WO2017158285A1

WO2017158285A1 - New cosmetic weight loss compositions

Info

Publication number: WO2017158285A1
Application number: PCT/FR2017/050585
Authority: WO
Inventors: Yves Le Guen; Guy Piacenza
Original assignee: Pharmasynthese
Priority date: 2016-03-16
Filing date: 2017-03-15
Publication date: 2017-09-21
Also published as: FR3048878A1; FR3048878B1

Abstract

The invention relates to new cosmetic compositions comprising: - at least two (L)-carnitine esters of general formula (I); and - a methylxanthine selected from among caffeine, theophylline and theobromine.

Description

NEW SLIMMING COSMETIC COMPOSITIONS

The present invention relates to novel cosmetic compositions comprising at least two esters of (L) -carnitine and a methylxanthine, and the use of these compositions for a cosmetic slimming treatment.

In the cosmetic field, there are many products known as "slimming" aimed in particular to fight against cellulite. Cellulite, or superficial lipodystrophy, is a physiological variation in the distribution of fat, increased at the level of the hypodermis of the thighs, buttocks and hips, which gives the skin a padded appearance called "orange peel" with a flaccid and untied consistency. Cellulite thus consists of large adipocytes, located under the skin, which gorget fat and hypertrophy. The inflated fat cells squeeze the blood and lymphatic vessels, resulting in poor elimination of toxins and liquids. The development of fat cells and connective cells located under the skin promotes cellulite. Adipocytes are spherical cells whose intercellular space is filled by a vacuole filled with triglycerides. These cells can grow to multiply their size by 50 (hypertrophic phase). The adipocyte is able to store (lipogenesis) or mobilize (lipolysis) triglycerides, which are an energetic source of the body.

Lipogenesis is a synthesis phase in the energetic reserve process of adipocytes that store free fatty acids as triglycerides. Conversely, lipolysis is the degradation of lipids that leads to the release of fatty acids esterifying glycerol by hydrolysis of triglycerides. This reaction is catalyzed by lipases. Fatty acids from lipolysis are then metabolized by a beta oxidation mechanism in mitochondria and by another mechanism called ketogenesis. When the storage of fat is more important than the elimination, lipogenesis-lipolysis balance is broken which leads to the development of cellulite. In the context of a slimming cosmetic treatment, it is therefore advantageous to reduce the storage of fat in adipocytes by inhibiting lipogenesis to promote lipolysis. In the adipocyte, triglycerides are progressively degraded into free fatty acids and glycerol. This degradation is carried out according to the following three enzymatic reactions:

Triglycerides lipase

Triglycerides ► Diglycerides + Fatty acids

Lipase diglycerides

Diglycerides ► Monoglycerides + Fatty acids

Monoglycerides lipase

Monoglycerides ► Glycerol + Fatty Acids

While the monoglyceride lipase and the diglyceride lipase intervening in this reaction chain are still active, the triglyceride lipase needs to be activated by phospho-regulation. The enzyme that catalyzes this phosphorylation is called Kinase A protein for cAMP dependent protein kinase. Thus, any increase in cAMP levels in the adipocyte will result in an increase in lipolysis.

However, since these reactions correspond to reaction equilibria, they can participate in triglyceride degradation as well as in their formation, the "sense" of the system depending on the amount of triglycerides and free fatty acids present in the cell.

Many triglycerides and few free fatty acids will cause lipolysis while few triglycerides and many free fatty acids will favor lipogenesis.

To be effective, a slimming product should therefore induce an increase in intracellular levels of cAMP and / or be able to reduce the amounts of free fatty acids present in the adipocyte. Carnitine is a compound comprising a quaternary ammonium function, bio-synthesized from lysine and methionine and having the following chemical structure:

Carnitine intervenes within the cell in the transport of fatty acids from the cytosol to the mitochondria during catabolism of lipids in energy metabolism. Carnitine has two stereoisomers: (L) -carnitine and D-carnitine. (L) -carnitine is biologically active while D-carnitine is inactive.

Caffeine, also referred to as theine, guaranine, 1,3,7-trimethylxanthine or methyltheobromine, is an alkaloid of the methylxanthine family, present in many foods, which acts as a psychotropic stimulant and a mild diuretic. It is also frequently used in cosmetics in slimming compositions.

The patent application FR2654619 describes a cosmetic composition comprising one or more L) -carnitine esters of general formula

wherein R is a saturated aliphatic chain of 2 to 22 carbon atoms such as acetyl, hexanoyl, octanoyl, lauroyl, myristoyl, palmitoyl, steroyl or arachidoyl, said composition providing improved penetration of the active ingredients. The patent application FR2654618 describes the cosmetic use of (L) - carnitine esters of general formula

wherein R is a saturated or unsaturated aliphatic chain of 12 to 22 carbon atoms for regulating the activity of protein kinase C.

The application FR2694195 describes a cosmetic composition comprising a mixture of coenzyme A, palmitoylcarnitine and caffeine for the slimming treatment. None of these applications describes the use of at least two (L) -carnitine esters combined with caffeine for a cosmetic slimming treatment.

Now, it has now been found, quite surprisingly, that there is a synergistic effect between certain (L) -carnitine esters and caffeine, and that the combined cosmetic use of these two active agents by the topical route makes it possible to significantly improve the functionality of adipose tissue by decreasing fat storage by activating lipolysis and limiting water retention, thereby producing a significant slimming effect.

Thus, the present invention relates to a cosmetic composition for a topical application comprising:

at least two (L) -carnitine esters of general formula (I)

X ^" is an addition salt chosen from the following salts: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulphonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulphonate, methylene-bis-b-oxynaphthoate, nitrate, oxalate, palmoate, phosphate, salicylate, sulfate, tartrate, theophyllinacetate and p-toluenesulfonate;

and a methylxanthine chosen from caffeine, theophylline and theobromine.

The cosmetic compositions according to the present invention have never been described before. Their topical application significantly improves the functionality of adipose tissue by decreasing the storage of fat by activation of lipolysis and limiting water retention, thus producing a significant slimming effect. In addition, a synergistic action has been observed between mixtures of (L) -carnitine esters and methylxanthine, in particular caffeine. In the context of the present invention:

the term "C _x -C _y -alkyl" means a saturated hydrocarbon chain, linear or branched, and comprising from x to y carbon atoms;

the term "C _x -C _y -alkenyl" _is understood _to mean a linear or branched unsaturated hydrocarbon-based chain containing at least one double bond and containing from x to y carbon atoms;

"Caffeine" means the compound registered under CAS No. 58-08-2 and having the name IUPAC 1,3,7-trimethyl-1H-purine-2,6 (3H, 7H) -dione;

"Theophylline" means the compound registered under the CAS number 58-55-9 and having the name IUPAC 1,3-dimethyl-7H-purine-2,6-dione;

"Theobromine" means the compound registered as CAS 83-67-0 and having the name IUPAC 3,7-dimethyl-1H-purine-2,6-dione;

- "esculin" means the compound registered as CAS RN 531-75-9 and having the name IUPAC 7-hydroxy-6 - {[(2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy- 6- (hydroxymethyl) -2-tetrahydropyranyl] oxy} -2-chromenone;

the term "slimming effect" is understood to mean any reduction in the volume of the hypodermic adipose tissue and / or reduction of stretch marks or the "orange peel" appearance of the cutaneous tissue; and

the term "cosmetic slimming treatment" is intended to mean any cosmetic treatment comprising the topical application of one or more active ingredients with a view to obtaining a slimming effect. In addition, in the context of the present invention, unless otherwise stated, the proportions expressed in% correspond to percentages by weight relative to the total weight of the entity (eg cosmetic composition) considered. The cosmetic composition according to the present invention contains at least two (L) -carnitine esters of general formula (I) as defined above. Preferably, the subject of the present invention is a cosmetic composition comprising at least two (L) -carnitine esters of general formula (I) as defined previously in which R is chosen to be a C ₆ -C ₂₈ -alkyl group or C ₆ -C ₂ 8-alkenyl; more preferably C ₇ -C ₂₆ alkyl or C ₇ -C ₂₆ alkenyl; more preferably as C ₈ -C ₂₄ -alkyl or C ₈ -C ₂₄ -alkenyl. So Most preferably, R is selected from the following linear hydrocarbon chains: Ci ₆ H _32, C ₈ H _30, C ₈ H _32, C ₈ H ₃₄ and C ₈ H _36.

Most preferably, the subject of the present invention is a cosmetic composition comprising at least three (L) -carnitine esters of general formula (I) as defined above, more preferably at least four esters of (L) - carnitine of general formula (I) as defined above, very preferably at least five esters of (L) -carnitine of general formula (I) as defined above. An example of a preferred composition according to the present invention comprises a mixture of four (L) -carnitine esters of general formula (I) as defined previously in which R is chosen from the following linear hydrocarbon chains: Ci ₆ H ₃₂ , Ci ₈ H _32, C ₈ H ₃₄ and C ₈ H _36. Another example of a preferred composition according to the present invention comprises a mixture of five (L) -carnitine esters of general formula (I) as defined previously in which R is chosen from the following linear hydrocarbon chains: Ci ₆ H ₃₂ , Ci ₈ o H _3, C ₈ H _32, C ₈ H ₃₄ and C ₈ H _3. 6

The cosmetic composition according to the present invention contains at least two (L) -carnitine esters of general formula (I) as defined above and a methylxanthine chosen from caffeine, theophylline and theobromine. Preferably, the subject of the present invention is a cosmetic composition as defined above in which the following characteristics are chosen alone or in combination:

X ^" is chosen as being a hydrochloride salt;

methylxanthine is chosen as being caffeine;

the composition contains from 0.05% to 5% of (L) -carnitine ester (s), more preferably from 0.05% to 2% of (L) -carnitine ester (s); the composition contains from 1% to 10% of methylxanthine, more preferably from 1% to 5% of methylxanthine;

the composition also contains one or more active agents capable of improving the vascularization of the skin chosen from esculin, aescin, ruscogenin, red vine, green tea and gotu kola; more preferably the composition contains esculin;

the composition contains from 0.05% to 5% of active agent capable of improving the vascularization, more preferably from 0.05% to 2% of active agent capable of improving vascularization.

The compounds of formula (I) may be prepared by any method known and conventionally used by those skilled in the art, especially any synthesis process associating (L) -carnitine with various fatty acids derived from the saponification of natural vegetable oils, in particular vegetable oils selected from the oils of sweet almond, argan, sea buckthorn, avocado, babassu, baobab, wheat, borage, broccoli, camellia, camelina, safflower, blackcurrant , hemp, Chaulmoogra, rapeseed, cucumber, poppy, crambe, black cumin, cuphea, desert date palm, raspberry, pomegranate, kakia, shea, kukui, macadamia, meadowfoam, hazelnut, evening primrose, papaya, grape seed, plum, castor, sesame, tamanu and tomato.

By way of example, the compounds of formula (I) according to the present invention can be obtained according to the following reaction scheme:

a) Obtaining vegetable oil fatty acids

Mixed

Natural vegetable oil Glycerol

of fatty acids

The vegetable oil is placed in the presence of aqueous sodium hydroxide solution and ethanol. The saponification reaction is followed by an acidification reaction, extraction, washing with water and concentration in vacuo. RCOCI + S0 ₂ + HCI

DMF

The synthesis of fatty acid chlorides is carried out in inert solvents such as methylene chloride, cyclopentyl methyl ether, ethyl acetate, acetonitrile, toluene, chlorobenzene, tert-butyl methyl ether. c) Condensation with (L) carnitine hydrochloride

Strong organic acid

RCOCI + (L) -carnitine, HCI

The condensation is carried out in the presence of strong organic acid chloracetic acid or trichloroacetic acid.

The cosmetic compositions according to the present invention may be formulated in any dosage form suitable for topical administration thereof. The compositions according to the present invention can thus be formulated as cream, gel, lotion, milk, oil-in-water emulsion or water-in-oil, solution, ointment, spray or body oil.

For the preparation of these cosmetic compositions according to the present invention, one or more compounds of formula (I) and one or more active agents capable of improving the vascularization of the skin as defined above are mixed with the excipients conventionally used in the cosmetics field.

The cosmetic compositions according to the present invention may take the form of a cream in which one or more compounds of formula (I) and one or more active agents capable of improving the vascularization of the skin as defined above are associated with the excipients commonly used. in cosmetology. The cosmetic compositions according to the present invention can take the form of gels in suitable excipients such as cellulose esters or other gelling agents, such as carbopol, sepinov (polyacrylate), guar gum, etc. The cosmetic compositions according to the present invention may also take the form of a lotion or a solution in which one or more compounds of Formula (I) and one or more active agents capable of improving the vascularization of the skin as defined above are in encapsulated form.

The microspheres according to the invention may for example consist of fatty substance, agar and water. One or more compounds of formula (I) and one or more active agents capable of improving the vascularization of the skin as defined above may be incorporated into liposomes, glycospheres, cyclodextrins, in chylomicrons, macro-, micro-type vectors. -, nano-particles as well as macro-, micro- and nanocapsules and also be absorbed on powdery organic polymers, talcs, bentonites and other mineral supports.

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

The cosmetic compositions according to the present invention may also contain additives or adjuvants that are customary in cosmetologies, such as, for example, antimicrobial agents or perfumes, but also extraction or synthetic lipids, gelling and viscosifying polymers, surfactants and emulsifiers, hydro- or liposoluble active ingredients, plant extracts, tissue extracts, marine extracts, synthetic actives. The cosmetic compositions according to the present invention may also comprise other complementary active ingredients chosen for their cosmetic action. When the compositions according to the present invention contain complementary active ingredients, they are generally present in the composition at a sufficiently high concentration so that they can exercise their cosmetic activity.

The cosmetic compositions according to the present invention are preferably used daily and applied one or more times per day. Finally, the present invention also relates to the use of a composition as defined above for a cosmetic slimming treatment.

The present invention is illustrated in a nonlimiting manner by the following examples. Example 1 Process for the Preparation of (L) -carnitine Esters According to the Invention a) Formation of Fatty Acids

In a 250 ml monocolon, 50 g of natural vegetable oil are mixed with 60 g of demineralised water, 0.3 g of EDTA-2H 2 O, 20 ml of 96 ° ethanol and 24 g of sodium hydroxide solution. 30 %.

The mixture is heated with stirring at 65-70 ° C. for approximately 3 hours, then the heating is stopped and 26.5 g of 10N hydrochloric acid (up to pH≤1) is rapidly added and the mixture is stirred for approximately 1 hour and cooled to 20 ° C.

The supernatant is extracted with 100 ml of hexane or heptane. The organic phase is then washed with water until the organic phase is neutral, and the solvent is distilled off under vacuum.

On average, 45 g of more or less liquid fatty acid are obtained at room temperature. b) General synthesis of acid chlorides of fatty acids

In a 250 ml monocol, dissolve 22 g of fatty acids obtained previously in about 100 ml of methylene chloride.

0.3 g are added to 0.6 g of Ν, Ν-dimethylformamide (catalyst) and 11 g of thionyl chloride are added dropwise.

After stirring for 1 hour at room temperature, the mixture is refluxed for 2 to 3 hours. It is cooled to 25 ° C. and the solvent and the excess of thionyl chloride are distilled at a reduced pressure of 20 mmHg at 40-50 ° C.

On average, 24 to 25 g of relatively fluid colored oil are obtained. c) Condensation with (L) -carnitine hydrochloride to obtain natural esters of (L) -carnitine hydrochloride.

In a monocolon of 0.5 liter, 11 g of (L) -carnitine hydrochloride obtained previously and 15 g of chloroacetic acid are charged.

It is heated with stirring at 65 to 70 ° C for 30 minutes until completely dissolved and then the acid chloride previously prepared is poured.

It is heated for 3 hours at 65 to 70 ° C. and then cooled to 60 ° C. and 0.150 l of acetone is poured. The mixture is stirred for 15 minutes and then cooled to 20 ° C. and the product is placed in the freezer at -20 ° C. for 24 hours.

The product (crude ester) precipitates and is filtered under vacuum.

Rinsed with 2 times 100 ml of acetone and then dried in air and then at 60 ° C and on average obtained 15 g of crude product which is recrystallized from 40 ml of isopropanol. After one night at 0 ° C., 100 ml of acetone are added. The mixture is stirred and the product is filtered under vacuum. After washing with 50 ml of acetone, it is dried at 60 ° C. About 10 g of compliant product is obtained.

The purity obtained by potentiometer with 0.1 N perchloric acid and with 0.1 N silver nitrate gives a titer of between 97% and 102%. Taking into account the average molecular mass of fatty acids.

Example 2 Esters of (L) -carnitine according to the invention

By the method described in Example 1, the following fatty acid mixtures were obtained.

Example 3 - Process for preparing natural esters of (L) -carnitine with in situ formation of (L) -carnitine hydrochloride with Rras acids of camellia oil oleifera.

In a tricolor of 500 ml, 25 g of (L) -carnitine and 150 ml of methylene chloride are charged. The mixture is stirred and bubbled at 5-15 ° C with hydrochloric acid gas until saturation is then allowed to raise the temperature to 20 ° and stirred for 1 hour. 76 g of trichloroacetic acid are added and the mixture is heated for 30 minutes at 30-35 ° C. and the solvent is then distilled off at 50 ° C. At the end of distillation, the vacuum is connected to remove all the solvent.

88 g of acid chlorides obtained from the fatty acids of the oil of camellia oleifera are then run according to the process described in Example 1 (b), and the mixture is kept at 65-70 ° C. 3 hours.

It is cooled to 50 ° C. and 250 ml of acetone is poured in and then stirred for 1 hour.

It is ice-free at -20 ° C. for 24 hours and then the precipitate formed is filtered off and rinsed with

50 ml of acetone. It is dried in air then at 60 ° C. and 32 g of a beige powder are obtained which is recrystallized from 140 ml of isopropanol.

After a few hours at 0 ° C., the product is drained, washed with 50 ml of acetone and then dried at 60 ° C. 28 g of a compliant product are obtained at all points by potentiometric assays (perchloric acid, sodium hydroxide and silver nitrate).

Example 4 - Activity of Cosmetic Compositions Comprising (L) -carnitine Esters and Caffeine

The activity of the cosmetic compositions of the invention was evaluated using a model of normal human adipocytes in suspension.

Human adipocytes were dissociated from the adipose tissue of an abdominoplasty performed in a 43-year-old woman, a 52-year-old woman, and a 58-year-old woman, then incubated with or without test assets.

The reference activator used in this study was caffeine 10 ^"4 and ^{10" 3} M. It came from Sigma Aldrich.

The adipocytes were incubated for 2 hours at 37 ° C., with shaking, in the absence (incubation medium alone) or in the presence of the reference products, or with increasing concentrations of the test products, associated or not with 10 ^-4. M caffeine (Sigma Aldrich) The concentration of all active ingredients tested is 1, 10 and 100 μg / ml.

All the active ingredients were solubilized directly in the cell incubation medium.

Each experimental condition was carried out in triplicate (n = 3). At the end of the incubation period, in the incubation medium using a sensitive and specific spectrophotometric technique, glycerol was quantified for some active ingredients or non-essential fatty acids (NEFA) were quantified for 'other assets. The results are given in the form of concentrations (in μg / ml) of glycerol or (μΜ) of AGNE present in the incubation medium of the adipocytes (average +/- standard deviation, SD). The statistical significance of the differences observed between the conditions "Control" and "reference product" was evaluated by a Student's test (Student t test; ***: p <0.001, *: p <0.05). The statistical significance of the observed differences between the "Vehicle" and "Test Assets" conditions was evaluated

produced by product, by one-way analysis of variance (One Way ANOVA) followed by Holm-Sidak test (*: p <0.05) when quantifying AGNE; - by a Student's test (Student t test; ***: p <0.001; **: p <0.01; *: p <0.05).

The results obtained are reported in Tables 1 to 9 below.

Table 1 - Incubation Medium and Caffeine

***: mean significantly different from control group "middle only" (p <0.001)

Table 2 - Incubation Medium and Caffeine

**: mean significantly different from control group "medium only" (p <0.01) ***: significantly different from control group "medium alone" (p <0.001) Table 3 - Mixture of Esters 16 (ug / ml)

*: mean significantly different from that of the control group "Control" (p <0.05) Table 4 - Mixture of esters 33 (μg / ml)

*: mean significantly different from control group control (p <0.05) Table 5 - Mixture of Esters 13 (ug / ml)

*: mean significantly different from that of the control group "Control" (p <0.05) Table 6 - Mixture of esters 4 (μg / ml)

*: mean significantly different from control group control (p <0.05) Table 7 - Ester Blend 41 (ug / ml)

*: mean significantly different from that of the control group "Control" (p <0.05) Table 8 - Mixture of esters 11 (μg / ml)

*: mean significantly different from that of the control group "Control" (p <0.05) **: mean significantly different from that of the control group "Control" (p <0.01) ***: average significantly different from that control group control (p <0.001) Table 9 - Ester Blend 34 (ug / ml)

*: mean significantly different from that of the control group "Control" (p <0.05) **: mean significantly different from that of the control group "Control" (p <0.01) ***: average significantly different from that control group control (p <0.001)

Conclusion

The experimental results obtained demonstrate the existence of a synergistic action between the (L) -carnitine esters of the invention and caffeine as part of their combined use as slimming agents.

Example 5 - Activity of Cosmetic Compositions Comprising (L) - Carnitine Esters, Caffeine and Esculin

The experimental protocol used is identical to that described in Example 4.

The results obtained are reported in Tables 10 to 12 below. Table 10 - Incubation Medium and Caffeine

significantly different from the "control only" control group (p <0.05): mean significantly different from the "control only" control group (p <0.01)

Table 11 - Micronized Esculin (uq / ml)

*: mean significantly different from control group control (p <0.05) Table 12 - Mixture 11 + esculin micronized (uq / ml)

*: mean significantly different from control group control (p <0.05)

Conclusion

The experimental results obtained demonstrate the existence of a synergy of action between the (L) -carnitine esters of the invention, caffeine and esculin as part of their combined use as slimming agents.

Claims

Cosmetic composition for topical application comprising:

at least two L-carnitine esters of general formula (I)

in which :

R is selected as C ₅ -C ₃ o -alkyl or C ₅ -C ₃ o -alkenyl; as well as their cosmetically acceptable salt;

and a methylxanthine chosen from caffeine, theophylline and theobromine.

2. Cosmetic composition according to Claim 1, characterized in that R is chosen as being a C ₆ -C ₂₈ -alkyl or C ₆ -C ₂ 8-alkenyl.

3. Cosmetic composition according to claim 2, characterized in that R is chosen to be a C ₇ -C ₂₆ -alkyl or C ₇ -C ₂₆ -alkenyl group.

4. Cosmetic composition according to claim 3, characterized in that R is chosen to be a C ₈ -C ₂₄ -alkyl or C ₈ -C ₂₄ -alkenyl group.

5. Cosmetic composition according to claim 4, characterized in that R is chosen from the following linear hydrocarbon chains Ci ₆ H ₃₂ , Ci ₈ H ₃₀ , Ci ₈ H ₃₂ ,

6. Cosmetic composition according to claim 1, characterized in that it comprises a mixture of four esters of (L) -carnitine of general formula (I) in which R is chosen from the following linear hydrocarbon chains: Ci ₆ H ₃₂ , Ci ₈ H _32, C ₈ H ₃₄ and C ₈ H _3. 6

7. Cosmetic composition according to claim 1, characterized in that it comprises a mixture of five esters of (L) -carnitine of general formula (I) in which R is chosen from the following linear hydrocarbon chains: Ci ₆ H ₃₂ , C18H30, C18H32, and C18H36 Ci8H3 _4.

8. Cosmetic composition according to any one of claims 1 to 7, characterized in that X ^" is a hydrochloride salt.

9. Cosmetic composition according to any one of claims 1 to 8, characterized in that the methylxanthine is caffeine.

10. Cosmetic composition according to any one of claims 1 to 9, characterized in that it also contains one or more active agents capable of improving the vascularization of the skin selected by esculin, aescin, ruscogenin , red vine, green tea and gotu kola.

11. Cosmetic composition according to claim 10, characterized in that the active agent capable of improving the vascularization of the skin is esculin.

12. Use of a composition according to any one of claims 1 to 11 for a cosmetic slimming treatment.