HK1091151B - Cosmetic use of a composition containing at least one oxazoline, serving as an active substance, as a slimming product and/or for preventing and/or treating cellulite - Google Patents

Description

The present invention relates to the use of a cosmetic composition with a slimming effect, including at least one oxazoline as an active ingredient. The present invention also relates to the use of such a composition to prevent and/or treat cellulite.

The thinning in the present invention is preferably by the control of localized overweight.

Odiposity, or excess fat in the subcutaneous tissue of cells, can have many causes, more or less complex, more or less known or more or less understood.

The adipose tissue, a special variety of connective tissue, is made up of adipocytes, separated by walls, themselves bounded by connective-vascular spans.

The adipocytes contain varying amounts of fat in the form of triglycerides, which are synthesized in vivo by the adipocytes themselves by enzymatic reactions from the free fatty acids and glycerol, the breakdown product of glucose, contained in the body and supplied to it by the diet. At the same time, the triglycerides thus formed and stored in the adipocytes can also be re-composed, again under the action of specific enzymes contained in these cells, by releasing fatty acids on the one hand and glycogen and/or triglycerides and/or glycogen diuretics on the other. The fatty acids can then be either consumed or reused in the body in a different way, either to be converted into fat or to be re-generated by the adipocytes, this time in a different way, and this time by triglycerides and/or mono- and/or di-fluoric acid.

The adipocytes, which thus play a vital role in the synthesis of lipids, their storage and release into the blood, are regulated by lipogenesis, which is the formation of triglycerides by enzymatic reaction between fatty acids and glycerol from glucose, and lipolysis, which is the enzymatic breakdown of triglycerides into fatty acids and glycerol.

These changes are controlled by mediators such as adrenaline, estrogen, which will block or not block lipids in adipocytes, alpha receptors, which block lipolysis, and beta receptors, which facilitate lipolysis.

Cellulite, or localized lipodystrophy, is characterized by an edematosis infiltration of the fat tissue that alters the aesthetics and harmony of the figure.

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This cellulite is not exclusive to men but is much more common in women, whether thin or round, and is found mainly in the lower half of the body, in the hips, thighs, belly, knees and ankles.

Cellulite is caused by a storage of triglycerides in adipocytes, which can increase in volume considerably, as these cells can reach, depending on the circumstances, 40 μm to 120 μm in diameter, i.e. an increase of 27 times in volume, and an increase in the viscosity of the basic substance of the dermis, which results in water retention and decreased cell exchange.

Some of the ways to prevent cellulite include: The following are the main effects of the drug on the body: decrease triglyceride formation; i.e. decrease lipogenesis; and/or increase lipolysis; and/or restore active and regular microcirculation; and/or eliminate edema.

Because of the severe physical, cosmetic, and sometimes psychological discomfort suffered by sufferers, especially women, localized overweight and cellulite are now less tolerated or accepted.

Methods have already been proposed to treat localized overweight and cellulite, some of which rely on surgical treatments such as liposuction, and which currently provide truly satisfactory results.

There are also many slimming and/or anti-cellulite cosmetics on the market. Examples of commonly used active substances include plant extracts, such as caffeine extracts, Gingko biloba, queen of spruce, Centalla asiatica, arnica, cola nuts, fracon, climbing ivy, rosemary, soursop, ginseng, millepertius, orthophosphates, brown algae, red algae, birch, which are lipolytic agents, and sphingosine and rutine, extracted from Ruta graveolens, which are lipoprotective agents.

Lipolytics work by removing excess fat (lipolysis) and liporeductors fight fat formation (lipogenesis).

These agents are most commonly administered topically, but may also be administered by bone.

In addition to these specific agents, there are disinfectants, such as virbunum, wild pineapple, and venotonic agents, such as ruscus, scine, which are often associated with slimming agents.

Finally, formulations containing these known slimming and/or anti-cellulite agents can be supplemented with restructuring and smoothing agents that fight against loosening of the skin.

The cosmetics industry is constantly looking for new molecules or extracts which are effective in combating adiposity in humans and animals, particularly with a view to achieving a general or a local effect of thinning and/or refinement of the skin or figure.

In its French patent application No 01/16917, the applicant describes the use of oxazolines, which allow the inhibition of the migration of Langerhans cells.

The applicant thus describes a medicinal product, containing at least one oxazoline as the active substance, intended for the treatment or prevention of allergic and/or inflammatory and/or irritant reactions of the skin and/or mucous membranes.

US Patent Application 4 876 249 describes compositions containing oxazolins, in which oxazolins are promoters of the penetration of physiologically active agents through the stratum corneum layer of the skin.

Surprisingly, the Applicant found that oxazolins are also able to inhibit lipogenesis in human adipocytes.

The applicant thus discovered that a composition containing at least one oxazoline as the active substance can be used as a slimming composition and/or to prevent and/or treat cellulite.

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According to an advantageous mode of the present invention, the oxazoline is a type 1 oxazoline selected from the group consisting of 2-undecyl-4-hydroxymethyl-4-methyl-1,3-oxazoline, 2-undecyl-4,4-dimethyl-1,3-oxazoline, (E)-4,4-diniethyl-2-heptadec-8-enyl-1,3-oxazoline, 4-hydroxymethyl-4-methyl-2-heptadec-1,3-oxazoline, the (E)-4-hydroxymethyl-4-methyl-2-heptadec-8-enyl-1,3-oxazoline, the formula 2-undecyl-4-hydroxymethyl-1,3-oxazoline. The advantage of this oxazoline is that it is called 2-undexymethyl-4-hydroxymethyl-1,3-oxazoline, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1, 2-undexymethyl-1,3-oxazoline, 2-undexymethyl-1, 2-undexymethyl-1, 2-deoxymethyl-1, 2-deoxymethyl-1,3-oxazoline, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy, 2-deoxy - What?

Many synthesis routes are known to prepare the compounds oxazolines according to the invention. For example, these can be prepared by chemical synthesis by reacting a fatty acid (or a methyl ester) and an amino alcohol, most often in the presence of an azootropic agent to promote the removal of the formed water (and the formed methanol). Another possible synthesis route is to condense a halo-amide in the presence of a strong base or sodium carbonate (R. M. Chemskin, J. Amer. Lusyam. Soc., 72, (1950), 5577).

The expression slimming or combating localized overweight is used to describe an action to prevent or at least reduce the formation of subcutaneous fat as described above, such as reducing unsightly overloads or reserves, finishing the figure, accelerating the elimination of excess weight, improving body contour or reshaping the figure.

The method of cosmetic treatment for the control of localized overweight means, according to the present invention, the implementation of a cosmetic treatment that allows the action described above to be visibly measured.

Thus, a topical composition containing one or more of the oxazolines of the invention may be applied to areas of the skin likely to form these localized weight overloads, i.e. areas where these overloads are already formed or are in the process of formation.

The cosmetic composition of the invention is characterised by the advantageous concentration of oxazoline between about 0,01 and about 10% by weight, and more advantageously between about 0,01 and about 3% by weight, in relation to the total weight of the composition.

The composition of the invention includes a cosmetically acceptable medium, i.e. a skin-compatible medium, and may be in all the galenic forms normally used for topical application, including aqueous, hydroalcoholic or oily solution, oil-in-water or water-in-oil or multiple emulsion, aqueous or oily gel, liquid, paste or solid anhydrous product; dispersion of oil in an aqueous phase by means of spherules, these spherules being polymeric nanoparticles such as nanospheres and nanocapsules or better lipid-type ionic or non-ionic transmixtures, where any other topical application is desirable.

This composition may be more or less fluid and may be in the form of a white or coloured cream, ointment, milk, lotion, serum, paste, foam or gel.

It may be applied to the skin as an aerosol, or in solid form, such as a stick, or as a patch.

The cosmetically acceptable medium is preferably an oily solution, an oil-in-water emulsion, an oil-in-water emulsion, a microemulsion, an oil gel, an anhydrous gel, a dispersion of vesicles, microcapsules or microparticles, a transdermal device

The composition of the invention may also contain adjuvants commonly used in cosmetics, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active substances, thickeners, preservatives, antioxidants, solvents, perfumes, chelating agents, odor absorbers, chemical or mineral filters, mineral pigments, surfactants, polymers, silicone oils and dyes. The quantities of these adjuvants are those typically used in the various fields, e.g. from 0.01 to 20% of the total weight of the composition. These adjuvants, depending on their nature, may be introduced into the grease phase, the grease phase, the vesicles or into nanoparticles and water.

When the composition of the invention is an emulsion, the proportion of the fatty phase may range from 5 to 80% by weight, and preferably from 5 to 50% by weight of the total composition. The oils, emulsifiers and co-emulsifiers used in the composition in the form of emulsion are selected from those traditionally used in the field under consideration. The emulsifier and co-emulsifier are present in the composition in a proportion of 0.3 to 30% by weight, and preferably 0.5 to 20% by weight of the total composition.

The oils used in the compositions to which the present invention relates are mineral oils, oils of vegetable origin (apricot oil, sunflower oil, plum oil), oils of animal origin, synthetic oils, silicone oils and fluorinated oils (perfluoropolyethers).

For emulsifiers and co-emulsifiers used in the invention, examples are fatty acid and polyethylene glycol esters such as PEG-40 stearate, PEG-100 stearate, fatty acid and polyol esters such as glyceryl stearate and sorbitol tristearate.

Hydrophilic gelling agents include carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides, natural rubbers and clays, and lipophilic gelling agents include modified clays such as bentones, metal salts of fatty acids, hydrophobic silica and polyethylene.

The optimal dosage and galenic forms of the compounds and compositions of the invention may be determined according to criteria generally taken into account in the establishment of a cosmetic treatment, preferably dermatological, appropriate to a patient, such as the patient's body weight, excess fat found, appearance of cellulite tissue, tolerance to treatment, skin type.

The composition used according to the invention may contain other slimming agents such as lipolytics and liporeductants as described in the introduction, leading to a complementary or possibly synergistic effect.

The invention relates to the use of oxazolins for the preparation of topical formulations useful for the prevention and/or treatment of cellulite and/or for promoting slimming and in particular for the control of localized overweight, characterised by the simultaneous, separate or spread over time application of one or more oxazolins and one or more lipolytic-type slimming agents and/or one or more liporeductant-type slimming agents.

The lipolytic type of dietary active substance can be selected from: caffeine, rhodesterol, palmitoylcarnitine, alpha and gamma bioactive substances, eschine, ginkgo biloba and sphingosine. The lipoprotective type of dietary active substance can be selected from andiroba, Garcinia Cambogia, rutine.

One or more disinfectant and/or veinotonic agents may also be applied simultaneously, separately or spread over time in addition to the application of the composition used according to the invention.

The composition used according to the invention may also include other active substances such as:An extract of sophora japonica flowers: this extract is rich in flavonoids (anti-radical) and rutine. This active substance promotes microcirculation, facilitating and activating drainage and tissue disinfiltration;Centella asiatica extract: extract of centella, a plant native to East Africa and Madagascar. This active substance contains terpenes (asiaticides, asiatic acid and madacasic acid), with draining, disinfiltrating and tissue-raising properties. It is used in soybean products, but also in anti-aging products, anti-aging and scarring agents; This active substance contains terpenes (asiaticides, asiatic acid and madacasic acid), with anti-inflammatory properties. It is used in soybean products, but also in anti-aging products, scarring and scarring agents. This active substance can be obtained from 5% Hydrolyzine Soy Protein which is a protein-stimulating compound.These soy peptides may be any peptide obtained by hydrolysis of proteins extracted from soy, under operating conditions known to the professional, in other words any hydrolysate of soy protein. The soy peptides described in patent application WO 00/19974 are particularly suitable for introduction into the compositions used in the context of the present invention. This active substance allows the restoration of cell renewal mechanisms, activates the synthesis of structural elements of the extracellular matrix and has a restructuring, regenerative and strengthening action.These include avocado furans, retinol and its derivatives, vitamin C, vitamin E, silicon, or soybean unsaponifiables;smoothing agents, such as AHA;antioxidants;actives capable of blocking the differentiation of pre-adipocytes into adipocytes, including triterpenes;PPAR antagonists (Perozysome Proliferator-Activated Receptor), MMP inhibitors, including lupin peptide extract as described in French patent application FR 2 792 202;thinning agents such as isoflavones,

The present invention also concerns a cosmetic treatment method for promoting thinning, characterized by the topical application of a cosmetic composition containing one or more oxazolins.

Another object of the present invention is a cosmetic treatment method for the prevention and/or treatment of cellulite, characterized by the topical application of a composition containing one or more oxazolins.

The present invention also relates to a cosmetic treatment method for finishing the figure, accelerating the elimination of excess, defining the body contour and/or reshaping the figure, characterized by the topical application of a composition containing one or more oxazolins.

Overweight is characterized, in the present invention, by being overweight, relative to ideal weight , non-pathological. The cosmetic treatment of the invention allows the loss or refinement of unnecessary localized roundness but is not identified with therapeutic treatment.

According to a variant of the invention, in these cosmetic treatment methods, one or more oxazolines and one or more lipolytic and/or lipoprotective-type slimming agents and/or one or more disinfiltrating and/or veinotonic agents are applied topically to areas of skin that are likely to form localized weight overloads, simultaneously, in preparation or over time.

Figures 1 and 2 illustrate the effect of OX100 on the incorporation of radiolabelled acetate into adipocytic lipids.

The following examples illustrate the present invention.

Example 1: oil cream in water

Eau	QSP 100
Squalane	5,00
Petrolatum	5,00
Glycérine	5,00
Isodecyl Neopentanoate	5,00
Pentaerythrityl Tetraethylhexanoate	5,00
Cyclométhicone	4,00
Alcool Cétéarylique	3,00
Myristyl Myristate	2,00
Laureth-23	2,00
Silice	2,00
Furane Heptadécadiénylique	0,1 à 10
Cire d'abeille	1,00
Gomme Sclerotium	1,00
PEG-6	1,00
Polyacrylamide	0,80
Stéarate de Glyceryl	0,70
Diméthiconol	0,70
Glucoside de Cetearyl	0,60
C13-14 Isoparafine	0,40
Acide Citrique	0,14
Laureth-7	0,10
4,5,7-Trihydroxyisoflavone	0,01 à 10
Caféine	0,1 à 10
Extrait de Enteromorpha Compressa	0,01 à 5
Extrait de Garcinia Cambogia	0,01 à 10
Extrait de Ginkgo Biloba	0,01 à 10
Extrait de Fleurs de Sophora Japonica	0,01 à 20
OX100	0,01 à 10
Conservateur	QS
Parfum	QS

QS = quantité suffisante QSP = quantité suffisante pour

Example 2: Cream of water in oil

Eau	QSP 100
Polyisobutène Hydrogéné	7,00
Stéarate Isocétylique	7,00
Cyclométhicone	4,80
Glycérine	4,00
Huile Minérale	3,00
Oxide de Zinc	3,00
Butylène Glycol	2,00
Isononyl Isononanoate	2,00
Cire d'abeille	2,00
Cétyl Diméthicone Copolyol	1,70
Polyglycéryl-4 Isostéarate	1,65
Hexyl laurate	1,65
Disodium tartrate	1,60
Chlorure de Sodium	1,00
PEG-6	1,00
4,5,7-Trihydroxyisoflavone	0,01 à 10
Retinyl palmitate	0,01 à 10
Extrait de Enteromorpha Compressa	0,01 à 5
Extrait de Fleurs de Sophora Japonica	0,01 à 20
Extrait de Centella Asiatica	0,01 à 5
OX100	0,01 à 10
Conservateur	QS
Parfum	QS

QS = quantité suffisante QSP = quantité suffisante pour

Example 3: stick

Huile de Castor	QSP 100
Alcool Oléylique	20,00
Huile de Noyaux de Palme Hydrogénée	17,00
Cire Candelilla	11,00
Polyglyceryl-3 Cire d'Abeille	10,00
Huile Minérale	9,57
Heptadecadienyl Furane	0,1 à 10
Beurre de Karité	2,00
4,5,7-Trihydroxyisoflavone	0,01 à 10
Quaternium-18 Hectorite	1,10
Dioxyde de Titane	1,00
Tocopheryl Acétate	0,50
Propylene Carbonate	0,33
Parfum	QS
Rétinol	0,01 à 10
Extrait de Enteromorpha Compressa	0,01 à 5
Extrait de Fleurs de Sophora Japonica	0,01 à 20
Extrait de Centella Asiatica	0,01 à 5
OX100	0,01 à 10

QS = quantité suffisante QSP = quantité suffisante pour

Example 4: cream gel

Eau	QSP 100
Cyclométhicone	5,40
Octyl Palmitate	5,00
Glycérides de Coco Hydrogénés	3,00
Alcool Béhénylique d'Arachide	2,55
Propylène Glycol	2,50
Isodécyl Néopentanoate	2,00
Stéarate de Glycéryle	1,70
Alcool Cétylique	1,30
Acide Stéarique	1,00
PEG-6	1,00
Cire d'Abeille	0,40
C13-14 Isoparafine	0,40
Butylène Glycol	0,16
Glycérine	0,16
Alcool Cétéarylique	0,10
Cetyl Palmitate	0,10
Cocoglycérides	0,10
Laureth-7	0,10
4,5,7-Trihydroxyisoflavone	0,01 à 10
Extrait de Enteromorpha Compressa	0,01 à 5
Extrait de Fleurs de Sophora Japonica	0,01 à 20
Extrait de Centella Asiatica	0,01 à 5
OX100	0,01 à 10
Conservateur	QS
Parfum	QS

QS = quantité suffisante QSP = quantité suffisante pour

Example 5: spray

Eau	QSP 100
Glycérine	4,00
Montmorillonite	3,00
PEG-6	3,00
Glycine	0,30
Acide Citrique	0,09
4,5,7-Trihydroxyisoflavone	0,01 à 10
Extrait de Enteromorpha Compressa	0,01 à 5
Extrait de Fleurs de Sophora Japonica	0,01 à 20
Extrait de Centella Asiatica	0,01 à 5
OX100	0,01 à 10
Conservateur	QS
Parfum	QS

QS = quantité suffisante QSP = quantité suffisante pour

Example 6: Assessment of lipid synthesis in suspended adipocytes Test product

A solution of OX100, diluted to a concentration of 10-2 M in DMSO, was tested.

Conditions of cultivation

Normal human adipocytes were isolated from abdominal biopsies (plastic surgery). Immediately after receipt, the samples are incubated for 30 minutes at 37°C in the presence of collagenase (provided by Sigma). The adipocytes suspension is then rinsed and diluted three times in the culture medium. 1.87 mg/ ml bicarbonate (provided by Life Technologies),25 IU/ ml/ 25μg/ ml penicillin/ streptomycin (provided by Life Technologies),2 mM glutamine (provided by Life Technologies),100% w/ v MEM (provided by Merck Eurolab), and0.5% w/ v bovine albumin (provided by Sigma).

The test chemical is used to determine the concentration of the active substance in the blood.

The adipocytes in suspension are incubated for 1 hour at 37°C in the presence of different concentrations of OX100. The OX100 concentrations tested are 20 μM, 4 μM and 0.8 μM. A volume of 10 ml of radiolabelled acetate (2-C14, 60.87 μCi/ml, supplied by Amersham) is then added to the preparation. After 4 hours of incubation, the lipids are extracted by the procedure described by Bligh and Dyer, Can J Biochem Physiol, 37, 922, (1959), (methanol/chloroform/water), evaporated under nitrogen and the incorporated radioactivity has been quantified by liquid scintillation (Liquid Scintillation Reference LKB 1210 provided by Rackbeta). The possible interaction between the radio-labelled acetate and OX100 was evaluated to confirm the specificity of the labelling by incubating the highest concentration of OX100 (20 μM) with acetate alone.

Results

The OX100 does not cause any interference with the radio-marking. After 4 hours of incubation, C14 uptake was high in control adipocytes (185 000 cpm). The reference molecule, cerulin (FAS inhibitor, Fatty Acid Synthase) tested at 10 μM inhibits acetate incorporation (95% inhibition/control). OX100 at 20 and 4 μM decreases acetate incorporation by 31 and 25% respectively in the control (Figure 1). It was shown quite unexpectedly that OX100 is able to inhibit lipogenesis in human adipocytes.

Example 7: Assessment of lipid synthesis in suspended adipocytes Test product

A solution of OX100 (10-2 M in DMSO) was tested.

Growing conditions: identical to example 6

The test chemical is used to determine the concentration of the active substance in the blood.

The adipocytes in suspension are incubated for 1 hour at 37°C in the presence of different concentrations of OX100 (10, 20 and 100 μM). A volume of 10 ml of radio-labelled acetate (2-C14, 60.87 μCi/ml, Amersham) is then added to the preparation. After 4 hours of incubation, the lipids are extracted according to the procedure described by Bligh and Dyer (methanol/chloroform/water), evaporated under nitrogen and the incorporated radioactivity quantified by liquid scintillation (LKB 1210 Rackbeta).

Results

The OX100 does not cause any interference with the radio-marking. The reference molecule, cerulin (FAS inhibitor, Fatty Acid Synthase) tested at 10 μM inhibits acetate incorporation (75% inhibition/control). OX100 tested at 10, 20 and 100 μM significantly decreases lipid acetate incorporation (35, 38 and 39% of the control, respectively; Figure 2).

OX100 has shown significant inhibitory activity of lipid synthesis, and is therefore able to inhibit lipogenesis in cultured human adipocytes.

Claims (9)

1. Cosmetic use of a composition containing at least one zoline, serving as an active substance, as a slimming product.
2. Cosmetic use of a composition containing at least one zoline, serving as an active substance, for preventing and/or treating cellulite.
3. Cosmetic use according to either one of Claims 1 and 2, characterized in that said oxazoline corresponds to the general formulae below: in which R₁ represents a linear or branched, saturated or unsaturated C₁-C₄₀ alkyl group optionally comprising one or more ethylenic unsaturation(s) and also one or more substituent(s) chosen from the group formed by hydroxyl (OH) and C₁-C₆ alkoxy (OC₁-C₆) radicals; R₂, R₃, R₄ and R₅ represent, independently, a hydrogen atom, a hydroxyl radical, or a linear or branched, saturated or unsaturated C₁-C₃₀ alkyl group optionally comprising one or more ethylenic unsaturations and also one or more substituent(s) chosen from the group formed by hydroxyl (OH), C₁-C₆ alkoxy (OC₁-C₆) and C₁-C₆ alkoxy carbonyl (COOC₁-C₆) radicals.
4. Cosmetic use according to any one of preceding claims, characterized in that said oxazoline is a type 1 oxazoline selected from the group composed of 2-undecyl-4-hydroxymethyl-4-methyl-1,3-oxazoline, 2-undecyl-4,4-dimethyl-1,3-oxazoline, (E)-4,4-dimethyl-2-heptadec-8-enyl-1,3-oxazoline, 4-hydroxymethyl-4-methyl-2-heptadecyl-1,3-oxazoline, (E)-4-hydroxymethyl-4-methyl-2-heptadec-8-enyl-1,3-oxazoline and 2-undecyl-4-ethyl-4-hydroxymethyl-1,3-oxazoline.
5. Cosmetic use according to any one of the preceding claims, characterized in that said oxazoline is 2-undecyl-4,4-dimethyl-1,3-oxazoline, called OX100, of formula:
6. Cosmetic use according to any one of the preceding claims, characterized in that the composition comprises between 0.01 and 10% by weight of oxazoline, advantageously between 0.01 and 3% by weight of oxazoline, relative to the total weight of the composition, and a cosmetically acceptable medium.
7. Cosmetic use according to any one of the preceding claims, characterized in that one or more oxazolines and also one or more slimming active agents of lipolytic type and/or one or more slimming active agents of liporeducing type are applied simultaneously, separately or spread out over time.
8. Cosmetic use according to any one of the preceding claims, characterized in that one or more anti-infiltration and/or venotonic active agents are also applied simultaneously, separately or spread out over time.
9. Cosmetic use according to any one of the preceding claims, characterized in that the composition is for topical application.