FR2787712A1 - PULVERISABLE COSMETIC COMPOSITION AND MATRIX USEFUL IN THIS COMPOSITION FOR DERMAL DELIVERY - Google Patents

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

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The present invention relates, in general, to a novel composition for dermal administration of a substance or active ingredient.

Active principles or substances or active substances means one or more medicinal active principles or not. It may thus be, for example, a peptide or nonpeptide compound, an extract of cells or tissues of animal or vegetable origin or a product obtained by fermentation of a microorganism, for example a bacterium or a fungus. Thus in the present description will be used indifferently the terms active principles or active substances or substances according to the above definitions.

More specifically, the invention relates to a composition for dermal administration, capable of forming a flexible film after drying on the skin and a matrix usable in such a composition.

The dermal administration of active substances represents an interesting technique, because it is noninvasive and has certain advantages such as the absence of side effects.

To be effective, however, this technique must allow skin penetration over a prolonged period and sufficient to reach the targeted cells and achieve 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.

For example known transdermal delivery device commonly called "patch" consists of a tank formed of synthetic plastics containing the active ingredient. This reservoir may be covered, on its face in contact with the skin, with 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, it may be preferred other systems. Indeed, it is known that the patch can peel off the skin and, moreover, have an often unsightly appearance.

Gels containing active substances have also been proposed. However, this mode of use may have certain disadvantages to use, generally an unpleasant sticky touch for the person using it as well as a difficult control of the administered dose.

Other systems have also been reported which assist in the transdermal administration of active substances.

In this respect, 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 ingredient for transcutaneous administration. Compositions of this type, described by

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 example in the patent EP 319555, comprise an active ingredient, a polymeric 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 triglyceride chain fatty acid medium or propylene carbonate and a solvent for the matrix, capable of evaporating on the skin and finally a propellant for spraying this composition contained in a suitable device.

In addition, the compositions of patent EP 319555, by the presence of polymethacrylic derivatives, emit a characteristic odor quite unpleasant for the user or his entourage.

Other pharmaceutical compositions for topical administration containing an active ingredient, 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 of: #a cellulose ether # from 2 to 10% of a spreading agent such as isopropyl myristate or palmitate isopropyl # of 1 to 8% of a solubilizing agent # of 0.05 to 1% of active principle # and a solvent such as isopropanol However, these compositions if they can be used for topical applications Dermatological studies prove totally unsuitable for spray application even after adding 10 to 40% of a propellant gas as recommended, because they appear too viscous and may cause various disadvantages such as clogging of the spray device.

Patent EP 319964 can also be cited, describing antifungal compositions capable of forming a film comprising: # from 0.1 to 1.5% tolnaphthalate # from 10 to 20% of a copolymer of dimethylaminoethyl methacrylate / methacrylate # from 0, 5 to 10% of a fatty acid ester of an alcohol solvent and optionally from 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.

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EP 289900 which relates to topical antibacterial compositions comprising: # from 0.5 to 10% of an antibacterial active ingredient # from 1 to 30% of a non-water-soluble polymer, in particular ethylcellulose, may also be mentioned. or a polyvinylpyrrolidone copolymer of 0.5 to 40% of a plasticizer, generally an essential oil, also acting as a transcutaneous absorption promoter of 50 to 95% of a solvent such as ethanol.

Finally, mention may be made of patent application WO 96/30000, whose main object is a pharmaceutical composition for transdermal administration comprising: 1) a polymeric release matrix capable of forming a flexible film after drying 2) an active principle 3) a promoter 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 on contact with the skin, intended, after administration of the drug, to provoke a preventive or therapeutic response.

The drug particularly used in this patent application is estradiol.

The search for a composition allowing diffusion through the dermis of active substances, from a low coverage surface and at rates compatible with a treatment while being free of the disadvantages reported previously remains of major interest.

However, it has surprisingly been found according to the invention that it is possible to provide compositions, more particularly cosmetic compositions for dermal administration, from a film formed at the level of the skin. without the drawbacks mentioned above, but capable, from a reduced and controllable recovery zone, of delivering the active substance in a regular, continuous manner and at levels largely reaching the possibility of achieving the desired effect.

Thus, the main subject of the invention is a cosmetic composition for dermal administration comprising: 1) a polymeric release matrix capable of forming a flexible film after drying,

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 2) one or more active substances, 3) a dermal absorption promoter of the active principle, 4) a non-aqueous solvent capable of dissolving the release matrix, the active ingredient and the dermal absorption promoter as well as eliminating rapidly by evaporation in contact with the skin, 5) at least one propellant.

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 polymeric matrix is generally chosen from polymeric or copolymeric substances capable both of forming a flexible film after evaporation of the solvent and of salting out 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 a proportion of from 0% to 7% by weight of the composition according to the invention, for example from 4% to 7%, for example 3%.

Preferably, from 1% to 5% by weight of matrix, in particular 3%, is used.

The choice of this matrix will be mainly on 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, cellulosic polymers or copolymers are more particularly chosen because they represent, after drying, 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 unsopped hydroxypropylmethylcellulose such as hydroxypropyl methylcellulose acetate succinate.

However, ethylcellulose is the preferred cellulosic polymer and, therefore, the polymeric release matrix of choice for the formation of a flexible film in contact with the skin.

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

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Accordingly, according to another of its aspects, the subject of the invention is a cosmetic composition for dermal administration comprising: 1) a polymeric release matrix capable of forming a flexible film after drying, chosen from cellulose polymers or copolymers or copolymers vinylpyrrolidone / vinyl acetate, 2) active substances, 3) a dermal absorption promoter of the active principle, 4) a solvent or non-aqueous solvents capable of dissolving the release matrix, the active ingredient and the absorption promoter dermal as well as to be rapidly eliminated by evaporation on contact with the skin, 5) at least one propellant gas.

The active substance, when it will be selected from substances soluble in the solvent and able to continuously cross the epidermis and / or the dermis with a sufficient flow to give an effective concentration from a cutaneous area of dimension reduced but sufficient.

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

In order to achieve an effective concentration of active ingredient without covering a skin surface too large, is associated with the polymeric matrix and the active ingredient, a dermal absorption promoter. The latter is advantageously in the compositions of the invention in the proportion 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 significant dermal fluxes to obtain the desired effects by means of an acceptable cutaneous recovery, that is to say less than 150 cm 2 but preferably between 10 and 40 cm 2 per example 30 cm2.

The skin absorption promoter in question, in order to be effective, must be capable of transiently disorganizing the skin barrier so as to increase the permeability of the skin without irritating it while promoting the diffusion of the active ingredient chosen according to kinetics and a sufficient concentration that can be maintained for a certain time.

This dermal 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 degree of

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 solubility necessary in the physiological solvent in question and which combine the best qualities reported above that is to say: # aliphatic fatty acid esters, essentially esters having a total of 10 to 30 optionally substituted carbon atoms by one or two hydroxyl, carboxylic or acyloxy groups C1-C4 such as acetoxy, or optionally interrupted by one or two ethyl bonds or with one or two oxygens ether # aliphatic fatty alcohols, essentially optionally substituted C10-C30 alcohols by one or two hydroxyl, carboxylic or acyloxy groups C1-C4 such as acetoxy or optionally interrupted by one or two ethylenic bonds or with one or two oxygens ether.

Particularly preferred absorption promoters which can be selected from aliphatic fatty acid esters and aliphatic fatty alcohols mentioned above are reported below, namely: a) aliphatic fatty acid esters of the general formula:
O #
RC-OR1 I wherein R represents a linear or branched alkyl or alkenyl group, in
C2-C7 optionally substituted with a hydroxyl, carboxylic or C 1 -C 4 acyloxy group and R1 represents a linear or branched C3-C8 alkyl group optionally substituted with one or two hydroxyl groups such as for example an isopropyl group, 2- ethyl-dihydroxyethyl or R1 represents a -CH2-CH2-O- (CH2) 2 -O-CH2-CH3 group, the aliphatic fatty acid ester having a minimum of 10 carbon atoms and a maximum of 2 hydroxyl groups. b) aliphatic fatty acid alcohols of the general formula:
Wherein R 2 represents a C 10 -C 20 alkyl group. As particular compounds which have shown the best potential for promoting the dermal absorption of active substances, mention may be made of: 2-ethyl-2-ethyl hexanoate hexyl isopropyl myristate diethylglycol monoethyl ether myristate isopropyl palmitate 2-octyldecanol 2-ethylhexyl undecylenate 2-ethylhexyl succinate

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 2-ethyl-hexyl 12-hydroxy-stearate 2-ethyl-hexyl 12-acetoxy stearate glycerol isostearate hexyl laurate isononyl isononanoate 2-ethyl-hexyl palmitate stearate 2 ethyl-hexyl diethylene glycol monoethyl ether 2-ethyl-hexyl 2-ethyl-hexanoate represents the preferred absorption promoter especially for cosmetic compositions according to the invention. This compound is marketed under the name of Dragoxat and is also called octyloctanoate.

When non-aqueous solvents, capable of dissolving the release matrix, the active ingredient and the dermal absorption promoter, it will be chosen from compounds of relatively low boiling point, ie less than 100 C at atmospheric pressure, of It can be quickly removed by evaporation in contact with the skin and help in the same way to the formation of a film by drying without causing local irritation.

Such solvents are generally used in a proportion of 44 to 84.9% by weight of the final composition and may be selected from volatile compounds such as dichloromethane, ethanol, isopropanol or ethyl acetate.

Ethanol and isopropanol are the solvents of choice. However, ethanol is a preferred solvent according to the invention since it contributes effectively to the formation of films on the skin while evaporating rapidly in contact with the skin.

The propellant gases that can be used according to the invention are chosen from: butane propane isobutane carbon dioxide dimethyl ether hydrochlorofluorocarbon hydrofluorocarbon nitrogen isopentane nitrous oxide pentane

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 Butane or propane is therefore preferred. According to one of its particular aspects, the invention relates to a cosmetic composition comprising: 1) from 0% to 6% of a polymeric salting 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 dermal absorption promoter of the active principle, in particular
15% to 25% of a fatty acid ester or a fatty alcohol chosen from: 2-ethyl-hexyl 2-ethyl hexanoate isopropyl myristate diethylglycol monoethyl ether myristate palmitate isopropyl 2-octyldecanol 2-ethylhexyl undecylenate 2-ethylhexyl succinate 2-ethylhexyl 12-hydroxystearate 2-ethylhexyl 12-acetoxystearate glycerol isostearate hexyl laurate 4) from 44% to 84.9% of a non-aqueous solvent capable of dissolving the release matrix, the active ingredient and the dermal absorption promoter as well as rapidly eliminating by evaporation in contact with the skin, in particular ethanol or isopropanol 5) at least one propellant gas In the context of the present invention, a sprayable composition to be applied as a metered-dose spray bottle to the skin has been experimentally tested. cosmetically satisfactory, and whose application surface characteristics and doses are controlled and reproducible.

There is thus formation of a "film" on the skin.

It is thus possible to obtain, according to the invention, the application to the skin of active substances in the form of a film.

Several biocompatible and skin-penetrating formulations have been made.

The active substances used may be intended for the manufacture of film for purposes such as slimming.

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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 referred to as "NPY" is a neuromediator which is involved in a certain number of physiological processes and for which an involvement in the regulation of lipolysis has been demonstrated (P.Valet and M.J.Clin.Invest, 1990, 85, 291-295).

It has been described in EP 838217 that NPY-antagonists can be used for the preparation of cosmetic compositions.

These cosmetic compositions containing an NPY-antagonist component can be used as regulators of lipolysis / lipogenesis in the skin without interfering with the natural functions thereof.

It has also been disclosed 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 NPYantagonist component with another active substance such as a2-antagonist. The NPYantagonist contained in the cosmetic composition may 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 a bacterium or a mushroom.

Advantageous α2-antagonists for use as additional components besides the NPY-antagonist are α2-antagonists.

These components are also nonpeptide 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 film deposited of course requires to be well tolerated but also to have an attractive cosmetic appearance with rapid evaporation of vehicles, leaving little residue on the surface of the skin.

The cosmetic evaluation of a series of formulations applied to film on the skin has been carried out.

More specifically, the objective was to characterize all the cosmetic properties of the spray solutions through a sensory analysis study.

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It 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: # ease of penetration: and evaporation # the residue: fat / dry (the touch is evaluated by sliding the index on the deposited film) gloss (visual presence of the residue) sticky (the touch is observed by tapping the film with the index) odor # overall assessment of the product: taking into account only the previous criteria.

The mode of application is as follows: After priming the pump by several pressures, the formulation is sprayed on the skin at a measured distance of 10 cm. Observations begin 10 minutes after application, this time is standardized for sensory analysis protocols.

A spray corresponds to 130 l of formulation over an area of about 35 to 40 cm 2.

The excipients used are as follows: # film-forming agent: ethylcellulose 99 N7NF (7 mPa.s.: Aqualon) # solvent: isopropanol (SDS), ethanol (Labover), # promoter and texture agent: Dragoxat # EH (penetrating cosmetic oil :
Dragoco), Dow Corning 556 silicone, light liquid paraffin (Sanofi Winthrop
Gentilly).

The spray system used is as follows: # pump VP7 / 130: Valois # push IN3 GP4 / 5: Valois # ONC 20ml varnished aluminum case.

The formulations contain: # 66 to 67% of the solvent: ethanol, isopropanol or a combination of both.

 # 20 to 30% of the promoter: Dragoxat # E.H # 3 at 5% ethylcellulose The formulation described in WO 98/30000 which has been studied with estradiol as a medicament serves as a reference, hereinafter referred to as (R).

The details of the compositions are shown in Table A.

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 All the criteria measured as well as the overall assessment for each formulation are evaluated on a scale of +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 composition modifications that affect or improve its cosmetic appearance.

Table B summarizes the main interpretations concerning the influence of the different excipients with respect to the reference formulation.

The perception of the reference formulation (R) is improved by limiting the amount of ethylcellulose to 3% (A) (less fat, less tacky and less residue). An improved spray capacity is thus obtained by better dispersion of the formulation by the pump of the device. With these 3%, it is even possible to increase the Dragoxat incorporated in 30% while keeping a very good perception of the sprayed formulation (C).

The formulation that is ranked right after (E) has a slightly larger residue. It still contains 3% ethylcellulose but the solvent has an isopropanol fraction which is more difficult to spray. The application surface should be smaller for the same volume of solution and therefore the residue should be thicker on the skin.

The less preferred formulations (B, R, F and G) because too fat or sticky still contain 4 to 5% ethylcellulose. The result is the same with ethanol or isopropanol. No improvement is observed by adding 1% of a compound described as spraying optimizer (silicone or liquid paraffin) (F and G).

Formulation (D) gave very scattered 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 by 5 to 3% the results are much improved and satisfactory: The residue is low to very low, rather bright but not greasy and not sticky.

The penetration is fast enough to very fast.

More particularly, according to the invention, a film formulation containing slimming active agents has been developed.

These slimming actives are preferably neuropeptide Y (NPY) receptor antagonists or α 2 -receptor antagonists. A large number of them are described in patent application EP 838217.

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In cosmetology and also in the field of slimming, skin absorption of an active ingredient is similar to a passive diffusion, the limiting step being at the time of crossing the stratum corneum, 1,000 times more impervious than the epidermis or dermis.

One of the main advantages expected of the films according to the invention is to lift this cutaneous resistance to diffusion. This increase in skin absorption is the result of an increase in hydration and temperature of the stratum corneum, resulting from the semi-occlusion of the application site, caused by the film.

The expected benefits of slimming films primarily target body areas characterized by the presence of a resistant cellulite.

For these sites where cellulite is well anchored, it must be possible to renew and maintain the action of active substances before they are naturally metabolized by adipocytes.

The technology of the films makes it possible to create from the active substances a reservoir effect at the stratum corneum, from which a regular and continuous diffusion of the active agents in the lower layers of the skin is exerted. Due to this continuous diffusion, a permanent presence of the assets is ensured in the vicinity of the adipocytes.

It follows a constant saturation of storage receptors that will act on the reduction of cellulite present in the areas of rebellious cellulite.

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 will form a thin film, flexible and invisible, from which the active substances will be released.

The small thickness of the formed film makes it possible not to disturb the gaseous and aqueous exchanges existing between the skin and its external environment, thus improving the tolerance of the product. The flexibility of the film also offers better comfort.

In terms of active substances, the film contains antagonistic and antagonist NPY active agents, in concentration 10 times higher than that retained in the conventional fluid as described in EP 838217.

Thus, thanks to its doubly controlled bioavailability: # in time by continuous diffusion of active substances, # and geographically, by an activity strictly limited to the spraying sites,

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 The film effectively and durably saturates the adipocyte storage receptors by the NPY receptor and the α2 receptor antagonists, resulting in a reduction of the areas traditionally refractory to slimming treatments.

The compositions according to the invention for dermal administration can be prepared, in a conventional manner, by mixing the various constituents in the chosen proportions.

For example, it is possible, with agitation, to dissolve the dermal absorption promoter in the solvent and then add the active ingredient and finally the release matrix.

All of the substances used in the compositions of the invention are 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 cutaneous zone, for example over an area of between 10 and 40 cm 2, for example 30 cm 2 in particular and preferably by direct spraying by means of a metering pump of the following type. known and marketed with the aid of propellant such as compressed or liquefied gas.

Although the state of the art claims the opposite, it has surprisingly been observed that a release matrix formed of ethylcellulose does not cause with the composition used bonding obstruction at the outlet of the tip of the spray head, so that the compositions of the invention could be sprayed in the presence of a propellant and without fear of deterioration of the spray container.

It is thus possible to administer the compositions of the invention by spraying from a container provided with a metering valve, containing in addition a propellant gas such as nitrogen or nitrous oxide, or liquefied such as butane or propane.

According to another subject, the invention relates to a matrix intended for cosmetic compositions for 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 dermal absorption of an active ingredient c) a non-aqueous solvent capable of dissolving the release matrix and the dermal absorption promoter as well as being rapidly eliminated by evaporation in contact with the skin d) a propellant gas The matrix polymeric material will be selected from polymeric or copolymeric substances, in particular from cellulosic polymers or copolymers as explained above, while the dermal absorption promoter will be one of

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 aliphatic fatty acid esters or aliphatic fatty alcohols as described above, in particular esters of formula 1 or alcohols of formula II.

When the non-aqueous solvent, it is a compound with a boiling point below 100 C at atmospheric pressure as mentioned above.

These different 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 ingredient, the release matrix represents from 0% to 7%, the dermal absorption promoter represents 15% to 30% and the non-aqueous solvent is 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 selected proportions, the various ingredients constituting them.

The propellant gases 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 undeniable advantages since they are capable of causing the cutaneous diffusion of an active substance, so as to produce constant effective levels and controlled on a prolonged period of at least 12 hours from a skin recovery zone of the order of 10 to 40 cm2.

In addition, the compositions and matrices for dermal compositions according to the invention, while being devoid of any unpleasant odor, are spread out in a homogeneous film over the entire cutaneous zone selected.

These films are sufficiently flexible and resistant to abrasion to avoid any deterioration on the skin of the user and have a better tolerance than the known dermal devices because of their thinness and the absence of any recovery gas exchange and aqueous with the outside are not disturbed.

Finally, the compositions of the invention, in the form of 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 in vivo so as to highlight the characteristics and features of the compositions of the invention.

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 In this case, the active substances used are, for example, Streptomyces sp SEBR 2794 strain extracts, deposited with C. N.C.M. of the Institut Pasteur under the number 1 1332, and the extracts of strain Bacillus licheniformis SEBR 2464, deposited with C. N.C.M. of the Institut Pasteur under number 1778. They will be hereinafter called slimming active substance.

A clinical efficacy study was performed with a slimming composition containing NPY and a2 receptor antagonists. The purpose of this study was to evaluate 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 covers 31 women. Inclusion of the subjects was performed 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 at random, the contralateral leg being taken as untreated control.

The fluid is applied discretely on the entire thigh, from the knee to the gluteal fold.

The application is performed 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 way on the following 4 sites: # external superior lateral surface of the thigh, # internal superior surface of the thigh, # posterior face (gluteal fold), # internal face of the knee.

The amount of film used per day corresponds to two sprays juxtaposed so as to cover the area concerned.

The efficacy evaluation is done at To (before treatment) and at T28 days and uses three different methods: # ultrasound to measure the thickness of the adipose tissue taken on three locations at the thigh level plus one at the level knee.

 # the clinical assessment of the macro-relief (dimpling) of the outer thighs.

 # the image analysis of the relief of the dimples.

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 b) Ultrasound results Table 1 presents the main characteristics of the subjects.

The weight of the subjects was checked at the end of the 28 days of the test. No significant variations were observed, which will confirm the attribution of the observed results to the activity of the products tested.

Table 1: Characteristics of the subjects

<Tb>
<tb> Criteria <SEP> Average <SEP> Maximum <SEP> Values <SEP> Minimum <SEP> Values
<tb> Age <SEP> 37 <SEP> years <SEP> 53 <SEP> years old <SEP> 19 <SEP> years old <SEP>
<tb> BMI <SEP> (a) <SEP> 21.8 <SEP> 26.9 <SEP> 18.5
<Tb>
(a) Body Mass Index Table 2 and Figure 1 express the average decrease in adipose tissue thickness after one month of testing.

According to the zones, a clear 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 as a function of the treated sites (expressed in% of variation with respect to TO)

<Tb>
<tb> Localization <SEP> Processed <SEP> Control <SEP> Tr-Control <SEP> Standard Deviation
<tb> External <SEP> of <SEP> thighs-10.1% <SEP> 0.5% -10.5% * <SEP> 2.8% <SEP>
<tb> Posterior <SEP><SEP> thighs-11.6% <SEP> 0.8% -12.4% * <SEP> 2.4% <SEP>
<tb> Internal <SEP> of <SEP> thighs-11.0% <SEP> -0.7% <SEP> -10.3% * <SEP> ~ 2%
<tb> Internal <SEP> of <SEP> Knees-10.6% <SEP> -1.5% <SEP> -9.1% * <SEP> ~ 1.9%
<Tb>
# S (p 0.05)

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Ces résultats apparaissent très significatifs et ne concernent que le côté traité. Dans le même temps, on observe en effet une bonne stabilité des localisations controlatérales témoins qui présentent des variations non significatives allant de-0,3 à +0,1 mm. Figure 1: Percentage changes between To and T28 days for each location

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

  Clinical evaluation and image analysis The clinical evaluation of the macro-relief is made from photographic images by five evaluators. After random distribution, all the images are scored by the evaluators compared to a standard range (reference photographs), structured around 7 intensity grades.

For five subjects a preliminary profilometric analysis was carried out so as to calculate the average relief of a zone defined on each image and corresponding to a skin surface equivalent to 3x130 mm.

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

This improvement is significant (p 0.05) for thighs treated between TO and T28 j while at the same time, no significant result is obtained on the untreated sides.

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Table 3: Compared results on 5 subjects between clinical evolution and image analysis

<Tb>
<tb> Topic <SEP> Evolution <SEP> Clinical <SEP> Analysis <SEP> of images
<tb> Topic <SEP> (improvement) <SEP>(SEP> mitigation of <SEP> Skin Relief <SEP>)
<tb> 1 <SEP> 30% -35%
<tb> 2 <SEP> 43% -24%
<tb> 3 <SEP> 18% -14%
<tb> 4 <SEP> 18% -22%
<tb> 5 <SEP> 52% <SEP> -11%
<Tb>
The concept of the film was evaluated in a study of 113 women recruited to have cellulite.

The film is applied for 4 weeks with two sprays juxtaposed to cover the area concerned.

The effectiveness of the film is evaluated at the end of the study.

From this study, it appears from the point of view of efficiency that, in a general way, the film allows a significant improvement in the orange skin located at the level of the lower limbs.

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EXAMPLE 1 Dermal composition containing 100 g of a dermal composition of the following formulation:% by weight
Ethyl cellulose 6 mPa.sec 5%
Slimming active ingredients 2%
2-Ethylhexyl 2-ethylhexanoate 20%
Ethanol 73%
Propylene glycol 0.5%
Propellant by stirring for 73 seconds et with magnetic stirring 73 g of ethanol and 20 g of 2-ethyl-hexyl 2-ethyl-hexanoate.

2 g of the thinning substance (s) obtained are then added in small portions and then, after complete dissolution (5 minutes), 5 g of ethylcellulose 6mPa are introduced. dry, with vigorous stirring, to avoid the formation of lumps. The final solution obtained is homogeneous slightly opalescent For the purpose of spray administration, aluminum boxes are filled with 5 ml of the solution previously obtained and provided with a crimped vasopump comprising a push button.

The pump is actuated twice to prime before 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 ingredient, by incorporation, so as to form a cosmetic composition containing 2% by weight of this active agent, which can be applied by spraying.

<Desc / Clms Page number 20>

EXAMPLE 3 Matrix for dermal composition The procedure is as in Example 2, mixing:

<Tb>
<tb> Ingredients <SEP>% <SEP> in <SEP> weight
<tb> Ethanol <SEP> 75 <SEP>
<tb> Isononylisononanoate <SEP> 20
<tb> Ethylcellulose <SEP> 5
<Tb>
EXAMPLE 4 Matrix for dermal composition The procedure is as in Example 2, mixing:

<Tb>
<tb> Ingredients <SEP>% <SEP> in <SEP> weight
<tb> Ethanol <SEP> 80 <SEP>
<tb> Isononylisononanoate <SEP> 15
<tb> Ethylcellulose <SEP> 5
<Tb>
EXAMPLE 5 Matrix for dermal composition The procedure is as in Example 2, mixing:

<Tb>
<tb> Ingredients <SEP>% <SEP> in <SEP> weight
<tb> Ethanol <SEP> 75 <SEP>
<tb> Isononylisononanoate <SEP> 15
<tb> Ethylcellulose <SEP> 5
<tb> Diethylene glycol <SEP> monoethyl ether <SEP> 5
<Tb>
EXAMPLE 6 Matrix for dermal composition The procedure is as in Example 2, mixing:

<Tb>
<tb> Ingredients <SEP>% <SEP> in <SEP> weight
<tb> Ethanol <SEP> 70 <SEP>
<tb> Isononylisononanoate <SEP> 15
<tb> Ethylcellulose <SEP> 5
<tb> Diethylene glycol <SEP> monoethyl ether <SEP> 10
<Tb>

<Desc / Clms Page number 21>

EXAMPLE 7 The following composition is prepared:

<Tb>
<tb> Ingredients <SEP>% <SEP> in <SEP> weight
<tb> Alcohol <SEP> 44,016 <SEP>
<tb> Butane <SEP> 23,20 <SEP>
<tb> Octyloctanoate <SEP> 12.00
<tb> Propane <SEP> 11,20
<tb> Isobutane <SEP> 5.60
<tb> Ethylcellulose <SEP> 3.00 <SEP>
<tb> Panthenol <SEP> 0.30 <SEP>
<tb> Propylene Glycol <SEP> 0.30
<tb> Diethylphthalate <SEP> 0.258
<tb> Sustance <SEP> (s) <SEP> active <SEP> (s) <SEP> slimming <SEP> (s) <SEP> 0,126
<Tb>

<Desc / Clms Page number 22>

Table A: Composition of the formulations

<Tb>
<tb> Reference <SEP> formulation <SEP>: <SEP> A <SEP> B <SEP> R <SEP> C <SEP> D <SEP> E <SEP> F <SEP> G <SEP>
<tb> aX <SEP> BV <SEP> VIII <SEP> 1001 ..
<Tb>

Percentage
<tb> ETHANOL <SEP> 95 <SEP> 77 <SEP> 76 <SEP> 75 <SEP> 67 <SEP> 66 <SEP> 18
<tb> ISOPROPANOL <SEP> 54 <SEP> 74 <SEP> 74
<tb> DRAGOXAT <SEP> EH <SEP> 20 <SEP> 20 <SEP> 20 <SEP> 30 <SEP> 30 <SEP> 25 <SEP> 20 <SEP> 20
<tb> ETHYLCELLULOSE <SEP> 7mPa. <SEP> s. <SEP> 3 <SEP> 4 <SEP> 5 <SEP> 3 <SEP> 4 <SEP> 3 <SEP> 5 <SEP> 5
<tb> Silicone <SEP> DC <SEP> 556 <SEP> 1
<tb> Paraffin <SEP> liquid <SEP> mild <SEP> 1
<Tb>
Recall of the reference formulation:
Ethanol 95: 75% Dragoxat: 20
Ethylcellulose: 5

<Desc / Clms Page number 23>

Table B: Classification of the Evaluation of Excipients Against the Reference Formulation

<Tb>
<tb> CRITERIA <SEP> Assessment <SEP> Sticky <SEP> Penetration <SEP> Glossiness <SEP> Fat <SEP> Residue <SEP> Odor
<tb> global <SEP> skin
<tb> EFFECT <SEP> BY <SEP> REPORT <SEP> A <SEP> THE <SEP> REFERENCE
<tb> (+ Better, -Less <SEP> Well, <SEP> Equivalent)
<tb> EXCIPIENTS
<tb> Isopropanol <SEP> = <SEP> = <SEP> = <SEP> = <SEP> =
<tb> 3% <SEP> ethyl <SEP> + <SEP> + <SEP> + <SEP> + <SEP> + <SEP> + <SEP> +
<tb> cellulose
<tb> 4% <SEP> ethyl
<tb> cellulose <SEP> = <SEP> = <SEP> = <SEP> = <SEP> = <SEP> = <SEP> =
<tb> 25% <SEP> Dragoxat <SEP> - <SEP> - <SEP> - <SEP> -
<tb> 30% <SEP> Dragoxat <SEP> - <SEP> - <SEP> - <SEP> -
<Tb>

<Desc / Clms Page number 24>

1. A composition for dermal administration characterized in that it comprises: a) optionally a polymeric release matrix capable of forming a flexible film after drying, chosen from cellulose polymers or copolymers; (b) an active ingredient; c) 5 to 30%, relative to the weight of the composition, of a transcutaneous absorption promoter of the active principle, d) a non-aqueous solvent, capable of dissolving the release matrix, the active principle and the promoter of dermal absorption as well as being rapidly eliminated by evaporation on contact with the skin, the dermal absorption promoter being chosen from: # an aliphatic fatty acid ester soluble in the physiologically acceptable nonaqueous solvent and of general formula:
O #
RC-OR1 I wherein R represents a linear or branched alkyl or alkenyl group, in
C2-C17 optionally substituted by a hydroxyl, carboxylic or C 1 -C 4 acyloxy group and R 1 represents a linear or branched C 3 -C 8 alkyl group optionally substituted with one or two hydroxyl groups or R 1 represents a -CH 2 -CH 2 -group; O- (CH 2) 2 -O-CH 2 -CH 3, the aliphatic fatty acid ester having 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
R2-OH II wherein R2 is a C1-C20 alkyl group. e) at least one propellant gas 2. Composition according to claim 1 characterized in that the polymeric release matrix is present in a proportion of 0% to 7% of the weight of the composition.

3. Composition according to claim 2 characterized in that the polymeric salting matrix is present in a proportion of 1% to 5% of the weight of the composition.

Claims (31)

4. Composition according to one of claims 1 to 3 characterized in that the active ingredient is present in a proportion of 0.1% to 20% of the weight of the composition. 5. Composition according to one of claims 1 to 4 characterized in that the dermal absorption promoter is present in a proportion 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 a proportion of 44% to 84.9% of the weight of the composition. 7. Composition according to one of claims 1 to 6 characterized in that the polymeric salting matrix is a cellulosic polymer or copolymer soluble in the non-aqueous solvent. 8. Composition according to claim 7 characterized in that the cellulose 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 ingredient is a slimming active substance antagonist NPY receptor and / or a2 receptor. 11. Composition according to one of claims 1 to 10 characterized in that the active ingredient is selected from extracts obtained by fermentation of a microorganism. 12. Composition according to claim 11, characterized in that the active substances are present in a proportion 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 a proportion 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 α2 antagonist, characterized in that the active substances used are the strain extracts. <Desc / Clms Page number 26> Streptomyces sp SEBR 2794, deposited with C. N.C.M. of the Institut Pasteur under the number 1 1332, and the extracts of strain Bacillus licheniformis SEBR 2464, deposited with 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 R1 represents an isopropyl group, 2-ethyl-hexyl or 1,2-dihydroxy-ethyl. 16. A composition according to claim 1 characterized in that the dermal absorption promoter is chosen from: 2-ethyl-hexyl 2-ethyl hexanoate # isopropyl myristate # diethylene glycol monoethyl ether myristate # palmitate isopropyl # 2-octyldodecanol # 2-ethylhexyl undecylenate # 2-ethylhexyl succinate # 2-ethylhexyl # 12-hydroxystearate # 12-acetylstearate 2-ethylhexyl # isostearate of glycerol # hexyl laurate. 17. A composition according to claim 1 or 15 characterized in that the dermal 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 of less than 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. <Desc / Clms Page number 27> 21. A composition according to claim 1, characterized in that: # the cellulosic polymer or copolymer is ethylcellulose # the active substance is a slimming active substance # the cutaneous absorption promoter is 2-ethyl-2-ethyl hexanoate hexyl # the solvent is ethanol.  # the propellant is butane. 22. Composition according to claim 21, characterized in that it comprises: # 3% of ethylcellulose; # 2% slimming substance (s); # 20% 2-ethyl-hexyl 2-ethylhexanoate; and # 75% of ethanol # propellant 23. Composition according to claim 1 characterized in that it comprises: # 5% of ethylcellulose; # 2% slimming substance (s); # 20% 2-ethyl-hexyl 2-ethyl hexanoate, and # 73% ethanol.  # propellant 24. Composition according to claim 1 characterized in that it comprises: # 5% ethylcellulose; # 2% slimming substance (s); # 20% 2-ethyl-hexyl 2-ethylhexanoate; and # 74% ethanol.  Propellant 25. Composition according to Claim 1, characterized in that it comprises: # 2% of ethylcellulose; # 1% slimming substance (s); # 20% 2-ethyl-hexyl 2-ethylhexanoate; and # 77% ethanol.  # propellant <Desc / Clms Page number 28>  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 gas. 27. Composition according to one of claims 1 to 26 characterized in that it is applied to a cutaneous area of 10 to 40 cm2. 28. Matrix for a 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 cellulose polymers or copolymers ; b) 15 to 30%, based on the weight of the composition, of a dermal absorption promoter of the active principle; c) a non-aqueous solvent capable of dissolving the release matrix and the dermal absorption promoter as well as being rapidly eliminated by evaporation in contact with the skin, the dermal absorption promoter being chosen from: # an ester of aliphatic fatty acid soluble in the physiologically acceptable nonaqueous solvent and of general formula: O # In which R represents a linear or branched C 2 -C 17 alkyl or alkenyl group optionally substituted with a hydroxyl, carboxylic or C 1 -C 4 acyloxy group and R 1 represents a linear or branched C 3 -alkyl group; C8 optionally substituted by one or two hydroxyl groups or R1 represents a group -CH2-CH2-O- (CH2) 2 -O-CH2-CH3, the aliphatic fatty acid ester having a minimum of 10 carbon atoms and a maximum of 2 hydroxyl groups # an aliphatic fatty alcohol, soluble in the non-aqueous solvent of general formula: R2-OH II in which R2 represents a C10-C20 alkyl group d) a propellant gas <Desc / Clms Page number 29>  29. Matrix for composition according to claim 28 characterized in that the cellulose 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 dermal absorption promoter is selected from: 2-ethyl-hexyl 2-ethyl hexanoate # isopropyl myristate # myristate diethylene glycol monoethyl ether # isopropyl palmitate # 2-octyldodecanol # 2-ethyl-hexyl undecylenate # 2-ethylhexyl succinate # 12-hydroxy-2-ethylhexyl stearate # 12-acetoxy-stearate 2 ethyl-hexyl # glycerol isostearate # hexyl laurate. 32. Matrix for composition according to claim 31 characterized in that the dermal absorption promoter is 2-ethyl-hexyl 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 of boiling point below 100 C is dichloromethane, ethanol, isopropanol or ethyl acetate. 35. Matrix for a dermal composition according to claim 33, characterized in that the compound with a boiling point of less than 100 ° C. is ethanol. <Desc / Clms Page number 30>  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 dermal absorption promoter represents 15% to 30% and the non-aqueous solvent is 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.