Orbignya speciosa Arecaceae Fruit 17 77 + 79% Terminalia macroptera Combretaceae Bark 3.2 98 + 77% Papaver rhoeas Papaveraceae seeds 40 100 Entada africana Mimosaceae Barks 13 95 + 45% Total ethanolic extracts show inhibitory activities on PDE3 phosphodiesterases involved in lipolysis and PDE4 (anti-inflammatory properties and mimicking the alpha-2-adrenergic antagonist effect) as well as stimulation of adenylate cyclase (AC), which is all the more interesting since these results act synergistically to increase the level of intracellular cAMP.

  Thus, all these extracts having an action on phosphodiesterases; extracts more or less purified and enriched in the active principles mentioned in this application, can be interesting also in other pathologies such as inflammation, vascularization, psoriasis, arthritis, viral diseases like herpes and all other diseases skin disorders involving a disruption of cGMP or cAMP.

  Example 4 Activity on GPCR and Phosphatase Four total ethanolic extracts described in Example 1 were tested on different biological targets according to methods described in the literature: 3 G-protein coupled receptors; the Y1 receptor of neuropeptide Y (NPY1R), the adenosine A1 receptor (A1R) and the alpha-2-adrenergic receptor (α 2 -adr R). The last target is a phosphatase which biochemically disables protein kinase B, itself involved in the activation of PDE3. All of these targets are involved in the indirect regulation of intracellular cAMP levels.

  Plants NPY1 R Al R a2-adr R PP 2A antagonist antagonist antagonist Inhibitor Hypericum perforatum IC50 = 45 g / ml Eschscholzia californica IC50 = 150 g / ml Aspidosperma quebracho-blanco - IC50 = 75 gg / ml Butea frondesa - IC50 = 500 g / These results indicate that such total extracts are capable of modulating the activity of these membrane receptors and enzymes involved in lipolysis, by controlling intracellular cAMP levels. The antagonist and inhibitory effects of the extracts lead to an increase in intracellular cAMP level; which promotes the lipolytic route. The expected effects are therefore thinning, weight loss, disappearance of cellulite ....

  The combination of such extracts of Examples 3 and 4 makes it possible to act at different levels (different biological targets) but with a common goal, the increase of the level of intracellular cAMP; modulation promoting lipolysis.

  EXAMPLE 5 Extraction, Purification and Bio-Guidance

  Among the plants on the list, various extracts (total, enriched in phytochemical families chosen according to the case or purified molecules) have demonstrated significant biological activities. This is the case of Papaver rhoeas and papaverine or rhoeadine, amentoflavone and Ginkgo biloba, hypericin and hypericum, chelerythrine and Eschscholzia, yohimbine and Catharanthus or Butea frondosa and palasonin. Indeed, the bioguidance method allowed us to identify these molecules as being responsible for the lipolytic activity observed on isolated adipocytes. Moreover, amentoflavone and papaverine have also demonstrated implications for pigmentation and the reduction of vascularization (couperose), two other complementary cosmetic applications that intervene thanks to the action of inhibition of phosphodiesterases modulating positively cGMP levels and / or cAMP.

  Thin layer chromatography and HPLC analysis of a poppy seed extract revealed the presence of 1% papaverine (TLC: RF [DCM / MeOH99 / 1] = 0.375), which is original for compared to data from the scientific literature.

  The invention may be used as such in liquid or powder form after spray-drying, evaporation or lyophilization, or encapsulated in liposomes or other vectors and supports for a better homogeneity of the cosmetic preparation and a better diffusion of the active product on the surface. skin. These extracts are particularly interesting for the problems of overweight and cellulite.

  For the cosmetic use, the extracts according to the present invention can be formulated in galenic form: creams, gels, lotions, milks, biphasic emulsions oil in water or water in oils, triphasic emulsions, hydrogels, solutions, ointments, sprays, body oils, hair lotions, shampoos, aftershave lotions, soaps, lip sticks, makeup sticks and pencils at levels of 0.01 and 5% by weight, preferably between 0.1 and 2.5% in the form of powder and at contents of between 0.01 and 25%, preferably between 0.5 and 10% in encapsulated form.

  For the preparation of these compositions, the extracts are mixed with the excipients generally employed in the cosmetic and dermopharmaceutical art.

  The form of the cosmetic composition of the present invention could be a cream in which the extracts are associated with excipients commonly used in cosmetology.

  The cosmetic compositions may also be presented in gel form in suitable excipients such as cellulose esters or other gelling agents, such as carbopol, guar gum, etc.

  The cosmetic compositions according to the invention may also take the form of a lotion or solution in which the extracts are in encapsulated form.

  The microspheres according to the invention may for example consist of fatty substance, agar and water.

  The extracts can be incorporated into liposomes, glycosphers, chylomicrons, macro-, micro-, nano-particles as well as macro-, micro- and nanocapsules vectors and also be adsorbed onto powdery organic polymers, talcs , bentonites and other mineral supports.

  These emulsions have good stability and can be stored for the time necessary for use at temperatures between 0 and 50 C without sedimentation of the constituents or phase separation.

  The cosmetic compositions of the invention may also contain additives or adjuvants customary in cosmetology, such as, for example, antibacterial agents or perfumes, but also extraction and / or synthetic lipids, gelling and viscosity polymers, surfactants and emulsifiers, hydro or liposoluble active ingredients, plant extracts, tissue extracts, marine extracts, synthetic actives.

  The cosmetic or dermopharmaceutical use of extracts includes all body and skin care products including sun, protective and tanning products, anti-aging, anti-seborrhoeic, tonic products, products ensuring the improvement of the skin. appearance of the skin including acne treatment and skin redness.

  The cosmetic compositions of the present invention may also comprise other complementary active ingredients chosen for their action, for example for sun protection, the anti-wrinkle effect, the antiradical and antioxidant activity, the anti-irritant activity, the cellular nutrition, cellular respiration, hydration and cellular regeneration, anti-seborrhoeic treatments, as well as other active ingredients having an effect on skin tone.

  When the cosmetic compositions of the present invention contain complementary active ingredients, these are generally present in the composition at a sufficiently high concentration so that they can exert their activity.

  The cosmetic compositions of the present invention are preferably used daily by applying them one or more times daily.

  The cosmetic compositions of the present invention are very well tolerated, they exhibit no phototoxicity and their application to the skin for prolonged periods of time does not imply any systemic effect.

  For dermopharmaceutical use, the extracts from the abovementioned group according to the present invention may be formulated in the form of a paste, emulsion or spray form in a quantity of between 0.01 and 25% by weight.

  For the preparations of these compositions, the extracts from the aforementioned group are mixed with excipients.

  For pharmaceutical use, the extracts of the aforementioned group according to the present invention can be used for the manufacture of medicaments or creams for the treatment of obesity and overweight.

  The dermopharmaceutical compositions using the present invention may contain complementary active ingredients, present in a sufficiently large amount in the preparation so that they can exercise their activity.

Claims (11)

CLAIMS:   1. Use as an active agent, having lipolytic, slimming, anti-cellulite and slimming activities, for the preparation of a cosmetic, nutraceutical or pharmaceutical product, of at least one extract of a plant whose botanical genus belongs to the group consisting of Aspidosperma, Catharanthus, Eschscholzia, Bocconia, Vismia, Orbignya, Terminalia, Entada, Hypericum, Ginkgo, Viburnum, Papaver and Butea.   2. Use as an active agent, having lipolytic, slimming, anti-cellulite and slimming activities, for the preparation of a cosmetic, nutraceutical or pharmaceutical product, of at least one molecule totally or partially purified from plants derived from claim 1 selected from the list papaverine, rhoeadine, palasonine, amentoflavone, yohimbine, chelerythrine, hypericin.   3. Use according to claims 1 and 2, characterized in that the active agent consists of at least one extract of a plant selected from the group formed by Aspidosperma quebracho-blanco, Eschscholzia californica, Bocconia frutescens, Vismia Latifolia, Orbignya speciosa, Terminalia macroptera, Entada Africana, Hypericum perforatum, Ginkgo biloba, Viburnum prunifolium, Papaver rhoeas and Butea frondesa.   4. Use according to any one of claims 1 to 3, characterized in that the parts of the plants used for the preparations of the extracts are roots, barks, leaves and leafy stems, fruits, seeds and / or flowers.   5. Use according to any one of claims 1 to 4, characterized in that the solvent used for carrying out the extractions is selected from the group consisting of water, alcohols, ketones, esters, ethers , polyols, chlorinated solvents and mixtures of at least two of the aforementioned solvents.   6. Use according to any one of claims 1 to 5, characterized in that the solvent used for carrying out the extractions is supercritical CO2, alone or in mixture with a cosolvent.   7. Use according to any one of claims 1 to 6, characterized in that the extract or extracts are obtained by means of an extraction method based on the wave radiation, such as microwaves, or ultrasound.   8. Cosmetic, nutraceutical or dermopharmaceutical composition according to any one of claims 1 to 7, characterized in that it contains, as active agent, alone or in combination with other active agents, between 0.01% and 25% by weight, preferably between 0.5% and 10% by weight.   9. Cosmetic, nutraceutical or dermopharmaceutical composition according to any one of claims 1 to 8, characterized in that the active agent or the mixture of active agents is used in a galenical form for use in cosmetics, especially in a dosage form selected from the group consisting of two-phase oil-in-water emulsions, water-in-oils, triphasic emulsions, lotions, milks, gels, hydrogels, creams, ointments, soaps, sticks and sprays.   10. Cosmetic, nutraceutical or dermopharmaceutical composition according to any one of claims 1 to 9, characterized in that the extract or the mixture of extracts is incorporated in dry form obtained by evaporation, atomization or lyophilization, in liquid form or under form encapsulated in glycospheres or vectors selected from the group consisting of liposomes, chylomicrons, macro-, micro- and nanoparticles, macro-, micro- and nanocapsules, or adsorbed onto powdery organic polymers, talcs, bentonites and other mineral supports.   11. Use according to any one of claims 1 to 10 characterized in that said cosmetic composition, nutraceutical or dermopharmaceutical is combined with one or more additives selected from the group consisting of lipids extraction and / or synthesis, gelling polymers and viscosants, surfactants and emulsifiers, hydrosoluble active ingredients, plant extracts, tissue extracts, marine extracts, active ingredients of synthetic origin.