EP1140040A1

EP1140040A1 - Spray-type cosmetic composition and matrix used in said composition for dermal administration

Info

Publication number: EP1140040A1
Application number: EP99973534A
Authority: EP
Inventors: Brigitte Illel; Henry Saunal
Original assignee: Sanofi Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1998-12-24
Filing date: 1999-12-08
Publication date: 2001-10-10
Also published as: AU4520500A; BR9916814A; HUP0200095A2; FR2787712B1; TR200101569T2; CN1331587A; IL143144A0; PL365376A1; NO20013117D0; JP2002533383A; WO2000038658A1; FR2787712A1; KR20010089699A; NO20013117L; CA2350685A1

Abstract

The invention concerns a novel composition for dermal administration of a substance or of an active principle. More precisely, the invention concerns a slimming composition for dermal administration, capable of forming a soft film after drying on the skin and a matrix capable of being used in said composition.

Description

PULVERISAB E COSMETIC COMPOSITION AND MATRIX FOR USE IN THIS COMPOSITION FOR DERMAL ADMINISTRATION. The present invention relates to a new composition for dermal administration of an active substance or principle. This composition can be a cosmetic composition, for example a slimming composition.

By active principles or active substances or substances is meant one or more active principles, whether medicinal or not. It may thus be, for example, a peptide or non-peptide compound, an extract of cells or tissues of animal or vegetable origin or a product obtained by fermentation of a microorganism, for example a bacteria or fungus. Thus in the present description, the terms active principles or active substances or substances according to the definitions specified above will be used interchangeably.

More specifically, the invention relates to a composition for dermal administration, capable of forming a flexible film after drying on the skin as well as a matrix which can be used in such a composition.

Dermal administration of active substances represents an interesting technique, endowed with certain advantages such as the absence of side effects. To be effective, this technique must, however, allow skin penetration over a prolonged period and sufficient to reach the targeted cells and obtain the desired effect.

To date, various systems or devices for this type of administration have been proposed. They allow the introduction of controlled doses of active substances. We know for example the transdermal administration device commonly called "patch" consisting of a reservoir formed of synthetic plastic materials containing the active ingredient. This reservoir can be covered, on its face in contact with the skin, by a microporous membrane whose permeability to the active substance regulates its diffusion and consequently its dosage. Despite the real possibilities offered by this device, in particular for an application, other systems may be preferred to it. Indeed, it is known that the patch can peel off from the skin and, moreover, present an often unsightly appearance. Gels containing active substances have also been proposed. However, this mode of use can have certain drawbacks to use, generally an unpleasant sticky feel for the person using it, as well as difficult control of the dose administered. Other systems assisting in the transdermal administration of active substances have also been reported. As such, mention may be made of sprayable compositions comprising in particular polymers capable of forming a film in contact with the skin and of releasing the active principle for transcutaneous administration. Compositions of this type, described for example in patent EP 319555, comprise an active principle, a polymer matrix forming a flexible film after drying, a solvent controlling the release of the active substance, namely a sorbitan macrogollaurate, a paraffin, a diglyceride or a medium chain fatty acid triglyceride or propylene carbonate as well as a solvent, for the matrix, capable of evaporating on the skin and finally a propellant making it possible to spray this composition contained in an appropriate device.

In addition, the compositions of patent EP 319555, by the presence of polymethacrylic derivatives, give off a characteristic odor which is quite unpleasant for the user and those around him. Other pharmaceutical compositions for topical administration containing an active principle, a solvent and various other ingredients are also known.

By way of example, mention may be made of patent EP 55396 which describes antimycotic compositions formed:

• a cellulose ether

• from 2 to 10% of a spreading agent such as isopropyl myristate or isopropyl palmitate

• from 1 to 8% of a solubilizing agent

• from 0.05 to 1% of active ingredient

• and a solvent such as isopropanol.

However, these compositions, if they can be used for topical dermatological applications, prove to be completely unsuitable for application by spraying even after adding 10 to 40% of a propellant gas as recommended, because they appear too viscous and likely to have various disadvantages such as blockage of the spray device.

Mention may also be made of patent EP 319964 describing antifungal compositions capable of forming a film comprising:

• 0.1 to 1.5% tolnaphthalate

• from 10 to 20% of a dimethylaminoethyl methacrylate / methacrylate copolymer

• from 0.5 to 10% of a fatty acid ester

• an alcohol type solvent and possibly 0.1 to 5% of a cellulose derivative. This composition also does not seem suitable for spraying. In addition, as already mentioned above, the presence of methacrylic derivatives gives it a redibitory odor.

We can also mention patent EP 289900 which relates to antibacterial compositions for topical use comprising:

• from 0.5 to 10% of an antibacterial active principle

• from 1 to 30% of a non-water-soluble polymer, in particular ethylcellulose or a polyvinylpyrrolidone copolymer

• from 0.5 to 40% of a plasticizer, generally an essential oil, also playing the role of promoter of transcutaneous absorption

• from 50 to 95% of a solvent such as ethanol.

Finally, mention may be made of patent application WO 96/30000, the main object of which is a pharmaceutical composition for transdermal administration comprising: 1) a salting-out polymer matrix capable of forming a flexible film after drying

2) an active ingredient

3) a promoter of transcutaneous absorption of the active ingredient

4) a physiologically acceptable non-aqueous solvent capable of dissolving the release matrix, the active principle and the transcutaneous absorption promoter as well as being rapidly eliminated by evaporation in contact with the skin, intended, after administration of the medicinal substance, to provoke a preventive or therapeutic response. The drug particularly used in this patent application is Pestradiol. The search for a composition allowing the diffusion through the dermis of active substances, from a small covering surface and at rates compatible with a treatment while being free from the drawbacks previously reported remains of major interest. Now, it has been discovered, surprisingly according to the invention, that it is possible to provide compositions, more particularly cosmetic compositions for dermal administration, from a film formed on the skin, which are devoid of the drawbacks mentioned above but capable, from a reduced and controllable overlap area, of delivering the active substance in a regular, continuous manner and at rates largely reaching the possibility of achieving the desired effect. Thus, the subject of the invention is a cosmetic composition for dermal administration comprising:

1) a salting-out polymer matrix capable of forming a flexible film after drying, 2) one or more active substances,

3) a promoter of cutaneous absorption of the active principle,

4) a non-aqueous solvent capable of dissolving the release matrix, the active principle and the skin absorption promoter as well as being rapidly eliminated by evaporation on contact with the skin, 5) at least one propellant gas.

In the present context, both in the description and in the claims, is meant either a substance intended, after administration, to cause a preventive or curative response or a combination of two or more substances of this type. The polymer matrix is generally chosen from polymeric or copolymeric substances capable of both forming a flexible film after evaporation of the solvent and of releasing the active substance.

This matrix is formed in the stratum corneum after evaporation of the solvent capable of releasing the active substances. Generally, this matrix is present in an amount of 0% to 7% of the weight of the composition according to the invention, for example from 4% to 7%, for example 3%. Preferably, 1% to 5% by weight of matrix, in particular 3%, is used. The choice of this matrix will mainly relate to polymeric or copolymeric substances soluble in the physiologically acceptable solvent so as to form a homogeneous solution.

Among the polymers or copolymers capable of meeting the above criteria, more particularly retained are cellulose polymers or copolymers, in particular because after drying they represent an appropriate abrasion resistance and mechanical stability. For this reason, cellulosic matrices of this type can be brought into contact with water without fear of deterioration.

By way of example of such cellulosic polymers or copolymers which can be used in the compositions of the invention, mention may be made of ethylcellulose, cellulose acetate butyrate, cellulose acetate propionate or a grafted or ungrafted hydroxypropylmethylcellulose such as hydroxypropylmethylcellulose acetate succinate. Ethylcellulose, however, represents the preferred cellulosic polymer and, therefore, the release matrix of choice for the formation of a flexible film in contact with the skin.

In addition, the polymer matrix can consist of a vinylpyrrolidone / vinyl acetate copolymer such as polyvinylpyrrolidone / vinyl acetate, hereinafter referred to as PVPVA.

Consequently, according to another of its aspects, the subject of the invention is a cosmetic composition for dermal administration comprising:

1) a salting-out polymer matrix capable of forming a flexible film after drying, chosen from cellulosic polymers or copolymers or vinylpyrolidone / vinyl acetate copolymers,

2) active substances,

3) a promoter of cutaneous absorption of the active principle,

4) a non-aqueous solvent or solvents capable of dissolving the release matrix, the active principle and the skin absorption promoter as well as being rapidly eliminated by evaporation on contact with the skin,

5) at least one propellant.

The active substance, for its part, will be chosen from substances soluble in the solvent and capable of continuously crossing the epidermis and / or the dermis with a sufficient flux to give an effective concentration from a cutaneous area of dimension reduced but sufficient.

These active substances will be incorporated into the compositions of the invention at a rate, in particular from 0.1 to 20% of the weight of these compositions, it being understood that each active substance will be introduced at individualized concentrations known in the art for dermal administration. or adapted to this route of administration.

In order to achieve an effective concentration of active principle without covering too large a skin surface, the polymer matrix and the active principle are combined with a skin absorption promoter. The latter enters into the compositions of the invention advantageously at a rate of 15 to 30% by weight of this composition, preferably from 15 to 25%, for example 20%.

This absorption promoter is chosen in such a way that it can bring about significant dermal flows in order to obtain the desired effects by means of an acceptable skin covering, that is to say less than 150 cm ² but preferably between 10 and 40 cm ² for example 30 cm ² . To be effective, the skin absorption promoter in question must be capable of temporarily disorganizing the skin barrier so as to increase the permeability of the skin without irritating it while promoting the diffusion of the active principle chosen according to kinetics and sufficient concentration that can be maintained for a period of time.

This skin absorption promoter will be selected from compatible substances in the non-aqueous solvent capable of evaporating rapidly on contact with the skin. Preferably, it will be chosen from the following compounds which have the necessary degree of solubility in the physiological solvent in question and which combine the best qualities reported above, that is to say:

• esters of aliphatic fatty acids, essentially esters having in total from 10 to 30 carbon atoms optionally substituted by one or two hydroxyl, carboxylic or acyloxy groups at dC ₄ such as acetoxy, or optionally interrupted by one or two bonds ethylenic or by one or two ether oxygen

• aliphatic fatty alcohols, essentially C ₁₀ -C ₃ alcohols optionally substituted by one or two hydroxyl, carboxylic or acyloxy groups at dC ₄ such as acetoxy or optionally interrupted by one or two ethylenic bonds or by one or two oxygen ether. Particularly preferred absorption promoters which can be selected from the esters of aliphatic fatty acids and aliphatic fatty alcohols mentioned above are reported below, namely: a) esters of aliphatic fatty acids of general formula:

in which R represents a C ₂ -C ₇ linear or branched alkyl or alkenyl group optionally substituted by a CC ₄ hydroxyl, carboxylic or acyloxy group and R 1 represents a linear or branched C ₃ -C ₈ alkyl group optionally substituted by one or two hydroxyl groups such as for example an isopropyl, 2-ethyl-dihydroxyethyl group or R _η represents a group -CH ₂ -CH ₂ -O- (CH ₂ ) ₂ -O-CH ₂ -CH ₃ , the aliphatic fatty acid ester comprising a minimum of 10 carbon atoms and a maximum of 2 hydroxyl groups. b) aliphatic fatty acid alcohols of general formula:

R ₂ -OH π in which R ₂ represents a Cι ₀ -C ₂₀ alkyl group As particular compounds which have shown the best potentials for promoting the cutaneous absorption of active substances, there may be mentioned: 2-ethylhexyl 2-ethylhexanoate isopropyl myristate myristate of monoethyl ether of diethylene glycol palmitate isopropyl 2-octyldecanol 2-ethylhexyl undecylenate 2-ethylhexyl succinate 2-ethylhexyl 12-hydroxystearate 2-ethylhexyl 12-acetoxystearate glycerol isostearate hexyl laurate isononyl isononitate isononate of 2-ethylhexyl 2-ethylhexyl stearate diethylene glycol monoethyl ether 2-ethylhexyl 2-ethylhexanoate represents the preferred absorption promoter in particular for cosmetic compositions according to the invention. This compound is marketed under the name Dragoxat® and is also called octyloctanoate. As for the non-aqueous solvent, capable of dissolving the release matrix, the active principle and the skin absorption promoter, it will be chosen from compounds with a relatively low boiling point, namely below 100 ° C. at atmospheric pressure, so that it can be quickly eliminated by evaporation on contact with the skin and likewise help the formation of a film by drying without, however, causing local irritation.

Such solvents are generally used in an amount of 44 to 84.9% by weight of the final composition and can be selected from volatile compounds such as dichloromethane, ethanol, isopropanol or ethyl acetate. Ethanol and isopropanol are the solvents of choice. However, ethanol represents a preferred solvent according to the invention since it contributes effectively to the formation of films on the skin while evaporating rapidly on contact with the skin. The propellants usable according to the invention are chosen from: butane propane isobutane carbon dioxide dimethyl ether hydrochlorofluorocarbon hydrofluorocarbon nitrogen isopentane nitrogen oxide pentane Butane or propane is preferred

Consequently, according to one of its particular aspects, the invention relates to a cosmetic composition comprising:

1) from 0% to 7% of a polymeric release matrix capable of forming a flexible film after drying, chosen in particular from cellulose polymers or copolymers such as ethylcellulose.

2) from 0.1% to 20% of an active substance

3) from 15% to 30% of a cutaneous absorption promoter of the active principle, in particular from 15% to 25% of a fatty acid ester or of a fatty alcohol chosen from: 2-ethylhexanoate 2-ethylhexyl isopropyl myristate myethylate of diethylene glycol monoethyl ether isopropyl palmitate 2-octyldecanol 2-ethylhexyl undecylenate 2-ethylhexyl succinate 12-hydroxystearear 2-ethylhexyl 2-ethylhexyl acetoxystearate glycerol isostearate hexyl laurate 4) from 44% to 84.9% of a non-aqueous solvent capable of dissolving the release matrix, the active principle and the skin absorption promoter as well than to be rapidly eliminated by evaporation on contact with the skin, in particular ethanol or isopropanol

5) of at least one propellant gas In the context of the present invention, a sprayable composition has been more particularly tested to be applied in a metered spray bottle, cosmetically satisfactory, and whose application surface and dose characteristics are controlled and reproducible.

There is thus the formation of a "film" on the skin. According to the invention, it is thus possible to obtain the application to the skin of active substances in the form of a film. Several biocompatible formulations favorable to skin penetration have been produced.

The active substances used can be intended for the production of a film for targeting, for example a slimming film. In particular, the film according to the present invention relates to a cosmetic composition containing slimming substances. This slimming substance may be a neuropeptide Y receptor antagonist. The neuropeptide Y hereinafter briefly designated "NPY" is a neuromediator which is involved in a number of physiological processes and for which an implication in the regulation of lipolysis has been demonstrated (P.Valet. J. Clin. Invest. 1990, 85, 291-295). It has been described in EP 838217 that the NP Y-antagonists can be used for the preparation of cosmetic compositions.

These cosmetic compositions containing an NPY-antagonist component can be used as regulators of lipoiysis / lipogenesis in the skin without interfering with the natural functions thereof. It has also been described that cosmetic slimming compositions containing an NPY-antagonist component and an α2-antagonist component are particularly advantageous.

Thus, according to one of its aspects, the present invention relates to a film containing a slimming cosmetic composition containing at least one NPY-antagonist component with another active substance such as an oc2-antagonist. The NPY-antagonist contained in the cosmetic composition can be a non-peptide compound, a peptide, an extract of cells or tissues of animal or vegetable origin or a product obtained by fermentation of a microorganism, for example of a bacteria or fungus. These components are also non-peptide synthetic compounds, peptides or products obtained by fermentation of a microorganism, for example a bacterium or a fungus or by extraction of cells or tissues of animal origin. or vegetable. The deposited film of course needs to be well tolerated but also to have an attractive cosmetic appearance with rapid evaporation of the vehicles, leaving little residue on the surface of the skin. The cosmetic evaluation of a series of formulations applied in film to the skin has been carried out.

More particularly, the objective was to characterize all of the cosmetic properties of the solutions to be sprayed using a sensory analysis study. This is a sensory study according to six criteria identified as being appropriate (the conduct of the protocols and the type of calculation adopted correspond to the AFNOR standards published for the food industry). These criteria are as follows:

• ease of penetration: absorption and evaporation “the residue: greasy / dry (the feel is evaluated by sliding the index finger on the deposited film) gloss (visual presence of the residue) sticky (the feel is observed by tapping the film with the index) odor.

• overall assessment of the product: taking into account only the previous criteria. The method of application is as follows:

After priming the pump by several pressures, the formulation is sprayed onto the skin at a measured distance of 10 cm. Observations begin 10 minutes after application, this duration is standardized for sensory analysis protocols. One spray corresponds to 130 μl of formulation on an area of approximately 35 to 40 cm ² . The excipients used are:

• film-forming agent: ethylcellulose 99 N7NF (7 mPa.s.: Aqualon)

• solvent: isopropanol (SDS), ethanol (Labover), • promoter and texture agent: Dragoxat ® E.H. (penetrating cosmetic oil: Dragoco), Dow Corning 556 silicone, light liquid paraffin (Sanofi Winthrop Gentilly). The spraying system used is as follows:

• VP7 / 130 pump: Valois • IN3 GP4 / 5 pusher: Valois

• 20ml ONC varnished aluminum housing. The formulations contain:

• 66 to 67% of the solvent: ethanol, isopropanol or a combination of the two.

• 20 to 30% of the promoter: Dragoxat ® EH • 3 to 5% of ethylcellulose The formulation described in WO 98/30000 which has been studied with estradiol as a medicament serves as a reference, and will be named below (R). The details of the compositions are given in table A.

All the criteria measured as well as the overall assessment for each formulation are evaluated on a scale ranging from +3 to -4 and reported in the form of histograms.

The average values obtained for the ten experimenters are accompanied by high and low values. The evaluation of the formulations is detailed here with respect to the reference formulation (R) by highlighting the changes in composition which affect or improve its cosmetic appearance.

Table B summarizes the main interpretations concerning the influence of the different excipients compared to the reference formulation. The perception of the reference formulation (R) is improved by limiting the amount of ethylcellulose to 3% (A) (less fatty, less sticky and less residue). An improved spraying capacity is thus obtained by better dispersion of the formulation by the device pump. With this 3%, it is even possible to increase the incorporated Dragoxat® to 30% while keeping a very good perception of the sprayed formulation (C). The formulation which is classified immediately after (E) has a slightly larger residue. It still contains 3% ethylcellulose but the solvent contains an isopropanol fraction which is more difficult to spray. The application surface must be smaller for the same volume of solution and therefore the residue must be thicker on the skin. The least appreciated formulations (B, R, F and G) because too greasy or sticky always contain 4 to 5% of ethylcellulose. The result is the same with ethanol or isopropanol. No improvement is observed by adding 1% of a compound described as optimizing the spraying (silicone or liquid paraffin) (F and G). Formulation (D) gave widely dispersed results. It contains 4% ethylcellulose and 30% Dragoxat®. The solution is not easy to spray. The use of ethanol or isopropanol is broadly equivalent.

The reference formulation is a bit greasy and sticky. By limiting only the amount of ethylcellulose from 0.5 to 3% the results are much improved and satisfactory.

The residue is weak to very weak, rather shiny but not greasy and not very sticky. Penetration is fairly rapid to very rapid. More particularly, according to the invention, a formulation of films containing slimming active agents has been developed.

These slimming active agents are preferably antagonists of the neuropeptide Y receptors (NPY) or antagonists of the α2 receptors. A large number of them are described in patent application EP 838217.

In cosmetology and also in the area of slimming agents, the cutaneous absorption of an active principle is akin to passive diffusion, the limiting stage being at the time of crossing the stratum corneum, 1,000 times more impermeable than epidermis or dermis. One of the main advantages expected from the films according to the invention is to remove this cutaneous resistance to diffusion. This increase in skin absorption is the result of an increase in hydration and temperature of the stratum corneum, following the semi-occlusion of the application site, caused by the film. The expected benefits of slimming films are primarily aimed at body areas characterized by the presence of resistant cellulite.

For those sites where cellulite is well established, it is necessary to be able to renew and maintain the action of the active substances before they are naturally metabolized by adipocytes. Film technology makes it possible to create a reservoir effect from the active substances at the level of the stratum corneum, from which a regular and continuous diffusion of the active agents is exerted in the lower layers of the skin. Due to this continuous diffusion, a permanent presence of the active agents is ensured in the vicinity of the adipocytes. It follows a constant saturation of the storage receptors which will act on the reduction of the dimples present in rebellious cellulite areas.

The advantageous aspect of the films results on the one hand from the structure of the matrix containing the active substances, and on the other hand from its application system. Being directly sprayable on the skin, the film forms a thin, flexible and invisible film, from which the active substances are diffused. The small thickness of the film formed makes it possible not to disturb the gaseous and aqueous exchanges existing between the skin and the external medium, thereby improving the tolerance of the product. The flexibility of the film also offers better comfort. In terms of active substances, the film contains antagonistic NPY and α2 antagonistic active agents, in a concentration 10 times greater than that retained in the conventional fluid as described in EP 838217. Thus, thanks to its bioavailability doubly controlled over time, by a continuous diffusion of the active substances and locally, by an activity strictly limited to the spraying sites, the film makes it possible to saturate the adipocyte storage receptors effectively and durably by the antagonists. of the NPY receptor and of the α2 receptor, leading to a reduction in areas traditionally resistant to slimming treatments.

The compositions according to the invention for dermal administration can be prepared, in a conventional manner, by a person skilled in the art, by mixing the various constituents in the chosen proportions. For example, it is possible, with stirring, to dissolve the skin absorption promoter in the solvent and then add the active principle and finally the release matrix. All of the substances included in the compositions of the invention constitute known products or can be prepared by known methods, some of these products being commercially available. The dermal compositions of the invention thus obtained can be applied by any means to a skin area for example to an area between 10 and 40 cm ² for example 30 cm ^{2 in} particular and preferably by direct spraying using a metering pump of known type and marketed with the aid of a propellant such as a compressed or liquefied gas. Although the state of the art asserts the opposite, it has been surprisingly noted that a release matrix formed of ethylcellulose does not cause, with the composition used, obstruction by gluing at the outlet of the nozzle. of the spray head, so that the compositions of the invention could be sprayed in the presence of a propellant gas and without fear of damaging the spray container.

The compositions of the invention can thus be administered by spraying from a container fitted with a metering valve, containing in addition a propellant gas such as nitrogen or nitrous oxide, or liquefied gas such as butane or propane. According to another object, the invention relates to a matrix intended for cosmetic compositions for the dermal administration comprising: a) a polymeric matrix, for the release of an active principle, capable of forming a flexible film after drying b) a promoter of skin absorption of an active ingredient c) a non-aqueous solvent capable of dissolving the release matrix and the skin absorption promoter as well as being rapidly eliminated by evaporation on contact with the skin d) a propellant

The polymer matrix will be selected from polymeric or copolymeric substances, in particular from cellulosic polymers or copolymers as explained above, while the cutaneous absorption promoter will appear from esters of aliphatic fatty acids or aliphatic fatty alcohols as described. previously in particular esters of formula I or alcohols of formula π.

When the non-aqueous solvent is a compound with a boiling point below

100 ° C at atmospheric pressure as mentioned previously.

These various components of the matrix for dermal cosmetic composition will be distributed in such a way that within the cosmetic composition in question containing the active principle, the release matrix represents from 0% to 7%, the skin absorption promoter represents from 15% to 30% and the nonaqueous solvent represents from 44% to 84.9%, these percentages being expressed by weight of the final cosmetic composition. These matrices for dermal compositions according to the invention can be prepared, in a conventional manner, by mixing, in the chosen proportions, the various ingredients which constitute them.

The propellants are advantageously chosen from propanol or butanol.

The film-forming compositions of the invention as well as the matrices for dermal compositions according to the invention have indisputable advantages since they are capable of causing the cutaneous diffusion of an active substance, so as to produce constant and controlled effective rates over a period of time. prolonged period of at least 12 hours from a skin covering area of the order of 10 to

40 cm ² . In addition, the compositions and matrices for dermal compositions according to the invention, while being devoid of any unpleasant odor, spread out in a homogeneous film over the entire selected skin area.

These films are sufficiently flexible and resistant to abrasion to avoid any deterioration on the skin of the user and have better tolerance than the known dermal devices since, because of their thinness and the absence of any covering, the gas exchanges and watery with the outside are not disturbed.

Finally, the compositions of the invention, in the form of a flexible film, provide better comfort for the user and, thanks to their transparency, are completely invisible.

Various tests have been carried out in vitro as well as in vivo so as to highlight the characteristics and particularities of the compositions of the invention. The cosmetic compositions according to the invention preferably contain slimming active substances.

The slimming active substances are preferably chosen from NPY or α2 receptor antagonists. The active substances used are in this case for example the extracts of strain

Streptomyces sp SEBR 2794, registered with the C.N.C.M. from the Institut Pasteur under number 1-1332, and extracts of the Bacillus licheniformis SEBR 2464 strain, deposited with the C.N.C.M. of the Institut Pasteur under the number 1-1778. They will be called hereafter slimming active substance. A clinical efficacy study was carried out with a slimming composition containing NPY and α2 receptor antagonists. The purpose of this study was to assess the effectiveness of the film in use coupled with the Lipofactor® fluid.

(Lipofactor: registered trademark of Sanofi). a) Protocol The test is carried out over a period of 28 days and involves 31 women. The inclusion of subjects was carried out after a clinical examination and verification of the presence of areas of anchored cellulite. The subjects apply the fluid and the film on the same leg, defined randomly, the contralateral leg being taken as an untreated control. The fluid is applied at discretion on the entire thigh, from the knee to the gluteal fold.

The application is carried out in the evening without massage apart from that necessary for the penetration of the product.

The film is applied in the morning in a very localized manner on the following 4 sites:

* external upper lateral side of the thigh, * internal upper side of the thigh,

* back side (gluteal fold),

* inner side of the knee.

The amount of film used per day corresponds to two sprays juxtaposed so as to cover the area concerned. The evaluation of the effectiveness is carried out at To (before treatment) and at T28 days and uses three different methods:

* ultrasound to measure the thickness of adipose tissue taken from three locations at the thigh plus one at the knee. clinical evaluation of the macro-relief (dimpling) of the external surface of the thighs. the analysis of relief images of the capitons.

b) Results ^ Ultrasound Table 1 presents the main characteristics of the subjects. The weight of the subjects was checked after the 28 days of the trial. No significant variations were observed, which will confirm the attribution of the results observed to the activity of the products tested.

Table 1: Characteristics of the subjects

(a) Body Mass Index Table 2 and Figure 1 show the average decrease in thickness of the adipose tissue after one month of testing.

Depending on the area, a marked reduction in the thickness of the adipose tissue, of the order of - 10% compared to the values measured at To, is observed.

Table 2: Average decreases in adipose tissue depending on the sites treated

(expressed in% of variation compared to TO)

^* S (p "0.05) Figure 1: Percentage changes between To and T28 days for each location

Ext. Post thighs. Thighs Int. Thighs Int. Knees

These results appear very significant and only concern the side treated. At the same time, good stability of the control contralateral locations is observed, which have non-significant variations ranging from -0.3 to +0.1 mm.

• * Clinical evaluation and image analysis

The clinical assessment of the macro-relief is carried out using photographic images by five assessors. After random distribution, all the photographs are scored by the assessors by comparison to a standard range (reference photographs), structured around 7 intensity grades.

For five subjects, a preliminary profilometric analysis was carried out in order to calculate the average relief of an area defined on each image and corresponding to a skin surface equivalent to 3x130 mm.

The images of the external faces of the treated thighs and controls of the 31 volunteers made it possible to clinically confirm, after analysis by the 5 evaluators, an improvement in skin relief.

This improvement is significant (p "0.05) for the thighs treated between T0 and T28 d while at the same time, no significant result is obtained on the untreated sides. Table 3: Results compared on 5 subjects between clinical evolution and image analysis

The concept of the film was evaluated during a study carried out with 113 women recruited to have cellulite.

The film is applied for 4 weeks at the rate of two juxtaposed sprays so as to cover the area concerned. The effectiveness of the film is evaluated at the end of the study.

It emerges from this study, in terms of effectiveness that, in general, the film allows a significant improvement of the orange peel localized in the lower limbs.

EXAMPLE 1

Dermal composition containing

100 g of a dermal composition of the following formulation are prepared:

% by weight Ethyl cellulose 6 mPa.sec 5%

Slimming active ingredients 2%

2-Ethylhexyl 2-Ethylhexanoate 20%

Ethanol 73%

Propylene glycol 0.5% Propellant gas by mixing for 30 seconds and with magnetic stirring 73 g of ethanol and 20 g of 2-ethylhexyl 2-ethylhexanoate. 2 g of active slimming substance (s) are then added, in small portions, to the mixture obtained, then, after complete dissolution (5 minutes), 5 g of 6mPa.sec ethylcellulose are introduced, with vigorous stirring. , in order to avoid the formation of lumps. The final solution obtained is slightly opalescent, homogeneous. For spray administration, aluminum boxes are filled with 5 ml of the previously obtained solution and they are fitted with a crimped pump pump comprising a push button. The pump is activated twice to prime before its first use.

EXAMPLE 2

Matrix for dermal composition

98 g of a dermal matrix are prepared by mixing, for 30 seconds, 73 g of ethanol and 20 g of 2-ethylhexyl 2-ethylhexanoate. 5 g of ethylcellulose 6 mPa.sec are then added, with vigorous stirring, in order to avoid the formation of lumps. The matrix thus obtained is ready to receive an active, by incorporation, so as to form a cosmetic composition containing 2% by weight of this active, applicable by spraying.

EXAMPLE 3

Matrix for dermal composition

We proceed according to Example 2 by mixing:

EXAMPLE 4

Matrix for dermal composition

We proceed according to Example 2 by mixing

EXAMPLE 5

Matrix for dermal composition

We proceed according to Example 2 by mixing

EXAMPLE 6 Matrix for dermal composition

We proceed according to Example 2 by mixing

EXAMPLE 7

We prepare the following composition

Table A: Composition of the formulations

Reminder of the reference formulation: 95 ° ethanol: 75%; Dragoxat®: 20%; ethylcellulose: 5%.

Table B: Classification of the evaluation of excipients compared to the reference formulation

Claims

1. Cosmetic composition for dermal administration, characterized in that it comprises: a) optionally a salting-out polymer matrix capable of forming a flexible film after drying, chosen from cellulosic polymers or copolymers; b) an active ingredient; c) 5 to 30%, relative to the weight of the composition, of a promoter of transcutaneous absorption of the active principle, d) a nonaqueous solvent, capable of dissolving the release matrix, the active principle and the promoter of skin absorption as well as being eliminated quickly by evaporation on contact with the skin, the skin absorption promoter being chosen from:

• an ester of aliphatic fatty acid soluble in the physiologically acceptable non-aqueous solvent and of general formula:

OR— C— OR, I in which R represents a linear or branched C ₂ -O ₇ alkyl or alkenyl group optionally substituted by a hydroxyl, carboxylic or acyloxy group at CC ₄ and R 1 represents a linear or branched alkyl group , C ₃ -C ₈ optionally substituted by one or two hydroxyl groups or Ri represents a group -CH ₂ -CH2-O- (CH ₂ ) 2-O-CH2-CH ₃ , the ester of aliphatic fatty acid comprising a minimum of 10 carbon atoms and a maximum of 2 hydroxyl groups

• an aliphatic fatty alcohol, soluble in the physiologically acceptable non-aqueous solvent of general formula

R ₂ -OH II in which R ₂ represents a Cιo-C ₂₀ alkyl group. e) at least one propellant

2. Composition according to claim 1 characterized in that the polymeric release matrix is present in an amount of 0% to 7% of the weight of the composition.

3. Composition according to claim 2 characterized in that the polymeric release matrix is present in an amount of 1% to 5% of the weight of the composition.

4. Composition according to one of claims 1 to 3 characterized in that the active principle is present in an amount of 0.1% to 20% by weight of the composition.

5. Composition according to one of claims 1 to 4 characterized in that the skin absorption promoter is present in an amount of 15% to 25% of the weight of the composition.

6. Composition according to one of claims 1 to 5 characterized in that the non-aqueous solvent is present in an amount of 44% to 84.9% by weight of the composition.

7. Composition according to one of claims 1 to 6 characterized in that the polymeric release matrix is a cellulosic polymer or copolymer soluble in the non-aqueous solvent.

8. Composition according to claim 7 characterized in that the cellulosic polymer or copolymer is ethylcellulose, cellulose acetate butyrate, cellulose acetate propionate or a hydroxypropylmethylcellulose grafted or not.

9. Composition according to claim 7 characterized in that the cellulosic polymer or copolymer is ethylcellulose.

10. Composition according to one of claims 1 to 9 characterized in that the active principle is a slimming active substance antagonist of the NPY receptor and / or of the α2 receptor.

11. Composition according to one of claims 1 to 10 characterized in that the active principle is chosen from extracts obtained by fermentation of a microorganism.

12. Composition according to claim 11, characterized in that the active substances are present in an amount of 0.5% to 6% of the weight of the composition.

13. Composition according to claim 12, characterized in that the active substances are present in an amount of 1% to 2% of the weight of the composition.

14. Composition according to one of claims 1 to 10 containing a combination of active substances consisting of an NPY antagonist and an oc2 antagonist characterized in that the active substances used are extracts of Streptomyces sp SEBR 2794 strain, registered with the CNCM from the Institut Pasteur under number 1-1332, and extracts of the Bacillus licheniformis SEBR 2464 strain, deposited with the C.N.C.M. of the Institut Pasteur under the number 1-1778.

15. Composition according to one of claims 1 to 14 characterized in that Ri represents an isopropyl, 2-ethylhexyl or 1, 2-dihydroxyethyl group.

16. Composition according to Claim 1, characterized in that the cutaneous absorption promoter is chosen from: 2-ethylhexanoate of 2-ethylhexyl isopropyl myristate myristate of the diethyleneglycol monoethyl ether of isopropyl palmitate 2-octyldodecanol undecylenate 2-ethylhexyl 2-ethylhexyl succinate 12-2-ethylhexyl 12-hydroxystearate 2-ethylhexyl acetoxystearate glycerol isostearate hexyl laurate.

17. Composition according to claim 1 or 15 characterized in that the skin absorption promoter is 2-ethylhexyl 2-ethylhexanoate.

18. Composition according to one of claims 1 to 17 characterized in that the non-aqueous solvent is a compound with a boiling point below 100 ° C at atmospheric pressure.

19. Composition according to Claim 18, characterized in that the compound with a boiling point below 100 ° C is dichloromethane, ethanol, isopropanol or ethyl acetate.

20. Pharmaceutical composition according to claim 18 characterized in that the non-aqueous solvent is ethanol.

21. Composition according to claim 1 characterized in that:

• the cellulosic polymer or copolymer is ethylcellulose

• the active substance is a slimming active substance

• the skin absorption promoter is 2-ethylhexyl 2-ethylhexanoate

• the solvent is ethanol. • the propellant is butane.

22. Composition according to Claim 21, characterized in that it comprises:

• 3% ethylcellulose;

• 2% of active slimming substance (s); • 20% of 2-ethylhexyl 2-ethylhexanoate; and

• 75% ethanol

• propellant

23. Composition according to claim 1 or 21 characterized in that it comprises: • 5% ethylcellulose;

• 2% of active slimming substance (s);

• 20% of 2-ethylhexyl 2-ethylhexanoate, and

• 73% ethanol.

• propellant

24. Composition according to claim 1 characterized in that it comprises:

• 5% ethylcellulose;

• 2% of active slimming substance (s);

• 20% of 2-ethylhexyl 2-ethylhexanoate; and • 74% ethanol.

• propellant

25. Composition according to claim 1 characterized in that it comprises:

• 2% ethylcellulose; • 1% of active slimming substance (s); • 20% of 2-ethylhexyl 2-ethylhexanoate; and

• 77% ethanol.

• propellant

26. Composition according to one of claims 1 to 25 characterized in that it is intended to be applied by spraying with the aid of compressed or liquefied propellant.

27. Composition according to one of claims 1 to 26 characterized in that it is applied to a skin area of 10 to 40 cm ² .

28. Matrix for cosmetic composition intended for dermal administration, characterized in that it comprises: a) a polymeric matrix, for the release of an active principle, capable of forming a flexible film after drying, chosen from cellulosic polymers or copolymers ; b) 15 to 30%, relative to the weight of the composition, of a skin absorption promoter of the active principle; c) a nonaqueous solvent capable of dissolving the release matrix and the skin absorption promoter as well as being rapidly eliminated by evaporation on contact with the skin, the skin absorption promoter being chosen from:

in which R represents a linear or branched C ₂ -C alkyl or alkenyl group | ₇ optionally substituted by a hydroxyl, carboxylic or acyloxy group at C _r C and Ri represents an alkyl group, linear or branched, at C ₃ -C ₈ optionally substituted by one or two hydroxyl groups or R _T represents a group -CH2-CH ₂ -O- (CH ₂ ) 2-

O-CH ₂ -CH ₃ , the ester of aliphatic fatty acid comprising a minimum of 10 carbon atoms and a maximum of 2 hydroxyl groups • an aliphatic fatty alcohol, soluble in the nonaqueous solvent of general formula:

R ₂ - OH π in which R ₂ represents a C10-C20 alkyl group d) a propellant

29. Matrix for composition according to claim 28 characterized in that the cellulosic polymer or copolymer is ethylcellulose, cellulose acetate butyrate, cellulose acetate propionate or a hydroxypropylmethylcellulose grafted or not.

30. Matrix for composition according to claim 29 characterized in that the cellulosic polymer or copolymer is ethylcellulose.

31. Matrix for composition according to one of claims 28 to 30 characterized in that the cutaneous absorption promoter is chosen from: 2-ethylhexanoate of 2-ethylhexyl isopropyl myristate myristate of monoethyl ether of diethylene glycol palmitate d 2-octyldodecanol isopropyl 2-ethylhexyl undecylenate 2-ethylhexyl succinate 12-2-ethylhexyl 12-hydroxystearate 2-ethylhexyl acetoxystearate glycerol isostearate hexyl laurate.

32. Matrix for composition according to claim 31 characterized in that the skin absorption promoter is 2-ethylhexyl 2-ethylhexanoate.

33. Matrix for composition according to one of claims 28 to 32 characterized in that the non-aqueous solvent is a compound with a boiling point below 100 ° C at atmospheric pressure.

34. Matrix for composition according to claim 33 characterized in that the compound with a boiling point below 100 ° C is dichloromethane, ethanol, isopropanol or ethyl acetate.

35. Matrix for dermal composition according to claim 33 characterized in that the compound with a boiling point below 100 ° C is ethanol.

36. Matrix for composition according to one of claims 28 to 35 characterized in that within said composition containing the active substances, the release matrix represents from 0 to 7%, the cutaneous absorption promoter represents from 15% to 30 % and the nonaqueous solvent represents from 44% to 84.9%, these percentages being expressed by weight of the final composition.

37. Pump spraying device containing a composition according to any one of claims 1 to 27.

38. Cosmetic composition according to claim 1 characterized in that it contains at least one slimming active substance.

39. Cosmetic slimming composition according to claim 38 characterized in that it contains an NPY receptor antagonist and an α2 receptor antagonist.

40. Slimming cosmetic composition according to claim 39, characterized in that it contains the extracts of Streptomyces sp SEBR 2794 strain, deposited with the C.N.C.M. from the Institut Pasteur under number 1-1332, and extracts of the Bacillus licheniformis SEBR 2464 strain, deposited with the C.N.C.M. of the Institut Pasteur under the number 1-1778